A facile preparation of tetralins from arene-1,4-diones using titanium(IV) chloride and triethylsilane

Article abstract of DOI:10.1016/j.tetlet.2011.10.054

A facile method for the synthesis of tetralins has been described which uses various substituted phenylpentane-1,4-diones as starting material with a combination of TiCl₄/Et₃SiH. The synthesis involves three reactions under mild conditions. A mechanism has been proposed for the reductive cyclization through ionic hydrogenation, and titanium(IV) chloride catalyzed cyclization.

Full text of DOI:10.1016/j.tetlet.2011.10.054

Tetrahedron Letters 52 (2011) 6827–6830
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Tetrahedron Letters
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A facile preparation of tetralins from arene-1,4-diones using titanium(IV)
chloride and triethylsilane
⇑
Gang Li, Qiong Xiao, Chun Li, Xiaojian Wang , Dali Yin
Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, State Key Laboratory of Bioactive
Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile method for the synthesis of tetralins has been described which uses various substituted phenyl-
pentane-1,4-diones as starting material with a combination of TiCl4/Et3SiH. The synthesis involves three
reactions under mild conditions. A mechanism has been proposed for the reductive cyclization through
ionic hydrogenation, and titanium(IV) chloride catalyzed cyclization.
Received 6 August 2011
Revised 9 October 2011
Accepted 11 October 2011
Available online 17 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetralin
Arene-1,4-dione
Intramolecular cyclization
Ionic hydrogenation
Tetralins are present as important structure motifs in many nat-
ural products and pharmaceuticals.1 Many methods have been
developed to construct the tetralin structure frameworks, such as
Darzens tetralin synthesis,2 hydrogenation of naphthalene,3 and
intramolecular Friedel–Crafts type cyclization.4 Recently the metal
catalyzed cyclization method regarded as intramolecular hydro-
arylation5 has been developed and widely used to generate the
annulated arene heterocycles and carbocycles. However, each of
these methods requires a suitable starting molecule that needs
several steps to reach. We herein report a facile method which
could convert substituted phenylpentane-1,4-diones directly to
tetralin derivatives.
(Scheme 1).6 It is anticipated that tetralins could be prepared with
a combination of suitable Lewis acid and triethylsilane directly
from the substituted phenylpentane-1,4-diones.
Then we screened various Lewis acids and Brønsted acids that
might promote the cyclization. The results indicated that only TiCl4
was found to be efficient to afford the desired compound B in good
yield (Table 1). Meanwhile the combination of SnCl4/Et3SiH could
reduce ketone but did not exert cyclization.
The scope of the method for tetralin synthesis was then inves-
tigated. To our delight, the substituted 1-phenylpentane-1,4-dione
substrates 1a–j smoothly underwent intramolecular reductive
cyclization and gave tetralins (2a–j) in good yields (Table 2). It
was noticed that the molecules with electron-donating groups,
such as phenoxyl and alkyl gave higher yields (entries 5–10), while
electron insufficient molecules with halogene substituents gave
We have serendipitously found that tetralin (B) was formed
when 1,4-dione (A) was treated with titanium chloride and trieth-
ylsilane instead of the attempted reduction product (C)
O
TiCl4/Et3SiH
TiCl4/Et3SiH
O
O
B
A
Scheme 1. Synthesis of tetralin in the presence of TiCl4 and Et3SiH.
C
⇑
Corresponding author. Tel./fax: +86 10 63165248.
E-mail address: wangxiaojian@imm.ac.cn (X. Wang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.054

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G. Li et al. / Tetrahedron Letters 52 (2011) 6827–6830
Table 1
Lewis or Brønsted acids for the reduction and cyclization of 1-phenylpentane-1,4-dione
O
O
Lewis or Bronsted acid
+
Et3SiH
OH
O
CH2Cl2 , rt
A
B
D
Entry
Catalyst
Reagent
Solvent
Temperature
Time (h)
Yieldc (%)
1a
2b
3a
4a
5a
6a
7a
TiCl4
TiCl4
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
6
10
6
6
6
B(86) D(0)
B(72) D(0)
No reaction
No reaction
No reaction
B(0) D(65)
No reaction
AlCl3
BF3
ZnCl2
SnCl4
CF3COOH
6
6
a
b
c
Using 3.8 equiv of the catalyst and 3.8 equiv of Et3SiH.
Using 2.1 equiv of TiCl4 and 3.1 equiv of Et3SiH.
Isolated yields.
Table 2
Reductive cyclization of selected substrates promoted by TiCl4 and Et3SiH
Entry
Substrate
Product
Time (h)
Yielda (%)
O
1
6
86
O
2a
1a
O
F
2
3
4
5
80
75
O
F
2b
1b
O
Cl
Br
O
Cl
Br
2c
2d
1c
O
4
5
6
2
72
87
O
1d
O
O
2e
1e
O
6
7
3
2
85
90
O
O
2f
1f
O
2g
1g

G. Li et al. / Tetrahedron Letters 52 (2011) 6827–6830
6829
Table 2 (continued)
Entry
Substrate
Product
Time (h)
Yielda (%)
O
O
8
9
2
93
O
O
2h
1h
O
O
O
O
2
92
2i
1i
O
O
O
10
3
6
88
80
O
O
O
2j
1j
O
OH
11
2k
1k
a
All the reactions were carried out in anhydrous dichloromethane at room temperature for 2–6 h, entries1–9 using TiCl4 (3.8 equiv), Et3SiH (3.8 equiv); entry 10 using TiCl4
(7.6 equiv), Et3SiH (7.6 equiv); entry 11 using TiCl4 (2 equiv), Et3SiH (2 equiv), Isolated yields.
TiCl4
triethylsilane. Another is the ketone reduced to alcohol first, then
cyclization takes place to form tetrahydronaphthalene. When
ketone E was treated first with TiCl4, then with triethylsilane, the
major product was 1-methylnaphthalene (F) whereas no tetralin
(B) formed. If triethylsilane was added first and followed by tita-
nium chloride, tetralin (B) was obtained. When alcohol G was trea-
ted with TiCl4, tetralin (B) was formed exclusively (Scheme 2). The
last question remained is which one of the two carbonyl is reduced
first. When a mixture of 1,4-dione (1g) and TiCl4 was treated with
1 equiv of Et3SiH, three products were isolated while phenylnaph-
thalene was not observed. The results indicated that the methyl
ketone is reduced prior to the benzyl ketone (Scheme 3).
O
OH
E
F
Et3SiH
Et3SiH
NaBH4
TiCl4
TiCl4
OH
With above observations, a mechanism of the reductive cycliza-
tion was proposed. The aliphatic carbonyl is converted to siloxane,
then benzyl carbonyl is reduced to methylene. Cyclization of silox-
ane generates the 1-methyl-tetrahydronaphthalene (Scheme 4).
In summary, we have described a mild and efficient method for
the synthesis of tetralins via ionic hydrogenation and cyclization in
the presence of TiCl4 and Et3SiH from the substituted phenylpen-
tane-1,4-dione substrates. This method involves three reactions
under mild conditions, ionic hydrogenation of remote ketone to
hydroxyl, deoxygenation of benzyl ketone, and cyclization cata-
lyzed by TiCl4. Although the method is not suitable to generate
five-membered arene carbocycles, it could potentially be useful
G
B
Scheme 2. Exploration of the mechanism.
lower yields (entries 2–4). However, when ketone 1k was used as
substrate, the reaction did not give five-membered ring but a re-
duced product (entry 11).
There are two possible pathways to realize the reductive cycli-
zation. One way is the ketone intermediate cyclized in the assis-
tance with a Lewis acid, then the tertiary alcohol is reduced by
O
O
2eq TiCl4
OH
+
+
OH
O
1eq Et3SiH
I
1g
H
Scheme 3. Reduction of arene-1,4-dione (1g) with 2 equiv TiCl4 and 1 equiv Et3SiH.

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G. Li et al. / Tetrahedron Letters 52 (2011) 6827–6830
Ti4+
Ti4+
O
O
O
2 Ti4+
Et3SiH
O
O
O
Et3Si
Ti4+
Ti4+
-H+
2 Et3SiH
O
H
SiHEt3
H
Ti4+
Scheme 4. Proposed mechanism for tetralin synthesis via reductive cyclization.
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the synthesis of tetralins.
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Acknowledgments
The authors are grateful to National Major Scientific and Tech-
nological Special Project (No. 2009ZX09301-003) and Taisho Phar-
maceuticals, Japan, for the financial support.
6. General procedure for the reductive cyclization of 1-phenylpentane-1,4-dione (1a):
To a magnetically stirred solution of 1-phenylpentane-1,4-dione (2.84 mmol) in
dry dichloromethane (10 mL) was added dropwise a solution of Et3SiH (1.73 mL,
10.8 mmol) at rt under an atmosphere of nitrogen. TiCl4 (1.20 mL, 10.8 mmol)
was then added with a syringe to the reaction mixture cooled with an ice bath.
The contents were stirred at rt for 6 h. The solution was poured slowly into ice
water and the aqueous phase was extracted with dichloromethane. The organic
layers were combined, washed with brine, dried over Na2SO4, and the solvent
was removed. Flash chromatography of the residue over silica gel using
petroleum ether as the eluent afforded the pure 1-methyl-tetralin (2a). The
product was identified by NMR and MS and the data are identical to the reported
values.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.054.
References and notes
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(b) Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. J. Med. Chem. 1984, 27, 1508;
(c) Wyrick, S. D.; Booth, R. G.; Myers, A. M.; Owens, C. E.; Kula, N. S.; Baldessarini,