A general thiolation of magnesium organometallics using tetramethylthiuram disulfide

Article abstract of DOI:10.1055/s-2005-917115

The reaction of various functionalized aryl and heteroaryl bromides with i-PrMgCl·LiCl produces highly reactive Grignard reagents complexed by LiCl, which react with tetramethylthiuram disulfide [(Me₂NCS ₂)₂] leading to th

Full text of DOI:10.1055/s-2005-917115

LETTER
2691
A General Thiolation of Magnesium Organometallics Using
Tetramethylthiuram Disulfide
A
G
eneral Thiolati
r
on of
M
k
agnesium
O
r
a
ganometall
d
ic
s
y Krasovskiy, Andrey Gavryushin, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 16 August 2005
S
Abstract: The reaction of various functionalized aryl and heteroar-
Me2N
S
S
yl bromides with i-PrMgCl·LiCl produces highly reactive Grignard
reagents complexed by LiCl, which react with tetramethylthiuram
disulfide [(Me2NCS2)2] leading to the corresponding dithio-
carbamates in excellent yields. Various transformations of the
dithiocarbamates to thiols, thiol salts or thioethers have been
demonstrated.
2
i-PrMgCl·LiCl
3
FG-Ar-Br
FG-Ar-MgCl·LiCl
FG-Ar-S
NMe2
THF
THF–CH2Cl2
0 °C, 2 h
1
4a–n: 81–96%
2
Scheme 1
Key words: Grignard reactions, sulfur, chirality, lithium chloride,
tetramethylthiuram disulfide
Table 1 Products of Type 4 Obtained by the Reaction of Poly-
functional Arylmagnesium Reagents with TMTD
Entry Grignard reagenta
Product of type 4
Yield
(%)b
Many aromatic and heteroaromatic thio derivatives have
biological activities and their synthesis has recently at-
tracted a lot of attention.1,2 A number of new copper- and
palladium-catalyzed aryl–sulfur bond formation reactions
have been described.2 Recently, we have reported a gen-
eral preparation of functionalized unsaturated Grignard
reagents using either an I–Mg3 or a Br–Mg4 exchange
reaction. The Br–Mg exchange is of special interest since
inexpensive aryl bromides can be used as precursors. It is
best performed with i-PrMgCl·LiCl in THF and converts
functionalized aryl bromides of type 1 (FG-ArBr) into
Grignard reagents (FG-ArMgCl·LiCl, 2).
1
2
84
F3C
MgY
F3C
S
N
S
2a
4a
91
O
O
O
O
S
N
MgY
S
2b
4b
Tetramethylthiuram disulfide (3, TMTD), a cheap and
commercially available reagent,5 could possibly serve as
a convenient precursor for the synthesis of various aryl
dimethyldithiocarbamates, since disulfides react usually
well with organometallic reagents and the dimethyldithio-
carbamoyl group may be converted further into a wide
range of thio derivatives. Surprisingly, there is a single re-
port concerning the reaction of TMTD with aryl Grignard
and the only example, phenyldimethyldithiocarbamate,
was obtained in 26% yield.6 Satisfactory results were ob-
tained only with more reactive and therefore not bearing
any functional groups organolithium reagents.6c–f The
reaction of Grignard reagents with elemental sulfur is
slow and not compatible with any functional groups, so it
also cannot be a general method for the preparation of
sulfur compounds from organometallic species. Herein,
we wish to report that the reaction between 3 (TMTD) and
Grignard reagents of type 2 (complexed with LiCl)7
provides functionalized aryl- and heteroaryl-N,N-di-
methyldithiocarbamates of type 4 in excellent yields
(Scheme 1 and Table 1).
3
88
O
O
MgY
S
N
S
2c
4c
4
5
83
94
MgY
S
N
S
2dc
Br
4d
MgY
S
N
S
2e
Br
4e
6
89
Br
Br
S
N
MgY
S
4f
2f
SYNLETT 2005, No. 17, pp 2691–2693
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0
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Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917115; Art ID: G25605ST
© Georg Thieme Verlag Stuttgart · New York

2692
A. Krasovskiy et al.
LETTER
Table 1 Products of Type 4 Obtained by the Reaction of Poly-
functional Arylmagnesium Reagents with TMTD (continued)
These thio derivatives 4 can be easily converted into
various sulfur-containing products by simple transforma-
tions shown below.
Entry Grignard reagenta
7
Product of type 4
Yield
(%)b
Thus, the reaction of 3-bromotrifluoromethylbenzene
(1a) with i-PrMgCl·LiCl (r.t., 1.5 h) affords the corre-
sponding Grignard reagent (2a; entry 1 of Table 1). Its re-
action at 0 °C with a CH2Cl2 solution of TMTD (3)
furnishes after two hours the dithiocarbamate 4a in 84%
yield. The presence of LiCl is essential for a high yield.
The role of LiCl is to increase the Grignard reagents reac-
tivity as well as to ensure a homogeneous reaction mix-
ture. The presence of an ortho-functionality as for the
arylmagnesium reagent 2b,c does not interfere and the
corresponding dithiocarbamates 4b,c are obtained in
excellent yields (88–91%; entries 2 and 3). The sterically
hindered mesitylmagnesium derivative 2d prepared by
the direct reaction of mesityl bromide with magnesium
turnings and LiCl in THF reacts as expected, providing
the thio derivative 4d in 83% yield (entry 4). Dibromo- or
diiodo-aromatics react selectively with i-PrMgCl·LiCl
(1.05 equiv) and afford the mono-Grignard reagents 2e–g.
Their reaction with TMTD (3) furnishes the bromo- and
iodo-substituted dithiocarbamates 4e–g in 81–94% yield
(entries 5–7). Polycyclic aromatic magnesium reagents
such as 2h (entry 8) and functionalized aryl magnesium
derivatives such as 2i and 2j bearing an ester or a nitrile
function provide the desired products 4h–j in 87–95%
yield (entries 8–10). Heterocyclic Grignard reagents are
also readily available via a Br–Mg exchange. Either elec-
tron-rich heterocycles such as 3-bromobenzothiophene
(1k) and 2-bromothiophene (1l) or an electron-poor
heterocyclic compound such as 3-bromopyridine (1m) are
converted in high yields to the corresponding Grignard
reagents (2k–m). Their reaction with TMTD (3) furnishes
the thio derivatives 4k–m in 92–96% yield (entries 11–
13). Interestingly, indole can be directly metalated by i-
PrMgCl·LiCl in THF and the resulting magnesium amide
2n (entry 14) reacts with TMTD in position 3, providing
the dithiocarbamate 4n in 92% yield. Thio derivatives are
also important ligands in asymmetric metal catalysis.6d,8
81
89
95
I
I
MgY
S
N
S
S
2gd
4g
8
N
MgY
S
2h
4h
9
MgY
S
S
EtO
EtO
N
O
O
2id
4i
10
11
87
93
CN
CN
MgY
S
N
S
S
2j
4j
MgY
N
S
S
2k
S
4k
4l
12
13
96
92
S
MgY
MgY
S
N
S
S
N
N
S
2l
S
Herein, we wish to report the synthesis of an interesting
binaphthyl-derived chiral ligand starting from (R)-io-
dohydroxybinaphthyl 5 (>99% ee).9 Thus, the reaction of
unprotected 5 with i-PrMgCl·LiCl (2.5 equiv, 0–25 °C, 3
h) provides the magnesium reagent 6 with the retention of
the axial chirality. Its reaction with TMTD (3) leads to the
chiral dithiocarbamate 7 with >99% ee (as indicated by
chiral HPLC analysis) and in 78% yield (Scheme 2).
N
2m
4m
14
92
N
S
N
S
MgY
2ne
N
H
Finally, the dithiocarbamates prepared by this method can
be easily converted into various thio derivatives. The
treatment of 4d with MeLi (0–20 °C, 12 h) followed by
aqueous work up provides mesitylthiol (8) in 83% yield.
The reaction of the heterocyclic dithiocarbamate 4l with
ethylenediamine (EDA, 20 °C, 24 h) followed by reaction
with benzyl chloride affords the thioether 9 in 84% yield.
The potassium thiolate 10 is obtained in almost quantita-
tive yield by the reaction of 4m with KOH in EtOH
4n
a Y = MgCl·LiCl.
b Isolated yield of analytically pure product.
c This Grignard reagent was prepared by the direct insertion of Mg
turnings to the corresponding bromide.
d The Grignard reagent was prepared by the reaction of the
corresponding aryl iodide with i-PrMgCl·LiCl.
e Indole was directly metalated by i-PrMgCl·LiCl.
Synlett 2005, No. 17, 2691–2693 © Thieme Stuttgart · New York

LETTER
A General Thiolation of Magnesium Organometallics
2693
(2) (a) Banwell, M. G.; Flynn, B.; Hochlers, D. C. R. Chem.
Commun. 1997, 2259. (b) Banwell, M. G.; Flynn, B. L.;
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Int. Ed. 2003, 42, 4302; Angew. Chem. 2003, 115, 4438.
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3333.
S
Me2N
S
2
i-PrMgCl·LiCl
OH
I
OMgCl·LiCl
MgCl·LiCl
3
2.5 equiv
0 °C to r.t., 3 h
THF–CH2Cl2
r.t., 2 h
5: >99% ee
6
OH
S
N
S
(5) The price of tetramethylthiuram disulfide is 30 Euro per kg
(Aldrich).
7: 78%; >99% ee
Scheme 2
(6) (a) Greenwell, J. R. J. Org. Chem. 1970, 35, 1500. (b) Jen,
K.-Y.; Cava, M. P. Tetrahedron Lett. 1982, 23, 2001.
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H. Jr. Organometallics 1998, 7, 825. (e) Laurence, L. M.;
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R.; Sulsky, R. B.; DiMarco, J. D.; Gougoukas, J. Z.; Beyer,
B. D.; Taylor, S. C.; Lan, S.-J.; Ciosek, C. P. Jr.; Harrity, T.
W.; Jolibois, K. G.; Knuselman, L. K.; Slusarchyk, D. A. J.
Am. Chem. Soc. 1996, 118, 11668. (f) Priefer, R.; Lee, Y. J.;
Barrios, F.; Wosmick, J. H.; Lebuis, A.-M.; Fasrell, P. G.;
Harpp, D. N. J. Am. Chem. Soc. 2002, 124, 5626.
(25 °C, 8 h). The 3-thiolated indole 4n is converted to the
thioether 11 by the reaction with EDA (50 °C, 2 h) fol-
lowed by the alkylation with butyl iodide (25 °C, 8 h, 77%
yield, Scheme 3).
SH
1) MeLi
2) H3O+
1) EDA
2) BnCl
4d
4l
SBn
S
(7) The complexation with LiCl enhanced the reactivity of the
organomagnesium reagent by generating in situ an ate-
8: 83%
9: 84%
–
species (ArMgCl2 Li+): (a) Farkas, J. J.; Stoudt, S. J.;
SBu
Hanawalt, E. M.; Pajerski, A. D.; Richey, H. G. J.
Organometallics 2004, 23, 423. (b) Hanawalt, E. M.;
Farkas, J. J.; Richey, H. G. J. Organometallics 2004, 23,
416.
SK
KOH
1) EDA
2) BuI
4m
4n
EtOH
N
N
H
10: 95%
(8) (a) Knotter, D. M.; Grove, D. M.; Smeets, W. J. J.; Spek, A.
L.; Van Koten, G. J. Am. Chem. Soc. 1992, 114, 3400.
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Bäckvall, J.-E.; Van Koten, G. Tetrahedron Lett. 1994, 35,
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(9) The iodonaphthol derivative 5 has been obtained from the
corresponding PhMe2Si derivative by treatment with ICl.
(10) We have treated also different alkyl magnesium compounds
with TMTD in the presence of LiCl and have obtained
corresponding thioderivates in excellent yields.
11: 77%
Scheme 3
In summary, we have shown that a wide range of aryl and
heteroaryl magnesium reagents react in the presence of
LiCl (1 equiv) with TMTD (3) affording the correspond-
ing dithiocarbamates in excellent yields. Due to the mild
conditions various functional groups are compatible with
this reaction. The dithiocarbamate function can be readily
converted into a thiol, a thiol salt or a thioether. So, this is
obviously facile, cheap and general10 method for the prep-
aration of the variety of sulfur-containing compounds
starting from easily accessible Grignard reagents. Exten-
sions of this method are currently being developed in our
laboratories.11
(11) Typical Procedure: Preparation of 3-Trifluoromethyl-
phenyl Dimethyldithiocarbamate (4a).
A 25 mL Schlenk flask containing a i-PrMgCl·LiCl solution
(10.5 mmol, 5.25 mL of 2.0 M solution in THF) was cooled
to 0 °C, and 3-bromotrifluoromethylbenzene (10.0 mmol,
2.25 g) was added slowly at this temperature. The mixture
was allowed to reach r.t. within 1.5 h. The exchange
completion was determined by the GC analysis of an aliquot.
The reaction mixture was cooled again to 0 °C and
tetramethylthiuram disulfide (3, 9.5 mmol, 2.28 g) in dry
CH2Cl2 (9.5 mL) was added at this temperature. After 2 h at
r.t., the mixture was poured into sat. NH4Cl solution (50
mL), the aqueous phase was extracted with CH2Cl2, the
combined organic phases dried (MgSO4), evaporated in
vacuo and the residue recrystallized from CH2Cl2–heptane.
Yield 2.12 g (84%), mp 83–84 °C.
Acknowledgment
We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We thank Chemetall
GmbH (Frankfurt), BASF AG (Ludwigshafen) and Lanxess AG for
generous gifts of chemicals.
References
(1) Solladié, G. In Comprehensive Organic Synthesis, Vol. 6;
Trost, B. M.; Fleming, I.; Winterfeld, E., Eds.; Pergamon
Press: Oxford, 1991, 133–170.
Synlett 2005, No. 17, 2691–2693 © Thieme Stuttgart · New York