Addition reaction of zinc acetylides to thioiminium salts leading to 3-amino-1-sulfenyl-1,4-enynes

Article abstract of DOI:10.1016/j.tetlet.2005.03.166

The reaction of thioiminium salts with zinc acetylides took place at 60°C to give 3-amino-1-sulfenyl-1,4-enynes in moderate to good yields. Two molecules of acetylides were incorporated into the products. Nucleophilic attack of zinc acetylides to thioimin

Full text of DOI:10.1016/j.tetlet.2005.03.166

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3637–3640
Addition reaction of zinc acetylides to thioiminium salts leading
to 3-amino-1-sulfenyl-1,4-enynes
Toshiaki Murai,* Yukiyasu Ohta and Yuichiro Mutoh
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
Received 2 March 2005; revised 22 March 2005; accepted 23 March 2005
Available online 8 April 2005
Abstract—The reaction of thioiminium salts with zinc acetylides took place at 60 °C to give 3-amino-1-sulfenyl-1,4-enynes in
moderate to good yields. Two molecules of acetylides were incorporated into the products. Nucleophilic attack of zinc acetylides
to thioiminium salts may initially occur to form alkynyl S,N-acetals, followed by their [1,3]-rearrangement to give 3-sulfenyl-
1-aminoallenes.
Ó 2005 Elsevier Ltd. All rights reserved.
Addition of metal acetylides to imines1 and iminium
salts2 is one of the most relevant methods for the
syntheses of propargyl amines. In these reactions, one
molecule of metal acetylides is efficiently introduced to
iminium salts. In contrast, we have recently disclosed
the synthesis of propargyl amines from thioiminium
salts 1 (Eq. 1). Two different types of organometallic
reagents, that is, lithium and magnesium acetylides,
are introduced to salts 1 in one operation via alkynyl
S,N-acetals 2.3
interest. We report here the addition reaction of zinc
acetylides to thioiminium salts leading to 3-amino-1-sul-
fenyl-1,4-enynes.
At the outset, to zinc acetylide 3a in situ generated from
Zn(OTf)2, phenylacetylene, and Et3N4 was added thio-
iminium salt 1a, and the mixture was stirred at room
temperature for 5 h to give three types of products 4–6
at most in 44% combined yields. To obtain one of the
three products more selectively, the reaction was exam-
ined under various reaction conditions. Consequently,
the reaction of 1a with 2 equiv of 3a at 60 °C gave
3-amino-1-sulfenyl-1,4-enyne 4a in 51% yield predomi-
nantly as the Z-isomer. Furthermore, 20 mol % of
Zn(OTf)2 was enough to run the reaction in Eq. 2,
and the product 4a was obtained in nearly equal yield.
SMe
–
MeS
OTf
R'C CLi
+
NR
2
H
NR
2
R'
2
1
NR
2
R"C CMgX
MeS
–
OTf
+
R"
R'
H
N
ð1Þ
1a
1) Et N
3
PhC CZnOTf
Zn(OTf)
2
2)
PhC CH
3a
The subtle difference of the reactivity of two organome-
tallic reagents toward 1 and 2 has enabled the selective
transformation in Eq. 1. The reactivity of 1 and 2
toward various organometallic reagents is of further
N
Ph
O
N
SMe
+
+
MeS
H
Ph
6
Ph
Ph
5
Ph
4a
ð2Þ
Keywords: Thioamides; Thioiminium salts; Zinc acetylides; Alkynyl
S,N-acetals; 3-Amino-1-sulfenyl-1,4-enynes; [1,3]-Rearrangement;
3-Sulfenyl-1-aminoallenes.
A variety of thioiminium salts 1 and zinc acetylides 3
were subjected to the reaction. The results are summa-
rized in Table 1.5,6 In all cases, the products where
*
Corresponding author. Tel./fax: +81 58 293 2614; e-mail: mtoshi@
cc.gifu-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.166

3638
T. Murai et al. / Tetrahedron Letters 46 (2005) 3637–3640
Table 1. Reaction of thioiminium salts 1 with zinc acetylides 3a
Entry
1
Thioiminium salt 1
Zinc acetylide 3
Product 4
Yieldb (%)
(34%)d,e
Ratioc (E:Z)
N
SMe
C H -Cl-4
–
OTf
MeS
25:75
4-ClC6H4C„CZnOTf 3b
4b
+
1a
6
4
H
N
4-ClC H
6
4
N
SMe
C H -Me-4
2
3
1a
4-MeC6H4C„CZnOTf 3c
4c
(66%)d
50%
33:67
0:100
6
4
4-MeC H
6
4
N
SMe
Ar
1a
ArC„CZnOTf 3d
4d
54%
Ar =
Ar
O
N
–
OTf
O
MeS
H
4f
1b
3a
4e
(51%)d,g
36:64
+
SMe
N
Ph
Ph
2
–
1
R
OTf
R
MeS
H
N
SMe
Ph
+
N
1
R
2
R
Ph
5e
6e
1c R1 = R2 = CH2CH@CH2
1d R1 = CH2CH@CH2,
R2 = CH2Ph
3a
3a
4f
4g
65%
66%
37:63
33:67
7e
1e R1 = R2 = CH2Ph
3a
4h
(78%)d
64%
36:64
a The reaction was carried out unless otherwise noted: thioiminium salts 1 (1 mmol) were added to zinc acetylides generated from Zn(OTf)2
(0.2 mmol), acetylene (2.1 mmol), and Et3N (2.1 mmol) in toluene (3.5 mL), and the mixture was stirred at 60 °C for 2 h.
b Isolated yields.
c The ratio was determined by 1H NMR spectra.
d The yield was determined by 1H NMR spectra.
e The product 4b and 3-aryl-3-methylsulfenylpropenal were obtained in 52% combined yields.
f
Zn(OTf)2 (2 mmol) was used.
g The product 4e and 4-(1,5-diphenylpent-1,4-diynyl)morpholine were obtained in 75% combined yields.
two molecules of acetylides were incorporated to 1
were obtained. Zinc acetylides 3b–d derived from
4-chloro-,4-methylphenylacetylenes, and 1-naphthylacet-
ylene, 20 mol % of Zn(OTf)2, and Et3N reacted with
thioiminium salt 1a to give the corresponding 3-ami-
no-1-sulfenyl-1,4-enynes 4b–d in 34–66% yields (entries
1–3), although the use of aliphatic acetylenes gave
complex mixtures. As for the reaction with 3d, Z-isomer
of 4d was selectively obtained probably because of the
steric reason. Thioiminium salts 1b–e, where morpholino,
diallylamino, allyl benzylamino, and dibenzylamino
groups were attached to the carbon atom bearing
MeS group, were also reacted with zinc acetylide 3a
(entries 4–7). The stoichiometric amounts of Zn(OTf)2
were necessary to perform these reactions effectively.
The reaction pathway of the present reaction is pro-
posed in Scheme 1. The reaction of Zn(OTf)2 and termi-
nal acetylenes takes place in the presence of Et3N to
form zinc acetylides 3 and ammonium triflate 7. Then,
3 attacks to thioiminium salts 1 to give alkynyl
S,N-acetals 2. Lewis acids such as Zn(OTf)2 and/or
3 mediate [1,3]-rearrangement of alkynyl S,N-acetals
2 to form 3-sulfenyl-1-aminoallenes 8,7,9 followed by the
protonation of 8 to give iminium salts 9. Finally, the
second molecule of zinc acetylides 3 adds to salts 9 to
end up the formation of 4.
The following two experiments have supported some
steps of the proposed reaction pathway. Initially, the
isolated alkynyl S,N-acetal 2a was reacted with

T. Murai et al. / Tetrahedron Letters 46 (2005) 3637–3640
3639
2
References and notes
1
R
ArC CH
R
N
SMe
Ar
Et N
3
1. For recent examples of the reaction of acyclic imines with
metal acetylides, see: (a) Aubrecht, K. B.; Winemiller,
M. D.; Collum, D. B. J. Am. Chem. Soc. 2000, 122,
11084; (b) Moroni, M.; Koksch, B.; Osipov, S. N.;
Crucianelli, M.; Frigerio, M.; Bravo, P.; Burger, K. J.
Org. Chem. 2001, 66, 130; (c) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124, 5638; (d) MevaÕa, L. M.; Ndom, J.
C.; Happi, E. N. Bull. Chem. Soc. Ethiopia 2002, 16, 169;
(e) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org.
Lett. 2003, 5, 3273; (f) Jiang, B. S. Y.-G. Tetrahedron Lett.
2003, 44, 6767; (g) Fischer, C.; Carreira, E. M. Org. Lett.
2004, 6, 1497; (h) Ji, J.-X.; Au-Yeung, T. T.-L.; Wu, J.;
Yip, C. W.; Chan, A. S. C. Adv. Synth. Catal. 2004, 346,
42.
2. The reaction of acyclic iminium salts with metal acetylides
is limited, see: (a) Courtois, G.; Harama, M.; Miginiac, P.
J. Organomet. Chem. 1981, 218, 1; (b) Ukhin, L. Y.;
Komissarov, V. N.; Orlova, Z. I.; Tokarskaya, D. A.;
Yanovskii, A. I.; Struchkov, Y. T. Zh. Org. Khim. 1987,
23, 1323; (c) Katritzky, A. R.; Yang, H.; Singh, S. K.
J. Org. Chem. 2005, 70, 286.
Zn(OTf)
2
Ar
4
3
2
+
N
1
R
R
MeS
Ar
+
–
OTf
–
Et NH
3
ArC CZnOTf
OTf
H
9
3
7
H
–
7
MeS
OTf
1
+
and/or
R
H
N
H O
2
1
2
R
3
1
and/or
R
SMe
2
Zn(OTf)
N
H
R
MeS
Ar
1
2
R
•
N
2
Ar
R
2
8
Scheme 1.
3. Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am.
Chem. Soc. 2004, 126, 5968.
4. Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira, E.
M. Acc. Chem. Res. 2000, 33, 373.
Zn(OTf)2 to give a,b-unsaturated aldehyde 6, which
may be formed by the hydrolysis of 3-sulfenyl-1-amino-
allene 8a (Eq. 3). Secondly, deuterated phenylacetylene
10 was used in the present reaction (Eq. 4). As a result,
acetylenic deuterium of 10 was partly transferred to the
alkenyl carbon atom of 4a0.10
5. A typical experimental procedure for the reaction of in situ
generated zinc acetylides with thioiminium salts: a 20 mL
two necked flask was placed with Zn(OTf)2 (73 mg,
0.2 mmol) and dried under high vacuum. To this were
added toluene (1.5 mL) and triethylamine (0.3 mL,
2.1 mmol). The resulting mixture was vigorously stirred
at 23 °C for 2 h, and to this was added phenylacetylene
(0.24 mL, 2.1 mmol) via syringe in one portion. On the
other hand, to a toluene (2 mL) solution of N,N-dimethyl
thioformamide (0.085 mL, 1.0 mmol) was added methyl
triflate (0.11 mL, 1.0 mmol) at room temperature, and the
mixture was stirred at this temperature for 30 s. Then, this
solution was added to the suspension of Zn acetylide via
cannula, and this was stirred at 60 °C for 2 h. The
resulting mixture was poured into a saturated aqueous
solution of NH4Cl and extracted with Et2O. The organic
layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromato-
graphy (SiO2, hexane–EtOAc = 1:1) to give 3-amino-1-
sulfenyl-1,4-enyne 4a (0.157 g, 51%, E:Z = 22:78) as a
dark red oil: E-isomer: 1H NMR (CDCl3): d 2.16 (s,
3H, SMe), 2.23 (s, 6H, NMe2), 3.91 (d, J = 9.6 Hz,
1H, CH), 5.54 (d, J = 9.6 Hz, 1H, HC@C), 7.22–7.24
(m, 6H, Ar), 7.25–7.33 (m, 4H, Ar). Z-Isomer: 1H
NMR (CDCl3): d 1.89 (s, 3H, SMe), 2.36 (s, 6H, NMe2),
4.79 (d, J = 8.8 Hz, 1H, CH), 5.95 (d, J = 8.8 Hz, 1H,
HC@C), 7.35–7.40 (m, 6H, Ar), 7.45–7.47 (m, 4H,
Ar); HRMS calcd for C20H21NS: 307.1395, found:
307.1411.
SMe
N
H
MeS
Ph
Ph
O
Zn(OTf)
2
•
N
MeS
H
toluene
rt, 1 h
Ph
2a
8a
6
52%
ð3Þ
–OTf
MeS
+
H
N
N
SMe
1a
1) Et3N
Ph
Zn(OTf)2
2)
PhC CD10
60 ˚C, 2 h
Ph
D
45% 40%D
rt, 2 h
4a'
ð4Þ
In summary, we have demonstrated the addition reac-
tion of zinc acetylides in situ generated from aromatic
terminal acetylenes, Zn(OTf)2, and Et3N to thioiminium
salts. Two molecules of acetylides were incorporated to
the salts to give 3-amino-1-sulfenyl-1,4-enynes predomi-
nantly as Z-isomers. The reaction may involve [1,3]-
rearrangement of alkynyl S,N-acetals leading to 3-sulfen-
yl-1-aminoallenes. Further studies on properties and
reactivity of reactive species with organosulfur function-
alities are underway.
6. The stereochemistry of product 4a was determined by
phase sensitive NOESY spectroscopy. The chemical shifts
of 4 were calculated with substituents constants for
chemical shifts of substituted ethylenes. Then, the stereo-
chemistry of 4 was estimated by comparing these values
with the observed values of 4.
7. Although the thermal [1,3]-rearrangement of alkynyl S,N-
acetal having cyclohexylsulfenyl group was reported,8
Lewis acid mediated [1,3]-rearrangement of alkynyl S,N-
acetals has not yet been reported.
8. Maas, G.; Wurthwein, E.-U.; Singer, B.; Mayer, T.;
¨
Krauss, D. Chem. Ber. 1989, 122, 2311.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.

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T. Murai et al. / Tetrahedron Letters 46 (2005) 3637–3640
9. The reaction of isolated alkynyl S,N-acetals 2 with zinc
10. This partial incorporation of deuterium has also sugg-
ested that the protonation of takes place with
acetylides gave 4 in lower yields. The results have implied
the importance of the in situ generation of 2 in the present
reaction.
8
small amounts of water contained in the reaction
mixture.