Titanocene(II)-promoted intramolecular olefination of thiol esters: A new route to substituted 2,3-dihydrothiophenes

Article abstract of DOI:10.1055/s-1999-2777

The treatment of S-[3,3-bis(phenylthio)propyl] thioalkanoates with the low-valent titanium species Cp₂Ti[P(OEt)₃]₂ in THF produced 5-substituted 2,3-dihydrothiophenes in good yields. These thiophene derivatives were found to be susceptible to photoirradiation and easily isomerized into 2-alkylidenetetrahydrothiophenes.

Full text of DOI:10.1055/s-1999-2777

LETTER
1029
Titanocene(II)-Promoted Intramolecular Olefination of Thiol Esters: A New
Route to Substituted 2,3-Dihydrothiophenes
Md. Abdur Rahim, Tooru Fujiwara, Takeshi Takeda*
Department of Applied Chemistry, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Fax +81 42 388 7034; E-Mail: takeda-t@cc.tuat.ac.jp
Received 23 March 1999
The starting thiol esters possessing a diphenyl thioacetal
Abstract: The treatment of S-[3,3-bis(phenylthio)propyl] thioal-
moiety 2 were easily prepared by the reaction of the
kanoates with the low-valent titanium species Cp2Ti[P(OEt)3]2 in
corresponding acyl chlorides with 3,3-bis(phenylthio)
propanethiol 4 or 4,4-bis(phenylthio)-2-butanethiol 5 (1.1
THF produced 5-substituted 2,3-dihydrothiophenes in good yields.
These thiophene derivatives were found to be susceptible to pho-
toirradiation and easily isomerized into 2-alkylidenetetrahy- equiv/triethylamine; 1.1 equiv/THF/0 °C-room tem-
drothiophenes.
perature/15-30 min) (2a; quant, 2b; 92%, 2c; 82%, 2d;
85%, 2e; 88%, 2f; 82%, 2g; 87%, 2h; 78%). The thiol 4
was prepared from commercially available 3,3-
Key words: 2,3-dihydrothiophene, thioacetal, thiol ester, cycliza-
tion, intramolecular carbonyl olefination
dimethoxypropionic acid methyl ester (6) (Scheme 2).
The ester 6 was treated with thiophenol (2 equiv) in the
presence of BF3◊OEt2 (2 equiv) in CHCl3 (0 °C-room
temperature/1 h) to produce the thioacetal which was then
reduced with lithium aluminum hydride (0.5 equiv/THF/
0 °C/1 h) to give the alcohol 7. The transformation of 7 to
the tosylate (TsCl; 1.1 equiv/pyridine/0 °C/overnight) fol-
lowed by the reaction with thiourea (1.5 equiv/methanol/
reflux/3 h) and the hydrolysis of the resulting S-thiouroni-
um salt (10% NH4OH/reflux/1.5 h) gave the thiol 4. The
secondary thiol 5 was prepared according to the method
reported by Fochi et al.6 using the tosylate prepared from
the alcohol 8 (TsCl; 1.1 equiv/pyridine/0 °C-room tem-
perature/overnight). The alcohol 8 was obtained by the
reaction of bis(phenylthio)methyllithium with propylene
oxide (1 equiv/THF/0 °C/15 min) (Scheme 3).
2,3-Dihydrothiophene is one of the most fundamental sul-
fur-containing heterocycles and is employed for protec-
tion of hydroxy group,1 the synthesis of certain 2,3-
dispirocyclohexanones containing tetrahydrothiophene
rings,2 and the preparation of 4-thio-1,2-dideoxy-ribose.3
The chemistry of this reactive compound and its deriva-
tives is, however, relatively unexplored. This is apparent-
ly due to the lack of appropriate method for their
preparation, and the instability of the compounds. As for
the preparation of unsubstituted 2,3-dihydrothiophene,
several methods including the thermal decomposition of
2-acyloxytetrahydrothiophene have been developed.1,4
Although Paquette et al. reported the preparation of 5-sub-
stituted derivatives by the reaction of 5-lithio-2,3-dihy-
drothiophene with aldehydes,2 the yields of adducts were
only moderate. The improved procedure using 5-tributyl-
stannyl-2,3-dihydrothiophene was reported by O’Neil and
co-workers.3 However the preparation of the requisite
starting material is rather complicated.
1) PhSH / BF3 •OEt2
2) LiAlH4
MeO
MeO
O
PhS
PhS
OMe
OH
6
7: 80%
1) TsCl / PyH
Recently we developed a new method for the carbonyl
olefination using a thioacetal-Cp2Ti[P(OEt)3]2 system.
We tentatively assume that the key intermediate of this
transformation is a titanium-carbene complex.5 Then we
have investigated the preparation of 5-substituted 2,3-di-
hydrothiophenes 1 by the intramolecular carbonyl olefi-
nation of thiol esters 2 outlined in Scheme 1.
PhS
2) (H2N)2CS
3) NH4OH
PhS
SH
4: 79%
Scheme 2
1) BuLi
2 Cp2Ti[P(OEt)3]2
PhS
PhS
R1
O
PhS
CH3
OH
3
R3
PhS
SPh
O
2)
S
PhS
CH3
- Cp2Ti(SPh)2
R2
8: 85%
2
1) TsCl / PyH
S
PhS
PhS
CH3
R1
O
R3
OBut
+
R3
2)
SH
K
R1
S
- Cp2Ti=O
S
S
Cp2Ti
5: 48%
R2
3) 70-80 °C
R2
1
Scheme 3
Scheme 1
Synlett 1999, No. 07, 1029–1032 ISSN 0936-5214 © Thieme Stuttgart · New York

1030
Md. A. Rahim et al.
LETTER
The treatment of 2a with 4 equiv of the low-valent titani- bonyl suppressed the formation of 10. The reactions of
um Cp2Ti[P(OEt)3]2 3 in THF at room temperature for 3 h other thiol esters 2b and e were performed, and it was ob-
produced the 2,3-dihydrothiophene 1a and its isomer 2- served that not only 5-substituted 2,3-dihydrothiophene 1
alkylidenetetrahydrothiophene 9a in a total 56% yield but also isomeric tetrahydrothiophene 9 were produced
along with 3-(phenylthio)propanethiol (10) (23%) (Table (entries 3 and 7). After several attempts, we found that the
1, entry 1). The latter compound 10 would be formed by dihydrothiophene 1 was easily isomerized to 9 when be-
the reductive cleavage of carbon-sulfur bond of the thiol ing exposed to sunlight. Then the reactions of 2 with the
ester and the partial desulfurization of thioacetal moiety low-valent titanium 3 and work-up were performed in the
through the action of 3. On the other hand, it was found dark, and the initial products 1 were isolated with 94-
that substitution of an alkyl group at the carbon a to car- >99% selectivity.7
Table 1 Preparation of 2,3-dihydrothiophenes 1a
Entry
Thiol esters
(Yield / %: Ratio of isomers 1 : 9b)
Products
+
2
PhS
PhS
O
S
1c
2
(56, 85 : 15)
(57; 95 : 5)
C6H13
C6H13
C6H13
S
S
2a
9a
1a
+
+
2a
9a
1a
PhS
PhS
O
S
3c
4
(56; 51 : 49)
(58; 94 : 6)
Ph
Ph
Ph
S
S
9b
2b
1b
+
1b
9b
2b
PhS
PhS
O
S
C4H9
C4H9
C2H5
(68; >99 : <1)
(61; >99 : <1)
5
6
S
C2H5
2c
2d
1c
1d
PhS
PhS
O
Ph
Ph
S
S
CH3
CH3
PhS
PhS
O
7c
S
+
(70; 58 : 42)
S
S
1e
2e
9e
+
(72; 97 : 3)
8
9
2e
1e
9e
PhS
PhS
O
Ph
Ph
S
(55; >99 : <1)
S
Ph
Ph
1f
2f
PhS
PhS
CH3
S
O
O
1g
10
11
H3C
H3C
(62; >99 : <1)
(65; >99 : <1)
S
S
2g
C6H13
C6H13
PhS
PhS
CH3
S
2h
1h
aAll reactions were performed following the procedure described in ref. 7. After the preparation of 3, all operations were
performed in the dark. bDetermined by NMR spectroscopy. cThe reaction and work-up were performed without special
care not to expose the product 1 to sunlight or fluorescent light.
Synlett 1999, No. 07, 1029–1032 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route to Substituted 2,3-Dihydrothiophenes
1031
It is known that 2,3-dihydrothiophene is thermally unsta- Further study on the synthesis of heterocyclic compounds
ble and easily polymerizes in the presence of a trace using various carboxylic acid derivatives is now in
amount of acid.4b,1 However, to the best of our knowledge, progress.
the photochemical behavior of 2,3-dihydrothiophene and
its derivatives has not yet reported. Then we examined the
isomerization of 5-substituted 2,3-dihydrothiophene 1 to
Acknowledgement
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Area No. 10125209 from the Ministry of Education, Sci-
ence, Sports, and Culture, Japan.
2-alkylidenetetrahydrothiophene 9 by the photoirradia-
tion with a high pressure mercury lamp (Scheme 4). Con-
trary to our expectation, the slow isomerization to 1 was
observed when a hexane-ether (9:1) solution of 1 in a Pyr-
ex test tube was irradiated with a 400W high pressure
mercury lamp under argon (see Table 2, entries 1 and 3).
It was found, however, that the isomerization was acceler-
ated when the irradiation was carried out under air (see en-
tries 2 and 4). The composition of 1 and 9 after irradiation
was found to depend on the substituent at 5-position. The
photoisomerization of 2,3-dihydrothiophene 1 possessing
a primary alkyl substituent afforded a mixture of the exo-
and endo-cyclic olefins with a ratio of 1:1 to 1:3. On the
other hand, the exocyclic isomer 9 predominantly formed
when 1 having a secondary alkyl substituent was irradiat-
ed (Table 2). Since essentially the same ratio of isomers
1e and 9e was obtained by the use of longer irradiation
time (see entries 6 and 7), the observed ratio would be the
composition of equilibrium for these compounds.
References and Notes
(1) Cohen, L. A.; Steele, J. A. J. Org. Chem. 1966, 31, 2333.
(2) Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmondson, S.
D.; Rogers, R. D. J. Am. Chem. Soc. 1994, 116, 506.
(3) O’Neil, I. A.; Hamilton, K. M.; Miller, J. A. Synlett 1995,
1053.
(4) (a) Birch, S. F.; McAllan, D. T. J. Chem. Soc. 1951, 2556.
(b) Sosnovsky, G. Tetrahedron 1962, 18, 903. (c) Gianturco,
M. A.; Friedel, M. A.; Flanagan, V. Tetrahedron Lett. 1965,
23, 1847. (d) Johnson, P. Y.; Koza, E.; Kohrman, R. E. J. Org.
Chem. 1973, 38, 2967. (e) Sauer, N. N.; Angelici, R. J.;
Huang, Y. C. J.; Trahanovsky, W. S. J. Org. Chem. 1986, 51,
113. (f) Delaney, P. A.; Johnstone, R. A. W. J. Chem. Soc.
Perkin Trans. 1 1986, 1861.
(5) (a) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J.
Am. Chem. Soc. 1997, 119, 1127. (b) Takeda, T.; Watanabe,
M.; Nozaki, N.; Fujiwara, T. Chem. Lett. 1998, 115.
(c) Rahim, M. A.; Taguchi, H.; Watanabe, M.; Fujiwara, T.;
Takeda, T. Tetrahedron Lett. 1998, 39, 2153. (d) Takeda, T.;
Watanabe, M.; Rahim, M. A.; Fujiwara, T. Tetrahedron Lett.
1998, 39, 3753. (e) Fujiwara, T.; Iwasaki, N.; Takeda, T.
Chem. Lett. 1998, 741.
R3
hν
R3
R1
R1
S
S
R2
R2
1
9
(6) Degani, I.; Fochi, R.; Santi, M. Synthesis 1977, 873.
(7) The following is a typical experimental procedure. After the
preparation of low-valent titanium 3, all operations were
performed in the dark. Magnesium turnings (49 mg, 2 mmol;
purchased from Nakarai Tesque Inc. Kyoto, Japan), finely
powdered molecular sieves 4 Å (200 mg), and Cp2TiCl2 (498
mg, 2 mmol) were placed in a flask and dried by heating with
a heat gun under reduced pressure (2-3 mmHg). Care was
taken not to sublimate Cp2TiCl2. After cooling, THF (6 ml)
and P(OEt)3 (0.69 ml, 4 mmol) were added successively with
stirring at room temperature under argon. After 3 h, 2c (209
mg, 0.5 mmol) in THF (10 ml) was added slowly to the
reaction mixture over 20 min. After being stirred for 3 h, the
reaction was quenched with 1M NaOH (15 ml) and the
resulting insoluble materials were filtered off through Celite.
The organic materials were extracted with ether, and the
extract was dried over Na2SO4. After removal of solvent, the
Scheme 4
In summary, we have shown that the intramolecular carb-
onyl olefination of thiol esters 2 can lead to 2,3-dihy-
drothiophenes 1. These endocyclic olefins easily
isomerized into the exocyclic olefins by photoirradiation.
Since the starting thiol esters are easily prepared from
carboxylic acids, these sequential reactions provide useful
methods for the synthesis of thiophene derivatives.
It should be noted that the present reaction is the first prac-
tical intramolecular carbonyl olefination of carboxylic
acid derivatives which affords heterocyclic compound.8
Table 2 Isomerization of 2,3-dihydrothiophenes 1 by photoirradation
Synlett 1999, No. 07, 1029–1032 ISSN 0936-5214 © Thieme Stuttgart · New York

1032
Md. A. Rahim et al.
LETTER
residue was purified by using PTLC (hexane) to give 1c (63
mg, 68%).
(8) Although Mortimore and Kocienski reported the preparation
of 6-phenyl-3,4-dihydro-2H-pyran by intramolecular
sequence using benzyl 2-benzyl-5-hexenoate and the tungsten
alkylidene, though the details of the reaction including the
yield of the product were not described.d (a) Mortimore, M;
Kocienski, P. Tetrahedron Lett. 1988, 29, 3357. (b) Stille, J.
R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 855. (c) Stille,
J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem. 1990,
843. (d) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
3800.
olefination of 4,4-dibromobutyl benzoate, the yield was only
15%.a Concerning the preparation of carbocycles, the
synthesis of cyclobutenes by the intramolecular carbonyl
olefination of carboxylic esters with the titanium alkylidenes
formed by the olefin metathesis process using highly strained
olefins was reported by Grubbs and his co-workers.b,c They
also reported that 3-benzyl-2-benzyloxy-1-cyclopentene was
produced by the similar olefin metathesis-carbonyl olefination
Article Identifier:
1437-2096,E;1999,0,07,1029,1032,ftx,en;Y05899ST.pdf
Synlett 1999, No. 07, 1029–1032 ISSN 0936-5214 © Thieme Stuttgart · New York