Reactions of Vinyl Sulfoxides with Magnesium Amides. One-Pot Synthesis of Symmetrical and Unsymmetrical β-(Dialkylamino) Dithioacetals

Article abstract of DOI:10.1021/jo970741r

Vinyl sulfoxides (PhSOCR¹=CHR²: R¹ = H, Me, or Ph; R² = H or Me) were treated with (dialkylamino)magnesium reagents, generated in situ from the reaction of EtMgBr with secondary amines (R³R⁴NH: R³ = Et, i-Pr, or Bn; R⁴ = Me, Et, or i-Pr) in refluxing Et₂O for 1 h, and stirring at room-temperature overnight gave the corresponding symmetrical β-(dialkylamino) dithioacetals [(PhS)₂CR¹CHR²NR³R⁴] in 24-84% yields. When the (diethylamino)magnesium reagent was treated with appropriate thiols (RSH; R = p-ClC₆H₄ or Bn) prior to the interaction with phenyl vinyl sulfoxide, the corresponding unsymmetrical β-(diethylamino) dithioacetals [(PhS)(RS)CHCH₂NEt₂] were produced in 63-67% yields.

Full text of DOI:10.1021/jo970741r

J . Org. Chem. 1997, 62, 8015-8017
8015
Rea ction s of Vin yl Su lfoxid es w ith Ma gn esiu m Am id es. On e-P ot
Syn th esis of Sym m etr ica l a n d Un sym m etr ica l â-(Dia lk yla m in o)
Dith ioa ceta ls
Masataka Kawakita, Kouichi Yokota, Hideki Akamatsu, Susumu Irisawa, Osamu Morikawa,
Hisatoshi Konishi, and Kazuhiro Kobayashi*
Department of Materials Science, Faculty of Engineering, Tottori University, Tottori 680, J apan
Received April 25, 1997X
Vinyl sulfoxides (PhSOCR1dCHR2: R1 ) H, Me, or Ph; R2 ) H or Me) were treated with
(dialkylamino)magnesium reagents, generated in situ from the reaction of EtMgBr with secondary
amines (R3R4NH: R3 ) Et, i-Pr, or Bn; R4 ) Me, Et, or i-Pr) in refluxing Et2O for 1 h, and stirring
at room-temperature overnight gave the corresponding symmetrical â-(dialkylamino) dithioacetals
[(PhS)2CR1CHR2NR3R4] in 24-84% yields. When the (diethylamino)magnesium reagent was treated
with appropriate thiols (RSH; R ) p-ClC6H4 or Bn) prior to the interaction with phenyl vinyl
sulfoxide, the corresponding unsymmetrical â-(diethylamino) dithioacetals [(PhS)(RS)CHCH2NEt2]
were produced in 63-67% yields.
Sch em e 1
In tr od u ction
Dithioacetals have been shown to be useful building
blocks for specific C-C bond formation and functional
group interconversion in organic synthesis.1 Moreover,
some of this class of compounds have attracted interest
because of their biological activities.2 Thus, â-amino
dithioacetals are potentially useful not only in synthetic
organic chemistry for further elaborations but also in
medicinal chemistry. However, few synthetic methods
are available for the formation of these derivatives,
though there are several established methods for the
preparation of simple dithioacetals.1 As the only reported
method, a two-step preparation of 2-amino-1,1-bis(alkyl-
thio)ethanes, which begins with 1,1-bis(alkylthio)ethenes
and has limited generality (three examples), has been
recorded by Hamberger et al.3 Therefore, any new
efficient route to this class of molecules from readily
accessible starting materials is of interest and value. In
the course of our exploration on application of the
magnesium amide-induced Pummerer-type reactions,4 we
examined the reaction of vinyl sulfoxides 1 with magne-
sium amides, generated by the treatment of ethylmag-
nesium bromide with secondary amines 2, aimed at the
development of a general method for the direct prepara-
tion of â-amino dithioacetal derivatives.5 We have found
that the reaction can afford symmetrical â-(dialkylamino)
dithioacetals 3 (Scheme 1) and that the reaction in the
presence of an appropriate thiol results in the formation
of unsymmetrical â-(dialkylamino) dithioacetals 6 (Scheme
2).
Sch em e 2
(see Experimental Section), into the amino dithioacetals
3 was performed as follows (Scheme 1). To a turbid
solution of a (dialkylamino)magnesium reagent, gener-
ated by treating ethylmagnesium bromide (6 mmol) with
one of the secondary amines 2 (12 mmol)6 in refluxing
Et2O for 1 h, was added one of the sulfoxides 1 (1 mmol).
The reaction mixture was stirred overnight at room
temperature. After usual workup, the expected product
3 was isolated by purification using preparative TLC on
silica gel. The results obtained by using four vinyl
sulfoxides and three secondary amines are summarized
in Table 1. It is very likely that the mechanism for the
formation of the products involves the initial formation
of the sulfonium ion intermediate 9 via the ylide 8 formed
by the addition of the magnesium amide 7 to 17a and that
the pathway from this intermediate to 3 is parallel to
that for the formation of dithioacetals from simple
sulfoxides and magnesium amides, which was proposed
by us in a previous paper,4a as depicted in Scheme 3.7b
With diethylamine (2a ), diisopropylamine (2b), and N-
Resu lts a n d Discu ssion
The transformation of vinyl sulfoxides 1, commercially
available or readily prepared by the reported procedures
(5) For reported examples of additive Pummerer-type reactions,
see: Russell, G. A.; Sabourin, E.; Mikol, G. J . J . Org. Chem. 1966, 31,
2854. Miyamoto, N.; Fukuoka, D.; Utimoto, K.; Nozaki, H. Bull. Chem.
Soc. J pn. 1974, 47, 1817. Kosugi, H.; Uda, H.; Yamagiwa, S. J . Chem.
Soc., Chem. Commun. 1976, 71. Reamonn, L. S. S.; O’Sullivan, W. I.
J . Chem. Soc., Chem. Commun. 1976, 642. King, R. R. J . Org. Chem.
1978, 43, 1262. Marino, J . P.; Neisser, M. J . Am. Chem. Soc. 1981,
103, 7687. Posner, G. H.; Asirvatham, E.; Ali, S. F. J . Chem. Soc.,
Chem. Commun. 1985, 542. Kita, Y.; Tamura, O.; Itoh, F.; Yasuda,
H.; Miki, T.; Tamura, Y. Chem. Pharm. Bull. 1987, 35, 3623. Craig,
D.; Daniels, K.; Mackenzie, A. R. Tetrahedron Lett. 1991, 31, 6441.
Craig, D.; Daniels, K.; Mackenzie, A. R. Tetrahedron Lett. 1991, 32,
6973.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) For a recent review, see: Vallee, Y.; Bulpin, A. In Comprehensive
Organic Functional Group Transformation; Kirby, G. W., Ed.; Elsevi-
er: Oxford, 1995; Vol. 4, p 243.
(2) Green, M. B.; J enkins, W. L. J . Sci. Food Agric. 1958, 536. J apan
Soda Co., Ltd., J apan Patent 5699 1963; Chem. Abstr. 1864, 60, 4720h.
(3) Hamberger, H.; Stutz, P.; Schultz, G. Tetrahedron Lett. 1977,
3623.
(4) (a) Kobayashi, K.; Kawakita, M.; Yokota, K.; Mannami, T.;
Yamamoto, K.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. J pn. 1995,
68, 1401. (b) Kobayashi, K.; Yokota, K.; Akamatsu, H.; Morikawa, O.;
Konishi, H. Bull. Chem. Soc. J pn. 1996, 69, 441. (c) Kobayashi, K.;
Kawakita, M.; Akamatsu, H.; Morikawa, O.; Konishi, H. Bull. Chem.
Soc. J pn. 1996, 69, 2645.
(6) We observed that the yields of the products decreased with
smaller molar amounts of either of ethylmagnesium bromide or
secondary amines.
S0022-3263(97)00741-X CCC: $14.00 © 1997 American Chemical Society

8016 J . Org. Chem., Vol. 62, No. 23, 1997
Kawakita et al.
Ta ble 1. Syn th esis of Am in o Dith ioa ceta ls 3 fr om Vin yl
Su lfoxid es 1 a n d Secon d a r y Am in es 2 Accor d in g to
Sch em e 1
result from deprotonation of the hydrogen Ha from the
intermediate 9e (see Scheme 3). Interestingly, the
deprotonation appears to be exclusive, because there was
no indication for the presence of products arising from
deprotonation of the hydrogen Hb in the reaction mixture
product(s)
entry
1
2
(yield/%)a
1
2
3
4
5
6
R1 ) R2 ) H (1a )
1a
1a
R3 ) R4 ) Et (2a )
R3 ) R4 ) i-Pr (2b)
3a (79)
3b (74)
1
as judged by its H NMR spectrum. Entry 6 of Table 1
indicates that, of four vinyl sulfoxides tested, phenyl
1-phenylethenyl sulfoxide (1d ) gave the best result.
It should be noted that attempts to prepare â-(alkyl-
amino) dithioacetals by using primary amines, such as
benzylamine and n-butylamine, instead of secondary
amines did not meet with success. The reactions each
resulted in formation of an intractable mixture of prod-
ucts, from which no trace of the expected product was
isolated.
R3) Me, R4 ) Bn (2c) 3c (71)
R1 ) H, R2 ) Me (1b)b 2a
R1 ) Me, R2 ) H (1c) 2a
R1 ) Ph, R2 ) H (1d ) 2a
3d (76), 4 (10)
3e (24), 5 (57)
3f (84)
a
Yields are based on 1 and isolated products after preparative
b
TLC on SiO2. A mixture of stereoisomers was used.
Sch em e 3
We next examined the reaction of vinyl sulfoxides 1
with the (dialkylamino)magnesium reagents in the pres-
ence of an appropriate thiol (Scheme 2), in expectation
of the formation of unsymmetrical â-(diethylamino) dithio-
acetals through addition of a thiolate anion to the
intermediate 9. As expected, when the (diethylamino)-
magnesium reagent was treated with a thiol, such as
4-chlorobenzenethiol or phenylmethanethiol, prior to the
interaction with 1a , the corresponding product 6a or 6b
was produced in fair yields.7c
a
a
In summary, the results reported in the foregoing part
indicate that the present reaction between vinyl sulfox-
ides and magnesium amides provides a simple and
general approach to the preparation of â-(dialkylamino)
dithioacetals. It has advantages not only in that the
starting materials are readily available but also in that
it can be applied to the preparation of the unsymmetrical
â-(dialkylamino) dithioacetal derivatives. These advan-
tages make this class of compounds potentially interest-
ing in organic and medicinal chemistry.
Exp er im en ta l Section
Sta r tin g Ma ter ia ls. Phenyl vinyl sulfoxide (1a ) was
commercially available. A mixture of phenyl (E)- and (Z)-1-
propenyl sulfoxides 1b was prepared according to the proce-
dure reported by Craig et al.8 1-Methylethenyl phenyl sul-
foxides (1c)9 and phenyl 1-phenylethenyl sulfoxide (1d )10 were
prepared by the NaIO4 oxidation of the corresponding sulfides,
which were obtained according to the procedure reported by
us.4a 1c: Rf 0.44 (1:1 EtOAc-hexane); IR (neat) 1632, 1048
cm-1; 1H NMR (60 MHz, CCl4) δ 2.73 (3H, d, J ) 1.6 Hz), 5.60
(1H, d, J ) 1.6 Hz), 6.02 (1H, s), 7.3-7.8 (5H, m). 1d : Rf 0.30
(1:3 EtOAc-hexane); IR (neat) 1614, 1575, 1051 cm-1; 1H NMR
(60 MHz, CCl4) δ 5.73 (1H, s), 6.10 (1H, s), 6.9-7.45 (10H, m).
2-(Dieth yla m in o)-1,1-bis(p h en ylth io)eth a n e (3a ). To a
stirred solution of EtMgBr (6 mmol) in Et2O (8 mL) at 0 °C
under argon was added diethylamine (2a ) (0.88 g, 12 mmol),
and the mixture was heated at reflux temperature for 1 h.
After cooling to 0 °C, phenyl vinyl sulfoxide (1a ) (0.15 g, 1
mmol) was added. The mixture was warmed to room temper-
ature and stirring was continued overnight. The resulting
mixture was quenched with aqueous NH4Cl and extracted with
Et2O three times. The combined extracts were washed with
brine and dried over anhydrous MgSO4. After evaporation of
the solvent, the crude product was purified by preparative TLC
on SiO2 to give 3a (0.13 g, 79%) as a yellow oil: Rf 0.47 (1:5
EtOAc-hexane); IR (neat) 1592, 1478, 1438, 1384, 1154, 1068,
1025, 748, 691 cm-1; 1H NMR (CCl4, 60 MHz) δ 0.93 (6H, t, J
methylbenzylamine (2c), compound 1a respectively af-
forded the corresponding products 3a , 3b, and 3c in good
yields (entries 1-3). The reaction of phenyl 1-propenyl
sulfoxide (1b) with the (diethylamino)magnesium reagent
leads to the formation of the expected product 3d along
with a small amount of 1-(phenylthio)-2-propanone (4)
(entry 4), which is thought to be derived from deproto-
nation of the sulfonium ion intermediate 9d followed by
hydrolysis of the resulting enamine 10 under the workup
and/or isolation conditions (see Scheme 3). These two
products were easily separated by preparative TLC on
silica gel. While the corresponding amino dithioacetal
3e could be obtained from the reaction of 1-methylethenyl
phenyl sulfoxide (1c) and the (diethylamino)magnesium
reagent, we found that the yield was rather lower and
that 3-(diethylamino)-2-(phenylthio)propene (5) was pro-
duced as a major product (entry 5). These products were
easily separated from each other by preparative TLC on
silica gel as well and are potentially usable for an
R-aminoacetone equivalent. Compound 5 is presumed to
(7) (a) The clear addition of the amide 7 to the vinyl sulfoxide 1
may be explained by a six-membered ring intermediate. (b) The
addition of 7 to the sulfonium ion 9 did not occur, most probably due
to the steric hindrance of 7. (c) Only a trace amount of the symmetrical
dithioacetal 3a was obtained in each reaction. This indicates that the
rate of addition of the thiolate anion to 9 was much faster than that of
formation of the â-aminoalkyl sulfide 11, the interaction of which with
9 leads to 3a .
(8) Craig, C.; Daniels, K.; Marsch, A.; Rainford, D.; Smith, A. M.
Synlett 1990, 531.
(9) Williams, R. V.; Chauhan, K. J . Chem. Soc., Chem. Commun.
1991, 1672.
(10) Shelton, J . R.; Davis, K. E. Int. J . Sulfur Chem. 1973, 3, 205;
Chem. Abstr. 1973, 79, 125593h.

Reaction of Vinyl Sulfoxides with Mg Amides
J . Org. Chem., Vol. 62, No. 23, 1997 8017
) 7.2 Hz), 2.56 (4H, q, J ) 7.2 Hz), 2.80 (2H, d, J ) 6.8 Hz),
4.33 (1H, t, J ) 6.8 Hz), 7.05-7.65 (10H, m); MS (rel intensity)
5.33 (1H, s), 7.25-7.4 (3H, m), 7.45-7.5 (2H, m); MS (rel
intensity) m/z 253 (M+, 54), 150 (100). Anal. Calcd for C13H19
-
m/z 317 (M+, 1.4), 208 (8.0), 86 (100). Anal. Calcd for C18H23
-
NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48. Found: C, 70.31; H,
8.70; N, 6.39; S, 14.19.
NS2: C, 68.09; H, 7.30; N, 4.41; S, 20.20. Found: C, 67.86; H,
7.35; N, 4.39; S, 19.97.
Compounds 3b-f, 4, and 5 were prepared following the
above-mentioned procedure. Spectral and analytical data of
these products are as follows.
2-(Die t h yla m in o)-1-p h e n yl-1,1-b is(p h e n ylt h io)e t h -
a n e (3f): Rf 0.31 (1:10 EtOAc-hexane); IR (neat) 1581, 1479,
1439, 1205, 899, 747, 689 cm-1 1H NMR (CCl4, 60 MHz) δ
;
0.78 (6H, t, J ) 7.2 Hz), 2.30 (4H, q, J ) 7.2 Hz), 3.16 (2H, s),
6.85-7.7 (15H, m); MS (rel intensity) m/z 284 [(M - SPh)+,
4.8], 256 (13), 110 (33), 77 (100). Anal. Calcd for C24H27NS2:
C, 73.24; H, 6.91; N, 3.56; S, 16.29. Found: C, 73.11; H, 6.70;
N, 3.57; S, 16.36.
2-(D iis o p r o p y la m in o )-1,1-b is (p h e n y lt h io )e t h a n e
(3b): Rf 0.43 (1:10 EtOAc-hexane); IR (neat) 1583, 1474, 1438,
1
1384, 1363, 1209, 1166, 1066, 1025, 742, 691 cm-1; H NMR
(CDCl3, 270 MHz) δ 0.95 (12H, d, J ) 6.9 Hz), 2.94 (2H, d, J
) 6.9 Hz), 2.95-3.1 (2H, m), 4.43 (1H, t, J ) 6.9 Hz), 7.2-7.3
(6H, m), 7.4-7.5 (4H, m); MS (rel intensity) m/z 236 [(M -
SPh)+, 6.3], 235 (6.3), 114 (100). Anal. Calcd for C20H27NS2:
C, 69.51; H, 7.88; N, 4.05; S, 18.56. Found: C, 69.28; H, 8.02;
N, 4.25; S, 18.30.
2-(N-Ben zyl-N-m et h yla m in o)-1,1-b is(p h en ylt h io)et h -
a n e (3c): Rf 0.33 (1:30 EtOAc-hexane); IR (neat) 1582, 1493,
1479, 1453, 1438, 1025, 737, 692 cm-1; 1H NMR (CCl4, 60 MHz)
δ 2.22 (3H, s), 2.80 (2H, d, J ) 6.8 Hz), 3.53 (2H, s), 4.43 (1H,
t, J ) 6.8 Hz), 7.05-7.55 (15H, m); MS (rel intensity) m/z 365
(M, 0.67), 218 (40), 134 (100). Anal. Calcd for C22H23NS2: C,
72.29; H, 6.34; N, 3.83; S, 17.54. Found: C, 72.15; H, 6.36; N,
3.61; S, 17.30.
1-[(4-Ch lor op h en yl)th io]-2-(d ieth yla m in o)-1-(p h en yl-
th io)eth a n e (6a ). A solution of 4-chlorobenzenethiol (0.43 g,
3 mmol) in Et2O (5 mL) was added slowly to a stirred solution
of the (diethylamino)magnesium reagent, prepared in situ from
EtMgBr (6 mmol) and diethylamine (12 mmol) in Et2O (8 mL)
under the same conditions as described above, at 0 °C under
argon. After stirring for 30 min, phenyl vinyl sulfoxide (1a )
(0.15 g, 1 mmol) was added at the same temperature. The
resulting reaction mixture was then allowed to warm to room
temperature and stirred overnight. Workup and subsequent
purification of the crude product were carried out in a similar
fashion as above to give 6a (0.22 g, 63%) as a yellow oil: Rf
0.31 (1:10 EtOAc-hexane); IR (neat) 1582, 1573, 1475, 1438,
2-(Dieth yla m in o)-1,1-bis(p h en ylth io)p r op a n e (3d ): Rf
0.31 (1:10 EtOAc-hexane); IR (neat) 1582, 1478, 1438, 1383,
1068, 1024, 743, 691 cm-1; 1H NMR (CDCl3, 270 MHz) δ 0.93
(6H, t, J ) 7.3 Hz), 1.26 (3H, d, J ) 6.5 Hz), 2.4-2.7 (4H, m),
3.16 (1H, dq, J ) 6.8, 6.5 Hz), 4.53 (1H, d, J ) 6.8 Hz), 7.15-
7.3 (6H, m), 7.35-7.45 (4H, m); MS (rel intensity) m/z 221 [(M
- PhSH)+, 8.0], 100 (100). Anal. Calcd for C19H25NS2: C,
68.83; H, 7.60; N, 4.23; S, 19.34. Found: C, 68.67; H, 7.47; N,
4.22; S, 19.45.
1
1387, 1094, 1025, 1013, 824, 746, 691 cm-1; H NMR (CCl4,
60 MHz) δ 0.93 (6H, t, J ) 7.2 Hz), 2.54 (4H, q, J ) 7.2 Hz),
2.78 (2H, d, J ) 6.4 Hz), 4.29 (1H, t, J ) 6.4 Hz), 7.0-7.5 (9H,
m); MS (rel intensity) m/z 242 [(M - SPh)+, 0.24], 208 (0.6),
144 (2.7), 86 (100). Anal. Calcd for C18H22ClNS2: C, 61.43; H,
6.30; Cl, 10.07; N, 3.98; S, 18.22. Found: C, 61.43; H, 6.19;
Cl, 9.90; N, 3.90; S, 18.39.
1-(Be n zylt h io)-2-(d ie t h yla m in o)-1-(p h e n ylt h io)e t h -
a n e (6b) was prepared following a procedure similar to that
described above for the preparation of 6a : Rf 0.42 (1:5 EtOAc-
hexane); IR (neat) 1601, 1583, 1494, 1478, 1453, 1438, 1069,
750, 693 cm-1; 1H NMR (CCl4, 60 MHz) δ 0.87 (6H, t, J ) 7.2
Hz), 2.42 (4H, q, J ) 7.2 Hz), 2.70 (2H, d, J ) 6.2 Hz), 3.87
(1H, t, J ) 6.2 Hz), 3.90 (2H, s), 7.0-7.5 (10H, m); MS (rel
intensity) m/z 331 (M+, 0.27), 274 (0.93), 220 (0.59), 209 (1.2),
110 (1.4), 91 (14), 86 (100). Anal. Calcd for C19H25NS2: C,
68.83; H, 7.60; N, 4.23; S, 19.34. Found: C, 68.57; H, 7.68; N,
4.35; S, 19.11.
1-(P h en ylth io)-2-p r op a n on e (4).11 Spectroscopic data of
this product were identical with the literature values reported
by Bordwell et al.11b
1-(Dieth yla m in o)-2,2-bis(p h en ylth io)p r op a n e (3e): Rf
0.38 (1:10 EtOAc-hexane); IR (neat) 1582, 1473, 1438, 1059,
1024, 749, 703, 692 cm-1; 1H NMR (CCl4, 60 MHz) δ 0.95 (6H,
t, J ) 7.2 Hz), 1.27 (3H, s), 2.69 (4H, q, J ) 7.2 Hz), 2.79 (2H,
s), 7.1-7.3 (6H, m), 7.4-7.6 (4H, m); MS (rel intensity) m/z
(%) 331 (M+, 8.0), 222 (59), 86 (100). Anal. Calcd for C19H25
-
NS2: C, 68.83; H, 7.60; N, 4.23; S, 19.34. Found: C, 68.69; H,
7.55; N, 4.17; S, 19.05.
3-(Dieth yla m in o)-2-(p h en ylth io)p r op en e (5): Rf 0.24 (1:
10 EtOAc-hexane); IR (neat) 1608, 1583, 1475, 1439, 1384,
1067, 748, 692 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.02 (6H, t,
J ) 7.4 Hz), 2.56 (4H, q, J ) 7.4 Hz), 3.21 (2H, s), 4.81 (1H, s),
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research No. 07651032
from the Ministry of Education, Science, Sports and
Culture, J apan. We wish to thank Mrs. Miyuki Tan-
matsu of this Department for obtaining mass spectra.
(11) (a) Werner, E. G. G. Recl. Trav. Chim. Pays-Bas 1949, 68, 1509.
(b) Bordwell, F. G.; Zhang, X.-M.; Alnajjar, M. S. J . Am. Chem. Soc.
1992, 114, 7623.
J O970741R