Convenient method for the preparation of 1-phenylthio-3-alken-1-ynes and 4-hydroxy-1-phenylthio-1,2-alkadienes from a common precursor

Article abstract of DOI:10.1016/S0040-4039(02)01380-1

4-Hydroxy-1-phenylthio-2-alkynes (5) reacted with dihydropyran to afford the corresponding 4-tetrahydropyranyloxy derivatives which, on treatment with KHMDS, gave a mixture of (E)- and (Z)-1-phenylthio-3-alken-1-ynes, with the former predominant. When MeLi was used in the place of KHMDS, the (Z)-isomers were formed in preference to the (E)-isomers. Further treatment of the mixture with a base converted the (Z)-isomers into (E)-isomers. On the other hand, the reaction of 5 with KHMDS gave the corresponding 4-hydroxy-1-phenythio-1,2-alkadienes.

Full text of DOI:10.1016/S0040-4039(02)01380-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6387–6389
Convenient method for the preparation of
1-phenylthio-3-alken-1-ynes and
4-hydroxy-1-phenylthio-1,2-alkadienes from a common precursor
Atsushi Ogawa, Kazunari Sakagami, Akiko Shima, Hitoshi Suzuki, Satsuki Komiya,
Yoshinori Katano and Oyo Mitsunobu*
Department of Chemistry, College of Science and Engineering, Aoyama Gakuin University, Chitosedai, Setagayaku,
Tokyo 157-8572, Japan
Received 30 May 2002; revised 4 July 2002; accepted 5 July 2002
Abstract—4-Hydroxy-1-phenylthio-2-alkynes (5) reacted with dihydropyran to afford the corresponding 4-tetrahydropyranyloxy
derivatives which, on treatment with KHMDS, gave a mixture of (E)- and (Z)-1-phenylthio-3-alken-1-ynes, with the former
predominant. When MeLi was used in the place of KHMDS, the (Z)-isomers were formed in preference to the (E)-isomers.
Further treatment of the mixture with a base converted the (Z)-isomers into (E)-isomers. On the other hand, the reaction of 5
with KHMDS gave the corresponding 4-hydroxy-1-phenythio-1,2-alkadienes. © 2002 Elsevier Science Ltd. All rights reserved.
Enynes, enediynes, allenes, and cumulenes are important
classes of compounds in synthetic organic chemistry as
well as natural product chemistry.1–3 In this communica-
tion, we wish to report a convenient method for the
preparation of 1-phenylthio-3-alken-1-ynes and 4-
hydroxy-1-phenylthio-1,2-alkadienes from a common
precursor.
of paraformaldehyde to afford 1-phenylthio-4-phenyl-3-
buten-1-yne (2a) in 56% isolated yield as a 1:0.23
mixture of (E)- and (Z)-isomers instead of the expected
alkynyl alcohol 3 or allenyl alcohol 4 (Scheme 1).
When the reaction of 1a with KHMDS in THF at −78°C
was quenched without addition of paraformaldehyde, 2a
was obtained in 76% yield as a 1.0:0.06 mixture of
(E)-2a and (Z)-2a (Scheme 1, Table 1, entry 1).4 In
contrast, when MeLi was used as a base, (Z)-2a was
formed as a major product in a ratio of Z/E=1:0.32
(entry 2).5a,6
In the course of our study to prepare nucleic acid
modifying molecules, 4-phenyl-1-phenylthio-4-(2-tetra-
hydropyranyloxy)-2-butyne (1a) was reacted with n-
BuLi (1.1 equiv.) in THF at −78°C, followed by addition
Scheme 1.
Keywords: enynes; allenes; isomerisation; 1-phenylthio-4-hydroxy-2-alkyne.
* Corresponding author. Tel.: +81-3-5384-2869; e-mail: mitsu@chem.aoyama.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01380-1

6388
A. Ogawa et al. / Tetrahedron Letters 43 (2002) 6387–6389
Table 1. Conversion of 1 to 2
Entry
Substrate
Base
Product
Yield (%)
No.
R
No.
E:Z
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
Ph
KHMDS
MeLi
KHMDS
MeLi
KHMDS
MeLi
KHMDS
MeLi
KHMDS
MeLi
KHMDS
MeLi
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
76
45
64
77
69
12
67
21
91
43
64
10
1.0:0.06
1.0:3.13
1.0:1.26
1.0:3.03
1.0:0.82
1.0:1.85
1.0:0.54
1.0:2.38
1.0:0.56
1.0:3.85
1.0:0.83
1.0:0.73
CH3
PhCH2CH2
cyclo-C6H11
1-Naphthyl
9-Anthryl
9
10
11
12
1f
2f
In order to study the effect of the substituent at the
position 4, 1-phenylthio-4-(2-tetrahydropyranyloxy)-2-
pentyne (1b), 6-phenyl-1-phenylthio-4-(2-tetrahydro-
pyranyloxy)-2-hexyne (1c), 4-cyclohexyl-1-phenylthio-4-
(2-tetrahydropyranyloxy)-2-butyne (1d), 4-(1-naphthyl)-
1-phenylthio-4-(2-tetrahydropyranyloxy)-2-butyne (1e),
and 4-(9-anthryl)-1-phenylthio-4-(2-tetrahydropyranyl-
oxy)-2-butyne (1f) were respectively reacted with
KHMDS and with MeLi in THF at −78°C to afford
the corresponding (E)-2 and (Z)-2 as summarized in
Table 1.5a,6 As can be seen from Table 1, the stereo-
chemistry of the reaction depends on both the substrate
and the base used. Thus, KHMDS was more favorable
for the formation of the (E)-isomer (entries 1, 5, 7, 9,
11) except for the case of 1b (entry 3), while MeLi gave
the (Z)-isomer in preference to the (E)-isomer (entries
2, 4, 6, 8, 10) with the exception of 1f (entry 12).
Scheme 3.
reacted smoothly with KHMDS to give the correspond-
ing allenes 6a–c in 87, 71, and 58% yields, respectively,
instead of enynes 2 (Scheme 3).5b,6
In summary, a variety of 1-phenylthio-3-alken-1-ynes
and 4-hydroxy-1-phenylthio-1,2-alkadienes (allenes)
could be readily prepared from a common precursor,
4-hydroxy-1-phenylthio-2-alkyne.6 Although stereose-
lective formation of allenes has not yet been attempted,
the present reactions suggest a number of interesting
possibilities for further work.
When a mixture containing (Z)-2a and (E)-2a in a ratio
of 1.0:0.20 was treated with KHMDS (1.1 equiv.) in
THF at −78°C for 1 h, the ratio was changed to
(Z)-2a/(E)-2a=0.07:1.0 (92% yield). Similarly, when a
mixture consisting of (Z)-2a and (E)-2a in a ratio of
0.17:1.0 was treated with MeLi (1.1 equiv.) under the
same conditions, the ratio was converted to (Z)-2a/(E)-
2a=0.05:1.0 (42% yield) (Scheme 2).
Acknowledgements
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan, the Science Fund
of Japan Private School Promotion Foundation, and
Research Institute of Aoyama Gakuin University.
References
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Scheme 2.
It would be reasonable to assume that the presence of a
masked hydroxyl group at the position 4 of the sub-
strate 1 is essential for the formation of enynes 2. As
expected,
4-hydroxy-1-phenylthio-2-alkynes
5a–c

A. Ogawa et al. / Tetrahedron Letters 43 (2002) 6387–6389
6389
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tion of saturated aqueous ammonium chloride. For flask
A, the organic layer was separated and the aqueous layer
was extracted with ethyl acetate. The combined organic
layers were dried with MgSO4, filtered and concentrated.
The products were separated by column chromatography
(n-hexane–EtOAc=30:1) to afford a mixture of (E)- and
(Z)-4-phenyl-1-phenylthio-3-buten-1-yne [(E)-2a and (Z)-
2a] in 76% yield (0.0491 g) in a ratio of 1.0:0.06 (Table 1,
entry 1). By a similar procedure, the reaction in flask B
gave a mixture of (E)-2a and (Z)-2a in a yield of 45%
(0.0317 g) in a ratio of 1.00:3.13. HRMS of purified
mixture; Found: m/z 236.0614. Calcd for C16H12S:
236.0660. 1H NMR. For (Z)-2a l 5.89 (1H, d, J3,4=12
Hz, H-3), 6.64 (1H, d, J4,3=12 Hz, H-4), 7.22–7.50 (10H,
m, aromatic H). For (E)-2a l 6.39 (1H, d, J3,4=16 Hz,
H-3), 7.02 (1H, d, J4,3=16 Hz, H-4), 7.22–7.50 (10H, m,
aromatic H).
(b) Preparation of 4-hydroxy-4-phenyl-1-phenylthio-1,2-
butadiene (6a). To a solution of 4-phenyl-1-phenylthio-2-
butyn-4-ol (5a: 0.2035 g, 0.8 mmol)) in THF (8.0 mL) at
−78°C was added KHMDS (0.5 M solution in toluene, 3.2
mL, 1.6 mmol). After the mixture was stirred at this
temperature for 1 h, the reaction was quenched by the
addition of saturated aqueous NH4Cl. The organic layer
was separated and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
2. For a recent report for the preparation of allenes and
reviews of allenes, see for example: (a) Tius, M. A.; Pal, S.
K. Tetrahedron Lett. 2001, 42, 2605–2608 and references
cited therein; (b) Pasto, D. J. Tetrahedron 1984, 40, 2805–
2827; (c) Nagashima, S.; Kanematsu, T. Yuki Gosei
Kagaku Kyukai Shi 1993, 51, 608–619.
3. For reviews of enediyne antibiotics and related com-
pounds, see for example: (a) Nicolaou, K. C. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1387–1416; (b) Maier, M.
E. Synlett 1995, 13–26; (c) Grissom, J. M.; Gunawardena,
G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52,
6453–6518.
4. Van Boom et al. have demonstrated that the thioethers
RSꢀCH2ꢀCꢁCꢀCH2ꢀOR1 reacted with EtO− in liquid NH3
to afford RSꢀCꢁCꢀCHꢂCH2 by the isomerization of ini-
tially formed cumulene, RSꢀCHꢂCꢂCꢂCH2 (R=alkyl). As
a possible alternative route, they also proposed 1,4-elimi-
nation of EtOH from allene intermediate EtSꢀCHꢂCꢂ
CHꢀCH2OEt. See: (a) Van Boom, J. H.; Brandsma, L;
Arens, J. F. Rec. Trav. Chim. 1966, 85, 580–600. See also:
(b) Montione, R.; Alves, A.; Montijin, P. P.; Wildschut,
G. A.; Bos, H. J. T.; Brandsma, L. Rec. Trav. Chim. 1970,
89, 97–109.
5. (a) Reaction of 1-phenylthio-4-(tetrahydro-2H-pyran-2-
yloxy)-2-butyn (1a) with KHMDS and with MeLi. The
reaction was carried out in parallel manner. 4-Phenyl-1-
phenylthio-4-(tetrahydropyranyloxy)-2-butyn (1a: 0.0931
g, 0.312 mmol and 0.1004 g, 0.308 mmol) was placed in
two-necked flask A and in flask B. The flasks were sealed
with a rubber septum. After flushing with Ar, 2.8 mL or
3.0 mL of THF was injected through the septum into the
flasks, which were then cooled to −78°C. KHMDS (0.5 M
toluene solution; 0.61 mL, 0.3 mmol) was injected into the
flask A and MeLi (1.14 M diethyl ether solution, 0.29 mL,
0.33 mmol) was injected into the flask B. After stirring at
−78°C for 1 h, the reactions were quenched by the addi-
(n-hexane–ethyl acetate=7:1) to afford 6a as
a
diastereomer mixture (syrup, 0.1771 g, 87%) in a ratio of
ca. 1:1 as determined by NMR. HRMS of the
diastereomer mixture; Found: m/z 254.0681. Calcd for
1
C16H14OS: 254.0766. H NMR (500 MHz; CDCl3; TMS=
0.00 ppm). For diastereomer A: l 5.25 (1H, dd, J1,4=2.29,
J3,4=5.96 Hz, H-4), 5.67 (1H, dd, J1,3=J3,4=5.96 Hz,
H-3), 6.16 (1H, dd, 1,3=5.96, 1,4=2.29 Hz). For
J
J
diastereomer B: l 5.22 (1H, dd, J1,4=2.29, J3,4=5.96 Hz,
H-4), 5.64 (1H, dd, J1,3=J3,4=5.96 Hz, H-3), 6.15 (1H,
dd, J1,3=5.96, J1,4=2.29 Hz). IR: w 1970 cm−1
.
6. 4-Hydroxy-1-phenylthio-2-alkynes 5 could be readily pre-
pared by treatment of 1-phenylthio-2-propyne with
EtMgBr, followed by reaction with an aldehyde. The
reaction of alcohol 5 with dihydropyran gave 1.