Stereoselective synthesis of (Z)-enethiols and their derivatives: Vinylic SN2 reaction of (E)-alkenyl(phenyl)-λ3-iodanes with thioamides

Article abstract of DOI:10.1021/ol016356c

(Equation presented) Exposure of (E)-β-alkylvinyl(phenyl)-λ³-iodanes to thioamides in dichloromethane at room temperature was found to result in a bimolecular nucleophilic substitution (S_N2) at the vinylic carbon atom to give inverted (Z)-enethiols and/or (Z)-S-vinylthioimidonium salts. Vinylic S_N2 reactions with thioureas are also discussed.

Full text of DOI:10.1021/ol016356c

ORGANIC
LETTERS
2
001
Vol. 3, No. 17
753-2756
Stereoselective Synthesis of
Z)-Enethiols and Their Derivatives:
Vinylic S 2 Reaction of
2
(
N
3
(E)-Alkenyl(phenyl)-λ -iodanes with
Thioamides
Masahito Ochiai,* Shinji Yamamoto, Takashi Suefuji, and Da-Wei Chen
Faculty of Pharmaceutical Sciences, UniVersity of Tokushima, 1-78 Shomachi,
Tokushima 770-8505, Japan
mochiai@ph2.tokushima-u.ac.jp
Received June 27, 2001
ABSTRACT
3
Exposure of (E)-â-alkylvinyl(phenyl)-λ -iodanes to thioamides in dichloromethane at room temperature was found to result in a bimolecular
N N
nucleophilic substitution (S 2) at the vinylic carbon atom to give inverted (Z)-enethiols and/or (Z)-S-vinylthioimidonium salts. Vinylic S 2
reactions with thioureas are also discussed.
3
Hypervalent alkenyl(phenyl)-λ -iodanes are highly reactive
mamides with rather low nucleophilicity also act as a
species in the reaction with nucleophiles because of the very
nucleophile toward (E)-â-alkylvinyliodanes 1 and afford (Z)-
vinyl formates stereoselectively via vinylic S
3
1
2 reaction.4
N
high leaving ability of λ -phenyliodanyl groups. We were
3
interested to see that (E)-â-alkylvinyl(phenyl)-λ -iodanes 1
This reaction requires heating at 50 °C. We report herein
3
underwent a bimolecular nucleophilic substitution (S
N
2) at
N
vinylic S 2 reaction of (E)-â-alkylvinyl(phenyl)-λ -iodanes
2
the vinylic carbon atoms, given that vinylic S
N
2 reactions
1 with thioamides, which proceeds under mild conditions
and yields (Z)-enethiols and/or (Z)-S-vinylthioimidonium
salts with exclusive inversion of configuration, depending
on the structure of thioamides and/or on the workup
procedure.
have been considered to be high-energy, low-probability
processes and, as such, have been neglected for a long time.
N
Nucleophiles that may participate in vinylic S 2 reaction with
1
include halides, dialkyl sulfides and selenides, phosphoro-
1
,3
selenoates, dithiocarbamates, and carboxylic acids. For-
Thioamides are more nucleophilic than the corresponding
5
3
amides, and thus nucleophilic substitutions of (E)-λ -
vinyliodanes 1 with thioamides proceed even at room
temperature. However, in contrast to the reaction with
formamides that affords inverted (Z)-vinyl formates stereo-
selectively, no formation of the corresponding (Z)-vinyl
thioformates was observed in the reaction with thioforma-
(1) (a) Ochiai, M. J. Organomet. Chem. 2000, 611, 494. (b) Ochiai, M.
In Chemistry in HyperValent Compounds; Akiba, K., Ed.; Wiley-VCH: New
York, 1999; Chapter 12. (c) Koser, G. F. In The Chemistry of Functional
Groups, Supplement D2; Patai, S., Rappoport, Z., Eds.; Wiley: New York,
1
995; Chapter 21.
2) (a) Ochiai, M.; Oshima, K.; Masaki, Y. J. Am. Chem. Soc. 1991,
13, 7059. (b) Okuyama, T.; Takino, T.; Sato, K.; Ochiai, M. J. Am. Chem.
(
1
Soc. 1998, 120, 2275. (c) Okuyama, T.; Takino, T.; Sato, K.; Oshima, K.;
Imamura, S.; Yamataka, H.; Asano, T.; Ochiai, M. Bull. Chem. Soc. Jpn.
(4) Ochiai, M.; Yamamoto, S.; Sato, K. J. Chem. Soc., Chem. Commun.
1999, 1363.
(5) Ohno, A. In Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum
Press: New York, 1977; Chapter 5.
1
998, 71, 243.
3) (a) Yan, J.; Chen, Z.-C. Tetrahedron Lett. 1999, 40, 5757. (b) Yan,
J.; Chen, Z.-C. Synth. Commun. 1999, 29, 2867.
(
1
0.1021/ol016356c CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/26/2001

mides, but instead, (Z)-enethiols 2 were obtained selectively
enethiols of the type RCHdCHSH are very limited and often
3
(Scheme 1). Exposure of (E)-1-decenyl(phenyl)-λ -iodane 1a
inefficient in terms of stereoselectivity and yields of the
7
b,c
products. The reaction described above provides a novel
method for the synthesis of aliphatic (Z)-enethiols 2 in a
highly stereoselective manner under mild conditions.
Scheme 1
Attempts at nucleophilic substitution of (Z)-1-decenyl-
3
(
phenyl)-λ -iodane 4 with N,N-dimethylthioformamide re-
sulted exclusively in the reductive elimination of iodobenzene
yielding 1-decyne (93%), as observed in the reaction of 4
4
with N,N-dimethylformamide (Scheme 2).
Scheme 2
to N,N-dimethylthioformamide (3 equiv) in dichloromethane
at room temperature for 20 h results in nucleophilic vinylic
substitutions. After quenching the reaction mixture with
water, extraction with dichloromethane, and evaporation
under aspirator vacuum afforded a mixture of (Z)-enethiol
The exclusive inversion of configuration observed strongly
suggests a vinylic S 2 mechanism for the reaction of (E)-
N
λ -vinyliodanes 1 with thioamides, which is shown in
Scheme 3. Nucleophilic attack by sulfur atoms of thioamides
3
2
a (70%) and iodobenzene (44%). Yields of the products
1
were determined by H NMR, because (Z)-enethiol 2a is
labile and tends to readily dimerize to (Z)-1-decenyl 1-mer-
captodecyl sulfide (3a) upon further purification by silica
gel chromatography or upon attempted removal of the
Scheme 3
6
byproduct iodobenzene under high vacuum. Reactions with
thioacetamide and thiobenzamide also afforded (Z)-enethiol
2a stereoselectively (Table 1). Similarly, (E)-5-phenyl-1-
Table 1. Synthesis of (Z)-Enethiols 2 by Reaction of
3
a
Vinyl-λ -iodanes 1 with Thioamides
entry
1
thioamide (equiv)
t (h)
2
yield (%)b
1
2
3
4
1a
1a
1a
1b
Me2NCHS (3.0)
MeCSNH2 (1.1)
PhCSNH2 (1.1)
Me2NCHS (3.0)
20
23
52
30
2a
2a
2a
2b
70
82
47c
82
a
Reactions were carried out in dichloromethane at room temperature
b
1
c
under nitrogen. Yields were determined by H NMR. (Z)-1-Decenyl
1
-mercaptodecyl sulfide (3a) was obtained in 32% yield.
on 1a from the side opposite the hyperleaving group PhI-
(
BF
4
) would produce the inverted (Z)-S-vinylthioimidonium
2 transition state
Subsequent hydrolysis of (Z)-S-vinylthioimidonium salt
affords the retained (Z)-enethiol 2a via decomposition of
salt 6 (X ) S) stereoselectively via an S
5
6
N
3
pentenyl-λ -iodane 1b gave (Z)-enethiol 2b in 82% yield
upon reaction with N,N-dimethylthioformamide.
1,12
.
Small vicinal coupling constants between the vinylic
the intermediate 7, derived from 6 by the addition of water.
In fact, it was possible to detect formation of the intermediate
(Z)-S-vinylthioimidonium salt 6 when the reaction mixture
was purified without treatment with water. For instance, (Z)-
S-vinylthioimidonium salt 6a (R′ ) Me, R′′ ) H, X ) S)
was obtained in the reaction of 1a with thioacetamide in 87%
yield when the reaction mixture was purified by decantation
with ether and hexane. Reaction of 1a with thiobenzamide
also afforded the inverted (Z)-S-vinylthioimidonium salt 6b
(R′ ) Ph, R′′ ) H, X ) S) in 77% yield after decantation.
These (Z)-S-vinylthioimidonium salts 6a and 6b are labile
and highly susceptible to hydrolysis with water, yielding (Z)-
enethiol 2a and/or the dimer 3a.
1
protons of 2a (J ) 9.6 Hz) and 2b (J ) 8.9 Hz) in H NMR
clearly indicate a cis structure.7 No evidence for formation
of either the (E) isomer of 2 or the corresponding thioalde-
hyde tautomer was found. In general, thioaldehydes are
highly unstable in solution and readily tautomerize into the
corresponding enethiols provided that they have R-ene-
thiolizable hydrogen atoms.5 For instance, a stereoisomeric
mixture of (E)- and (Z)-1-mercaptopropenes was the only
product obtained from ethyl 1-propenyl sulfide in the reaction
with lithium in liquid ammonia.10 Facile enethiolization of
thioaldehydes is probably due to the weak π-bond of
thiocarbonyl groups.11 Methods for synthesizing acyclic
,8
,9
2754
Org. Lett., Vol. 3, No. 17, 2001

As shown in Scheme 3, decomposition modes of tetrahe-
dral intermediates 7 will determine the structure of products.
hydrolysis with water; in fact, the reaction of 1 with thioureas
9a-f did not show, after aqueous workup, any sign of
formation of the hydrolysis product (Z)-enethiol 2a. In
addition, exposure of isothiouronium salts 10c and 10f to
aqueous sodium carbonate solution at room temperature did
not give (Z)-enethiol 2a at all, but instead, (Z)-S-vinylisothio-
ureas 11c and 11f were obtained in high yields.
N
In the vinylic S 2 reaction of 1a with amides yielding the
(
Z)-vinyl ester 8, intervention of the intermediates 7 (X )
O) has also been proposed, in which liberation of amino
groups (or ammonio groups) preferentially takes place. In
marked contrast, tetrahedral sulfur analogues 7 (X ) S)
collapse to (Z)-enethiol 2a exclusively with the vinylthio
group being released. These results probably reflect differ-
ences in leaving ability of the vinylthio groups and the
vinyloxy groups.
N
Thioureas also act as good nucleophiles in vinylic S 2
3
reactions of (E)-λ -vinyliodanes 1. Thus, nucleophilic sub-
stitution of (E)-1-decenyl(phenyl)-λ -iodane 1a with thiourea
3
Isothiouronium salts are useful building blocks for the
synthesis of heterocycles such as triazines, pyrimidines, and
(
9a) (1.1 equiv) in dichloromethane took place at room
temperature and gave, after decantation with hexane at -78
C, (Z)-S-vinylisothiouronium salt 10a in 77% yield (Table
, entry 1). Other acyclic 9b-e and cyclic 9f thioureas also
1
4
thiazoles. As an example, we have prepared substituted
pyrimidine 12 in 56% yield from isothiouronium salt 10a
by the reaction with (ethoxymethylidene)malononitrile in the
presence of diisopropylethylamine in DMF at room temper-
ature (Scheme 4).
°
2
Table 2. Synthesis of Vninylisothiouronium Salts 10 by
3
a
Reaction of λ -Iodane 1a with Thioureas 9
Scheme 4
entry
9 (equiv)
T (°C)/t (h)
10
yield (%)b
1
2
3
4
5
6
7
9a (1.2)
9b (1.2)
9c (1.0)
9d (1.1)
9e (1.0)
9f (1.0)
9g (1.2)
25/17
25/8
10a
10b
10c
10d
10e
10f
10g
77
63
76
91
68
92
0c
All of the 2-mercapto heterocycles 13a-c, tautomers of
thioamides 14a-c, also react with (E)-λ -vinyliodanes 1 via
3
25/16
25/24
25/10
25/21
50/62
N
a vinylic S 2 pathway; thus, 2-mercaptobenzimidazole (13a),
2-mercaptobenzoxazole (13b), and 2-mercaptobenzothiazole
3
(
13c), on treatment with (E)-1-decenyl(phenyl)-λ -iodane 1a
in dichloromethane at room temperature, afforded (Z)-vinyl
sulfides 15a-c in high yields (Table 3). These reactions
proceed with complete inversion of configuration. As
a
Reactions were carried out in dichloromethane under nitrogen. b Isolated
yields. (Z)-S-Vinylisothiourea 11g was obtained in 51% yield.
c
N
undergo vinylic S 2 reaction with 1a to give (Z)-S-vinyl-
Table 3. Synthesis of (Z)-Vinylsulfides 15 by Reaction of
Iodanes 1 with Thiols 13a
isothiouronium salts 10b-f in good to excellent yields. Here
again, exclusive inversion of configuration was observed in
the reaction, and no formation of the (E) isomer of 10 was
detected. To our knowledge, synthesis of (Z)-S-vinylisothio-
uronium salts has not been reported previously.13
entry
1
13 (equiv)
t (h)
15
yield (%)b
1
2
3
4
1a
1a
1a
1b
13a (1.2)
13b (1.2)
13c (1.2)
13c (1.2)
9
44
11
22
15a
15b
15c
15d
80
89
91
83
a
Reactions were carried out in dichloromethane at room temperature
In contrast to (Z)-S-vinylthioimidonium salts 6, (Z)-S-
vinylisothiouronium salts 10 proved to be stable toward
under nitrogen. b Isolated yields.
Org. Lett., Vol. 3, No. 17, 2001
2755

3
observed in the reaction of (Z)-vinyl-λ -iodane 4 with N,N-
In conclusion, we have shown that thioamides and their
derivatives act as good nucleophiles in vinylic S 2 reactions
with (E)-â-alkylvinyl(phenyl)-λ -iodanes, and these reactions
dimethylthioformamide (Scheme 2), reductive elimination
yielding 1-decyne takes place exclusively in the reaction of
N
3
4
with 2-mercaptobenzothiazole (13c).
proceed under mild conditions.
(
6) (a) Campaigne, E.; Moss, R. D. J. Am. Chem. Soc. 1954, 76, 1269.
b) Selzer, T.; Rappoport, Z. J. Org. Chem. 1996, 61, 5462.
7) (a) Stacey, F. W.; Harris, J. F. J. Am. Chem. Soc. 1963, 85, 963. (b)
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
(
Strausz, O. P.; Hikida, T.; Gunning, H. E. Can. J. Chem. 1965, 43, 717. (c)
Vallee, Y.; Khalid, M.; Ripoll, J.-L.; Hakiki, A. Synth. Commun. 1993, 23,
1
267. (d) Nocher, A.-M. L.; Metzner, P. Tetrahedron Lett. 1992, 33, 6151.
8) Large coupling constants for the SH group of 2a (J ) 8.6 Hz) and
b (J ) 8.9 Hz) were observed.
9) For synthesis of thioaldehydes, see: (a) Okazaki, R.; Ishii, A.; Fukuda,
N.; Oyama, H.; Inamoto, N. J. Chem. Soc., Chem. Commun. 1982, 1187.
b) Vedejs, E.; Perry, D. A. J. Am. Chem. Soc. 1983, 105, 1683. (c) Ando,
W.; Ohtaki, T.; Suzuki, T.; Kabe, Y. J. Am. Chem. Soc. 1991, 113, 7782.
OL016356C
(
2
3
(
(12) For very high leaving group ability of the λ -aryliodanyl groups,
see: Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J. Am. Chem. Soc.
1995, 117, 3360.
(
3
(13) Phenyldimedonyl-λ -iodane, a stable iodonium ylide, undergoes
(
10) Brandsma, L. Recl. TraV. Chim. Pays-Bas 1970, 89, 593.
substitution by the reaction with thiourea to give isothiouronium zwitterion;
see: Koser, G. F.; Yu, S.-M. J. Org. Chem. 1976, 41, 125.
(14) (a) Masquelin, T.; Delgado, Y.; Baumle, V. Tetrahedron Lett. 1998,
39, 5725. (b) Masquelin, T.; Sprenger, D.; Baer, R.; Gerber, F.; Mercadal,
Y. HelV. Chim. Acta 1998, 81, 646.
(
11) For ab initio theoretical calculations on tautomerization of thioal-
dehydes into enethiols, see: (a) Zhang, X.-M.; Malick, D.; Petersson, G.
A. J. Org. Chem. 1998, 63, 5314. (b) Bruno, A. E.; Steer, R. P.; Mazey, P.
G. J. Comput. Chem. 1983, 4, 104.
2756
Org. Lett., Vol. 3, No. 17, 2001