E/Z Isomerization of 3,3-disubstituted allylic thioethers

Article abstract of DOI:10.1016/j.tetlet.2007.07.164

Allylic thioethers of the general structure 1 underwent E/Z isomerization during both basic and acidic hydrolysis of the ester moiety at the remote end of the molecule. The isomerization was dependent on the substitution of the allylic moiety. The presenc

Full text of DOI:10.1016/j.tetlet.2007.07.164

Tetrahedron Letters 48 (2007) 6970–6973
E/Z Isomerization of 3,3-disubstituted allylic thioethers
Miroslav Havranek,a,* Per Sauerberg,b Pavel Kratinaa and Pavel Piheraa
a
´
RE&D VUFB, s.r.o., Podeˇbradska´ 56/186, 180 66 Praha 9, Czech Republic
b
˚
Novo Nordisk A/S, Novo Nordisk Park, DK-2670 Maløv, Denmark
Received 18 May 2007; revised 18 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Allylic thioethers of the general structure 1 underwent E/Z isomerization during both basic and acidic hydrolysis of the
ester moiety at the remote end of the molecule. The isomerization was dependent on the substitution of the allylic moiety. The pres-
ence of a 5-membered heterocycle on the double bond supported the isomerization. However, analogous oxy-ethers were stable.
ꢀ 2007 Elsevier Ltd. All rights reserved.
During our research on the biological activities of
various allylic thioethers (2)1,2 we noticed unprecedented
E/Z isomerization of the double bond during hydrolysis
of the remote ester group (Scheme 1).
enrichment of one isomer of 1h. However, hydrolysis9
of the remote ester moiety led to isomerization once
again. The quantity of unwanted E isomer was increased
after attempted crystallization from a toluene/cyclohex-
ane mixture. On the other hand, only one isomer was de-
tected after heating a solution of 2h in toluene at reflux
for 5 h. The ratio of isomers was determined by 1H
NMR spectroscopy by monitoring the vinylic hydrogen
(Scheme 2).
The isomerization was first noticed during the synthesis
of compound 2h, which was prepared in order to con-
duct our biological study. The synthesis started from
ketone 3,3 which was converted into alkene 4 by a
Horner–Emmons reaction4 (Scheme 2).
A cross-
coupling reaction5 with thienyl stannane6 afforded com-
pound 5. The predominantly formed Z isomer of 5 was
obtained by crystallization of the mixture and the con-
figuration was determined by NMR spectroscopy
This phenomenon was studied further. Esters 1 and 11
were prepared from iodides 10 using a cross-coupling
reaction5 (Scheme 3). 3-Iodoallylic alcohols 9 were pre-
pared stereoselectively by hydroalumination10 of the
corresponding propargylic alcohols.11 Conversion into
an allylic bromide or chloride followed by alkylation
or direct Mitsunobu reaction of the alcohols to the
corresponding thioether or ether8 was not accompanied
by isomerization of the esters 10. Similarly, a one-pot
hydroalumination–cross-coupling procedure12 was used
for the stereoselective syntheses of the allylic alcohols 14
and 15 (Scheme 4), which were the precursors for the
syntheses of the E and the Z isomers of the ether analogs
of compound 2h, respectively.
1
(NOE, 13C, H NMR). DIBAL-H reduction7 led to
the isomerically pure allylic alcohol 6. The conversion
of 6 to the corresponding bromide and then to the thio-
ether8 was, however, accompanied by E/Z isomeriza-
tion. Crystallization of this mixture led to the
R1
R2
R1
R2
S
1. LiOH
2. H+
S
All the esters were hydrolyzed;9 the isomerization was
strongly influenced by the character of the double bond
substituents and the type of heteroatom at the allylic
position (O vs S). Some of the thioethers were stable
(Table 1) and did not undergo isomerization, while
others were isomerized. Phenyl analogs were stable,
whereas furyl (2a vs 2b) and thienyl analogs were isom-
erized (2c,e vs 2d,f). Heating solutions of the E/Z mix-
tures of these compounds did not lead to one isomer
O
O
2
1
COOH
COOEt
Scheme 1. Isomerization of allylic thioethers accompanying hydrolysis
of the ester group.
Keywords: Allylic thioether; Allyl sulfide; E/Z Isomerization.
Corresponding author. Tel.: +420 266 107 827; fax: +420 266 107
*
852; e-mail: havranek@readvufb.cz
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.164

M. Havranek et al. / Tetrahedron Letters 48 (2007) 6970–6973
6971
EtO OEt
Br
F
F
COOEt
Br
F
P
SnBu3
F
S
S
S
DIBAL-H
O
Pd2dba3, t-Bu3P
dioxane 70 °C
62%
NaH, THF
reflux, 62%
THF, -30 to -5 °C, 67%
O
5
EtOOC
COOEt
crystallization
(cyclohexane)
40%
E/Z mixture
pure Z isomer
3
4
6
OH
S
F
F
S
heating
COOH
F
1. LiOH
S
1. CBr4, Ph3P, CH2Cl2, r.t.
2.
THF, MeOH, H2O
2. H2O, H+, 29%
H
H
HS
S
S
DIEA
CH2Cl2, r.t.
S
O
COOEt
7a 25%
1h
2h
COOH
O
O
O
COOEt
Scheme 2. Synthesis of compound 2h and monitoring of the E/Z isomerization by 1H NMR (CDCl3, 300 MHz) spectroscopy. Vinyl hydrogen
resonances are only shown.
1. LiAlH4
THF, 0 ˚C
1.CBr4,PPh3,
CH2Cl2, 0 ˚C
nol–water). When the ethyl ester was replaced with a
t-butyl ester and the cleavage performed under acidic
conditions (dilute TsOH) isomerization also occurred
(Scheme 5).
R1
I
R1
OH
OH
2. AcOEt
3.I2
2. 7a, DIEA, CH2Cl2
8
9
HO
or
Cs2CO3
MeCN, r.t.
7b
We have not found any precedents for this phenomenon
in the literature and the reason for its occurence is un-
clear. We assume that electronic effects of the carboxylic
group could be transferred via the phenol system to the
sulfur atom where the large d-orbitals can overlap with
the double bond system. Such electronic influences
together with electron-rich (5-memebered heterocyclic)
substituents on the double bond may lead to
isomerization.
O
COOMe
R2 B(OH)2
or
R1
R2
R1
R2 Sn(Bu)3
X
I
X
or alkyne
Pd-cat.
O
O
COOR
COOR
1 X=S, R=Et
11 X=O, R=Me
10
X=O,S
R=Me, Et
Scheme 3. Stereoselective syntheses of compounds 1 and their oxy-
analogs 11 (for R1 and R2 see Table 1).
We previously reported1 that slight changes in the sub-
stitution pattern of allylic systems with an alkyne at-
tached to the double bond (R2 = alkyne) led in some
cases to instability of such compounds.
as in the case of compound 2h. Oxy-ethers 18f–i were
however stable. The latter two compounds differed only
in the configuration of the double bond, which shows
that there was no E/Z isomerization equilibrium.
In summary, the E/Z isomerization of the allylic
thioethers occurred during hydrolysis of esters 1 and
depended strongly on the substituents. Oxygen analogs
were stable underscoring the role of the sulfur
atom.
The isomerization was not a consequence of the basic
conditions during the hydrolysis (LiOH in THF–metha-
I
1. LiAlH4
THF, 0 °C
F
I
I
F
F
X
F
S
Pd2dba3, (2-furyl)3P
ZnCl2, 65 °C
OH
2. AcOEt
Ar
14
7b
12
13
SnBu3
S
43%
F
OH
OH
+ Al O
DIAD,PPh3
toluene-THF3:1
Li
Pd2dba3, tBu3P
DMF, 50 °C
O
I
O
Br
OEt
EtO
r.t., ~65%
F
O
~85%
O
Br
COOMe
COOMe
OH
16 X=I, Z-isomer
17 X=Br, E-isomer
15
11i E-isomer
11h Z-isomer
36%
Scheme 4. Stereoselective syntheses of oxy-analogs of 1 via one-pot hydroalumination and cross-coupling reactions.

6972
M. Havranek et al. / Tetrahedron Letters 48 (2007) 6970–6973
Table 1. Stability of compounds 2 and their oxy-analogs (18) prepared by ester hydrolysis
R1
R2
COOH
X
O
Acida R1
R2
X
S
E/Z Method of preparationb Yield of hydrolysis, stability (ratio of isomers)
2a
E
A
63%, stable
Cl
N
N
O
2b
2c
2d
S
Z
E
Z
E
Z
Z
Z
Z
Z
Z
E
B
72%, isomerizes (1:1)
36%, stable
S
C
S
B
60%, isomerizes (1:1)
65%, stable
S
2e
S
A
Br
2f
S
B
69%, isomerizes (2:1)
76%, stable
Br
S
S
18f
2g
O
S
B
Br
O
B
57%, isomerizes (1:1)
90%, stable
F3C
F3C
O
18g
2h
O
S
B
Scheme 2
Scheme 4
Scheme 4
29%, isomerizes (3:2)
73%, stable
F
F
S
18h
18i
O
O
S
50%, stable
F
S
a E/Z Purity of esters 1, 11 > 95% (by NMR spectroscopy), except for compound 1h, see Scheme 2.
b Esters were prepared according to Schemes 2–4; transformation of iodide 10 was accomplished using the following methods: (A) arylboronic acid,
Pd2dba3 (1.5 mol %), t-Bu3P (3 mol %), Cs2CO3 (2 equiv), dioxane, 70–80 ꢁC, 70–80%; (B) tributylaryltin, Pd2dba3 (1.5 mol %), t-Bu3P (3 mol %),
DMF, 50–80 ꢁC, 50–77%; (C) byproduct of the synthesis 1e, 23%.
S
SH
S
Boc2O
DMAP
Ph3P
HCl
Acknowledgements
tBuOH
DMF 2:1
40 °C, 47%
dioxane
H2O 4:1
40 °C
O
The technical assistance of P. Kovarova, M. Jelinkova
and V. Balsanek is greatly appreciated.
O
O
COOtBu
2
COOH
2
COOtBu
CF3
CF3
References and notes
1. Havranek, M.; Sauerberg, P.; Mogensen, J. P.; Kratina,
P.; Jeppesen, C. B.; Pettersson, I.; Pihera, P. Bioorg. Med.
Chem. Lett. 2007, 17, 4144–4149.
2. Sauerberg, P.; Olsen, G. S.; Jeppesen, L.; Mogensen, J. P.;
Pettersson, I.; Jeppesen, C. B.; Daugaard, J. R.; Galsg-
aard, E. D.; Ynddal, L.; Fleckner, J.; Panajotova, V.;
Polivka, Z.; Pihera, P.; Havranek, M.; Wulff, E. M. J.
Med. Chem. 2007, 50, 1495–1503.
I
TsOH
S
S
SnBu3
S
acid
69%
isomer ratio
~ 2:1
S
Toluene
50 °C
Pd2dba3, t-Bu3P
DMF, 50 °C, 84%
O
O
COOtBu
COOtBu
Scheme 5. Synthesis of t-Bu protected thioethers.13

M. Havranek et al. / Tetrahedron Letters 48 (2007) 6970–6973
6973
3. Vejdelek, Z.; Metys, J.; Holubek, J.; Svatek, E.; Protiva,
M. Collect. Czech. Chem. Commun. 1984, 49, 2649–2660.
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reaction Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
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Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729–1731.
6. Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi,
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Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.;
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8. Alkylation of thiophenol 7a or phenol 7b with allyl
chloride, bromide or allyl alcohol using the Mitsunobu
reaction is described in Ref. 1. Synthesis of 7a: Martin, M.
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9. General procedure for ester hydrolysis: Ester (1, 11,
ꢀ0.3 mmol) was dissolved in a mixture of THF (3 mL)
and MeOH (1 mL) and an aqueous solution of lithium
hydroxide monohydrate (22 mg, 0.5 mmol, 1 mL) was
added. The mixture was stirred for 2 h at 0 ꢁC and then
diluted with a saturated aqueous solution of ammonium
chloride (20 mL). The resulting mixture was extracted with
ethyl acetate (3 · 15 mL); the organic layers were com-
bined and dried with sodium sulfate. The product was
purified by column chromatography.
10. Hydroalumination was performed according to procedure
described in Ref. 1, see also: Corey, E. J.; Katzenellenb-
ogen, J. A.; Posner, G. H. J. Am. Chem. Soc. 1967, 89,
4245–4247.
11. (a) Jeppesen, L.; Olesen, P. H.; Hansen, L.; Sheardown,
M. J.; Thomsen, C.; Rasmussen, T.; Jensen, A. F.;
Christensen, M. S.; Rimvall, K.; Ward, J. S.; Whitesitt,
C.; Calligaro, D. O.; Bymaster, F. P.; Delapp, N. W.;
Felder, C. C.; Shannon, H. E.; Sauerberg, P. J. Med.
Chem. 1999, 42, 1999–2006; (b) Tretyakov, E.; Tkachev,
A. V.; Rybalova, T. V.; Gatilov, Y. V.; Knight, D. V.;
Vasilevsky, S. F. Tetrahedron 2000, 56, 10075–10080.
12. Havranek, M.; Dvorak, D. J. Org. Chem. 2002, 67, 2125–
2130, tri-2-furylphosphine was used as a ligand for Pd
catalysis.
13. Starting disulfide was obtained by hydrolysis of its diethyl
ester, which was formed by standing a solution of 7a8 in
THF. t-Bu ester formation: Takeda, K.; Akiyama, A.;
Nakamura, H.; Takizawa, S.-i.; Mizuno, Y.; Takayanagi,
H.; Harigaya, Y. Synthesis 1994, 1063–1066; reduction of
disulfide: Overman, L. E.; Smoot, J.; Overman, J.
Synthesis 1974, 59–60, The thiol was alkylated with allyl
bromide in dichloromethane in the presence of DIEA
under an inert atmosphere.