Direct transformation of allylic and benzylic thiols, thioethers, and disulfides into organolithium compounds

Article abstract of DOI:10.1081/SCC-120021518

The reaction of allylic and benzylic thiols 1, disulfides 3, and thioethers 4 and 5 with an excess of lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5mol%) afforded the corresponding allylic and benzylic organolithium reagents via reductive cleavage of the carbon-sulfur bond. The generated organolithium compounds gave the expected products 2 by reaction with several electrophiles followed by hydrolysis with water. The reaction conditions and the lithiation procedure (stepwise of Barbier-type process) depended on the starting sulfur containing compound.

Full text of DOI:10.1081/SCC-120021518

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Direct Transformation of Allylic and Benzylic Thiols,
Thioethers, and Disulfides into Organolithium
Compounds
Miguel Yus a , Pedro Martínez a & David Guijarro a
a Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante,
Alicante, Spain
Published online: 17 Aug 2006.
To cite this article: Miguel Yus , Pedro Martínez & David Guijarro (2003): Direct Transformation of Allylic and Benzylic Thiols,
Thioethers, and Disulfides into Organolithium Compounds, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:13, 2365-2376
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2365–2376, 2003
Direct Transformation of Allylic and Benzylic
Thiols, Thioethers, and Disulfides into
Organolithium Compounds
*
Miguel Yus, Pedro Martınez, and David Guijarro
Departamento de Quımica Organica, Facultad de
Ciencias, Universidad de Alicante, Alicante, Spain
ABSTRACT
The reaction of allylic and benzylic thiols 1, disulfides 3, and
thioethers 4 and 5 with an excess of lithium and a catalytic amount
of 4,40-di-tert-butylbiphenyl (DTBB, 5 mol%) afforded the corre-
sponding allylic and benzylic organolithium reagents via reductive
cleavage of the carbon–sulfur bond. The generated organolithium
compounds gave the expected products 2 by reaction with several
electrophiles followed by hydrolysis with water. The reaction condi-
tions and the lithiation procedure (stepwise of Barbier-type process)
depended on the starting sulfur containing compound.
*Correspondence: Miguel Yus, Departamento de Quımica Organica, Facultad
de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain;
Fax: þ34-965903549; E-mail: yus@ua.es.
2365
DOI: 10.1081/SCC-120021518
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2366
Yus, Martınez, and Guijarro
Key Words: Lithium; Organolithium; Thiol; Sulfide; Disulfide;
Carbon–sulfur bond cleavage.
1. INTRODUCTION
In recent years, the chemistry of organosulfur compounds has
attracted much attention to organic chemists. Several research groups
have contributed to the development of methods of synthesis of thiols
and sulfides and to the knowledge of their reactivity.[1–3] Reductive cleav-
age of the carbon–sulfur bond in thiols may be performed by several
reagents,[4] but, to the best of our knowledge, it always leads to reduction
to the corresponding hydrocarbons. In order to achieve the functional-
ization of the carbon atom that initially was bearing the sulfur atom,
mercaptans can be transformed into alkyl halides[5] or phenyl sulfides,[6]
which are suitable precursors of alkyllithium reagents.[7,8] However, it
would be very interesting from a synthetic point of view to be able to
achieve the direct conversion of a thiol into an organolithium compound.
In the last few years, we have been using an arene-catalyzed lithia-
tion[9,10] to prepare a variety of organolithium compounds,[11–14] includ-
ing allylic and benzylic organolithium reagents.[13–16] Some years ago, we
reported on the direct transformation of allylic and benzylic alcohols into
the corresponding organolithium reagents.[15c] Since the carbon–sulfur
bond is weaker than the carbon–oxygen bond,[17] we decided to try the
same transformation from allylic and benzylic thiols, the process having
also been extended to the corresponding disulfides and thioethers.
2. RESULTS AND DISCUSSION
When benzyl mercaptan 1a (Sch. 1) was deprotonated with n-butyl-
lithium and the obtained thiolate was treated with an excess of lithium
powder and a catalytic amount of DTBB at 0ꢀC, followed by addition of
an electrophile at À30ꢀC, the expected products 2aa–2ae were obtained in
moderate to good yields (Table 1, Entries 1–5). However, when the lithia-
tion of 1-phenylethyl mercaptan 1b was carried outusing 3-pentanone or
pivalaldehyde as electrophiles, an intractable mixture of compounds was
obtained from which the expected products could not be separated.
The reaction with allyl mercaptan 1c (Sch. 1) had to be performed at
room temperature during 3 h in order to complete the reductive cleavage.
However, only a very small amount of the expected products was formed
after the addition of benzaldehyde or cyclohexanone as electrophiles. We
decided to test geranyl mercaptan 1d (Chart 1), in order to check if the

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Allylic and Benzylic Thiols, Thioethers, and Disulfides
2367
Table 1. DTBB-catalyzed lithiation of thiols 1, disulfides 3, and sulfides 4 and 5.
Producta
Entry Substrate Electrophile No.
R
E
Yield (%)b
1
2
1a
1a
1a
1a
1a
3a
3a
3a
3b
4a
4a
4b
4b
5a
5a
5a
Me3SiCl
ButCHO
PhCHO
Et2CO
2aa PhCH2
Me3Si
59
48
2ab PhCH2
2ac PhCH2
2ad PhCH2
2ae PhCH2
2aa PhCH2
2ab PhCH2
2ad PhCH2
2ba Geranyl
2ac PhCH2
2ad PhCH2
ButCHOH
PhCHOH
Et2COH
(CH2)5COH
Me3Si
3
65
43
4
5
(CH2)5CO
Me3SiCl
ButCHO
Et2CO
49
6
40c
48c
23c
38c
67
7
ButCHOH
Et2COH
Me3Si
8
9
Me3SiCl
PhCHO
Et2CO
10
11
12
13
14
15
16
PhCHOH
Et2COH
50
59
PhCHO
Prn2CO
2ca CH2¼CHCH2 PhCHOH
2cb CH2¼CHCH2 Prn2COH
35
Me3SiCl
ButCHO
Et2CO
2aa PhCH2
2ab PhCH2
2ad PhCH2
Me3Si
33c
26c
36c
ButCHOH
Et2COH
1
aAll compounds 2 were ꢀ95% pure (GLC and/or 300 MHz H NMR).
bIsolated yield after column chromatography (silica gel, hexane/ethyl acetate)
based on the starting material 1, 3, 4, or 5.
cIsolated yield based on the starting material 3 or 5 corresponding to the
stoichiometry 3 (or 5) !2 2.
Scheme 1. Reagents and conditions: (i) BunLi, THF, 20ꢀC; (ii) Li, DTBB
(5 mol %), THF, 0ꢀC (for 1a and 1b) or 20ꢀC (for 1c); (iii) E+¼ Me3SiCl,
ButCHO, PhCHO, Et2CO, (CH2)5CO, THF, À30 to 0ꢀC; (iv) H2O.
reduction of the allylic organolithium reagent was the preferred pathway
in this case. We found some problems in the preparation of 1d, since itwas
oxidized to some extent to the corresponding disulfide 3b (Chart1) during
the work-up.[18] A mixture of thiol and disulfide was obtained, which could
not be separated. This mixture was submitted to oxidation with sodium
hypochlorite and digeranyl disulfide 3b was exclusively obtained.

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2368
Yus, Martınez, and Guijarro
DTBB-catalyzed lithiation of 3b at20 ꢀC for 2.5 h, followed by
addition of trimethylsilyl chloride at À30ꢀC, led to the expected product
2ba in 38% yield based on the starting disulfide for the formation of
2 equiv. of geranyllithium (Chart 1, Sch. 2, Table 1, Entry 9, footnote
c). However, when 3-pentanone was used as electrophile, only a very small
[19]
amount of the expected alcohol 2bd (Chart1) was formed,
the major
product being the one resulting from sulfur–hydrogen exchange (GC–
MS). We also tried the lithiation of commercially available diallyl disul-
fide, but it failed. We think that the long reaction time and the high
temperature necessary to achieve the carbon–sulfur bond cleavage could
cause the decomposition of the generated allylic organolithium reagents
by proton abstraction from the reaction medium.[20] This behavior could
also be the reason for the failure of the lithiation of allyl mercaptan 1c.
Dibenzyl disulfide 3a (Sch. 2) was also submitted to the DTBB-cata-
lyzed lithiation process at 0ꢀC and, after addition of the corresponding
electrophile at À30ꢀC, the expected products 2aa, 2ab, and 2ad were
obtained in moderate yields (Sch. 2, Table 1, Entries 6–8, footnote c).
Chart 1.
Scheme 2. Reagents and conditions: (i) Li, DTBB (5 mol%), THF, 0ꢀC
(for 3a) or 20ꢀC (for 3b); (ii) E+¼ Me3SiCl, ButCHO, Et2CO, THF, À30 to
0ꢀC; (iii) H2O; (iv) Li, DTBB (5 mol%), E+¼ Me3SiCl, PhCHO, Et2CO,
(CH2)5CO, Prn CO, THF, 0ꢀC.
2

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Allylic and Benzylic Thiols, Thioethers, and Disulfides
2369
In the second part of this study, we decided to investigate if some other
sulfides different from the commonly used phenyl sulfides could be utilized
as sources of allyl- and benzyllithium. The reaction of benzyl methyl sul-
fide 4a (Sch. 2) with an excess of lithium and a catalytic amount of DTBB
in THF at0 ꢀC in the presence of benzaldehyde or 3-pentanone [Barbier-
type reaction conditions[21]] gave the expected addition products 2ac and
2ad in 67% and 50% yield, respectively (Sch. 2, Table 1, Entries 10 and 11).
Commercially available allyl methyl sulfide 4b (Sch. 2) was also tested as
starting material. The DTBB-catalyzed lithiation of 4b under the reaction
conditions described above for sulfide 4a gave the expected products in
moderate to good yields (Sch. 2, Table 1, Entries 12 and 13).
We thought that the lithiation of dibenzyl sulfide 5a (Sch. 2) could
lead us to the generation of 2 equiv. of benzyllithium. Sulfide 5a was
submitted to a DTBB-catalyzed lithiation reaction at 0ꢀC in the presence
of several electrophiles and the expected products were formed in mod-
erate yields, assuming that the stoichiometry of the reaction is 5a!2 2
(Table 1, Entries 14–16). As occurred for allyl mercaptan and diallyl
disulfide, the reductive cleavage of diallyl sulfide 5b had to be performed
ꢀ
at20 C, but it did not afford the expected addition products. A likely
explanation for this could be the decomposition of the generated allyl-
lithium by proton abstraction from the reaction medium[20] due to the
temperature used in the process.
3. CONCLUSIONS
In this article, we have proven that allylic and benzylic thiols, sulfides
and disulfides can directly be transformed into the corresponding orga-
nolithium reagents. The lithiation of allyl methyl sulfide and benzyl
methyl sulfide has proved to be a good alternative to the reductive cleav-
age of the commonly used phenyl sulfides for the generation of allyl- and
benzyllithium, respectively. Although yields are moderate, the DTBB-
catalyzed lithiation of benzylic substrates represents a new method for
the preparation of benzyllithium from non-halogenated materials.
4. EXPERIMENTAL
4.1. General
For general information, see Ref.[15 k] Thiols 1a and 1c, disulfide 3a,
sulfides 4a, 4b, 5a, and 5b, DTBB and all the electrophilic reagents were
commercially available (Aldrich, Acros) and were used as received, with

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2370
Yus, Martınez, and Guijarro
the exception of benzaldehyde, which was distilled before use. Lithium
powder was prepared according to the procedure described in Ref.[15 k]
Commercially available n-butyllithium was titrated with a 1 M solution of
sec-butanol in xylene using 1,10-phenanthroline as indicator,[22] THF was
dried over sodium benzophenone ketyl under an argon atmosphere and
distilled before use. 1-Phenylethanethiol (1b)[23] and digeranyl disulfide
(3b)[24] were prepared according to literature procedures and were fully
characterized by spectroscopic means.
4.2. Lithiation of Thiols 1 and Reaction with Electrophiles.
Isolation of Compounds 2
n-Butyllithium (0.66 mL of a 1.6 M solution in hexane, 1.1 mmol) was
added dropwise to a solution of the corresponding thiol 1 (1.0 mmol)
ꢀ
under argon at20 C. After 5 min, the resulting lithium thiolate solution
was added dropwise to a green suspension of lithium powder (70 mg,
10.0ꢀmmol) and DTBB (27 mg, 0.1 mmol) in THF (5 mL) under argon
at0 C (for 1a and 1b) or 20ꢀC (for 1c) and the reaction mixture was
stirred for 1 h (for 1a and 1b) or 3 h (for 1c). After cooling to À30ꢀC, the
corresponding electrophile (1.2 mmol) was added dropwise and the mix-
ture was stirred for ca. 3 h allowing the temperature to rise to 0ꢀC. The
reaction was then hydrolyzed with water (10 mL), acidified with 2 M HCl,
and extracted with ethyl acetate (3 ꢁ 20 mL). The combined organic
layers were successively washed with a saturated solution of NaHCO3
(5 mL), water (5 mL), and brine (5 mL), being then dried (Na2SO4). After
evaporation of the solvents (15 Torr), the resulting residue was purified
by column chromatography (silica gel, hexane/ethyl acetate) to yield
products 2aa–2ae in the yields indicated in Table 1. Compounds
2aa,[15b] 2ab,[15e] and 2ac–2ae,[15a] previously prepared in our laboratory,
were identified by comparison of their spectroscopic data with authentic
samples.
4.3. Lithiation of Disulfides 3 and Reaction with
Electrophiles. Isolation of Compounds 2
A solution of disulfide 3 (1.0 mmol) in THF (2 mL) was added drop-
wise to a green suspension of lithium powder (70 mg, 10.0ꢀmmol) and
DTBB (27 mg, 0.1 mmol) in THF (5 mL) under argon at0 C (for 3a)
or 20ꢀC (for 3b) and the reaction mixture was stirred for 1 h (for 3a) or
2.5 h (for 3b). After cooling to À30ꢀC, the corresponding electrophile
(2.4 mmol) was added dropwise and the mixture was stirred for ca. 3 h
allowing the temperature to rise to 0ꢀC. The reaction was then hydro-

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Allylic and Benzylic Thiols, Thioethers, and Disulfides
2371
lyzed with water (10 mL), acidified with 2 M HCl, and extracted with
ethyl acetate (3 ꢁ 20 mL). The combined organic layers were successively
washed with a saturated solution of NaHCO3 (5 mL), water (5 mL), and
brine (5 mL), being then dried (Na2SO4). After evaporation of the
solvents (15 Torr), the resulting residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate) to yield products 2aa, 2ab, 2ad,
and 2ba in the yields indicated in Table 1. Compounds 2aa,[15b] 2ab,[15e]
2ad,[15a] and 2ba[15c] previously prepared in our laboratory, were identi-
fied by comparison of their spectroscopic data with authentic samples.
4.4. Lithiation of Sulfides 4 and 5 Under Barbier-Type
Reaction Conditions. Isolation of Compounds 2
To a green suspension of lithium powder (70 mg, 10.0 mmol) and
DTBB (27 mg, 0.1 mmol) in THF (5 mL) under argon at0 ꢀC was
added dropwise a solution of sulfide 4 or 5 (1.0 mmol) and the corre-
sponding electrophile (2.4 mmol) in THF (2 mL) during ca. 1 h using a
syringe pump. After the addition was complete, the reaction mixture
was stirred for ca. 2 h at the same temperature. The reaction was then
hydrolyzed with water (10 mL), acidified with 2 M HCl, and extracted
with ethyl acetate (3 ꢁ 20 mL). The combined organic layers were suc-
cessively washed with a saturated solution of NaHCO3 (5 mL), water
(5 mL), and brine (5 mL), being then dried (Na2SO4). After evapora-
tion of the solvents (15 Torr) the resulting residue was purified by
column chromatography (silica gel, hexane) to yield products 2aa,
2ac, 2ad, 2ca, and 2cb in the yields indicated in Table 1.
Compounds 2aa,[15b] 2ac,[15a] 2ad,[15a] 2ca,[15a] and 2cb,[25] previously
prepared in our laboratory, were identified by comparison of their
spectroscopic data with authentic samples.
ACKNOWLEDGMENTS
This work was financially supported by the DGES from the Spanish
Ministerio de Educacion y Cultura (MEC) (project no. PB97-0133).
P. M. thanks the University of Alicante for financial support.
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2372
Yus, Martınez, and Guijarro
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Allylic and Benzylic Thiols, Thioethers, and Disulfides
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Yus, Martınez, and Guijarro
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new way for sulfur-containing organolithium compounds.
Tetrahedron 1997, 53, 5563; (c) Yus, M.; Foubelo, F. DTBB-
catalysed lithiation of 1,7-dihydrodibenzothiepin. Tetrahedron
Lett. 2001, 42, 2469.
15. Via carbon–oxygen bond cleavage: (a) Guijarro, D.; Mancheno, B.;
Yus, M. Naphthalene-catalyzed lithiation of allylic and benzylic
mesylates: a new method for allyl-, methallyl-, and benzyllithium.
Tetrahedron 1992, 48, 4593; (b) Guijarro, D.; Mancheno, B.; Yus,
M. Direct transformation of trialkyl phosphates into organo-
lithium compounds by a DTBB-catalyzed lithiation. Tetrahedron
1994, 50, 8551; (c) Alonso, E.; Guijarro, D.; Yus, M. Directrtans-
formation of allylic and benzylic alcohols or their silylated deriva-
tives into organolithium compounds. Tetrahedron 1995, 51, 11457;
(d) Alonso, E.; Ramon, D.J.; Yus, M. Simple synthesis of 5-sub-
stituted resorcinols: a revisited family of interesting bioactive mole-
cules. J. Org. Chem. 1997, 62, 417; (e) Alonso, E.; Guijarro, D.;
Martinez, P.; Ramon, D.J.; Yus, M. Generation of allylic and
benzylic organolithium reagents from the corresponding ester,
amide, carbonate, carbamate, and urea derivatives. Tetrahedron
1999, 55, 11027; Via carbon–sulfur bond cleavage: (f ) Guijarro,
D.; Yus, M. Naphthalene-catalyzed reductive desulfonylation with
lithium: alkyllithiums from alkyl phenyl sulfones. Tetrahedron
Lett. 1994, 35, 2965; (g) Alonso, E.; Guijarro, D.; Yus, M.
Arene-catalyzed reductive desulfonylation and desulfinylation reac-
tions: new routes for alkyllithiums. Tetrahedron 1995, 51, 2699;
Via reductive decyanation of nitriles: (h) Guijarro, D.; Yus, M.
Organolithium reagents by reductive decyanation of nitriles with
lithium and a catalytic amount of 4,40-di-tert-butylbiphenyl in a
barbier-type reaction. Tetrahedron 1994, 50, 3447; Via addition of
lithium to double bonds: (i) Guijarro, D.; Mancheno, B.; Yus, M.
C,O-dilithiated diarylmethanols: easy and improved preparation by
naphthalene-catalyzed lithiation of diaryl ketones and reactivity
toward electrophiles. Tetrahedron 1993, 49, 1327; (j) Guijarro,

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Allylic and Benzylic Thiols, Thioethers, and Disulfides
2375
D.; Yus, M. Naphthalene-catalyzed lithiation of phenone imines in
the presence of carbonyl compounds: preparation of 1,2-amino
alcohols. Tetrahedron 1993, 49, 7761; (k) Yus, M.; Martinez, P.;
Guijarro, D. DTBB-catalysed dilithiation of styrene and its
methyl-derivatives: introduction of two electrophilic reagents.
Tetrahedron 2001, 57, 10119.
16. We have been able to trap the allylic and benzylic organolithium
reagents generated by an arene catalyzed lithiation of allylic and
benzylic chlorides (16a) and fluorides (16b) under Barbier type
reaction conditions: (a) Gomez, C.; Huerta, F.F.; Yus, M. DTBB-
catalyzed lithiation of chlorinated benzylic chlorides, alcohols, thiols
or amines. Tetrahedron 1998, 54, 1853; (b) Guijarro, D.; Yus, M.
Generation of allylic and benzylic organolithium compounds by
fluorine-lithium exchange. J. Organomet. Chem. 2001, 624, 53.
17. Kerr, J.A. Strengths of chemical bonds. In Handbook of Chemistry
and Physics, 78th Ed.; Lide, D.R., Ed.; CRC Press: Boca Raton,
USA, 1997; 9–51.
18. It has been reported that thiols and thiolates oxidize very easily
to the corresponding disulfides even in an inert atmosphere.
Zhang, Z.; Martell, A.E.; Motekaitis, R.J.; Fu, L. Synthesis of
pentadentate mixed N/S dithiolate chelating ligands derived from
heterocycles and 2-mercaptoethylamines. Tetrahedron Lett. 1999,
40, 4615.
19. For examples of the difference in regiochemistry in the reaction of
geranyllithium with different electrophiles, see Ref.[15c,e,16b]
20. (a) Bates, R.B.; Kroposki, L.M.; Potter, D.E. Cycloreversions of
anions from tetrahydrofurans. Convenient synthesis of lithium eno-
lates of aldehydes. J. Org. Chem. 1972, 37, 560; (b) Mills, N.S.;
Shapiro, J.; Hollingsworth, M. Dianions of 2-methyl-2-butene:
evidence for the stability of a Y-aromatic species. J. Am. Chem.
Soc. 1981, 103, 1263; (c) Walfort, B.; Pandey, S.K.; Stalke, P. The
inverse podant[Li {(NBut)3S}]+ stabilises a single ethylene oxide
3
OCH¼CH2 anion as a high- and low-temperature polymorph of
[(THF)3Li3(OCH¼CH2){(NBut)3S}]. Chem. Commun. 2001, 1640.
21. (a) Monograph: Blomberg, C. The Barbier Reaction and Related
One-Step Processes; Springer-Verlag: Berlin, Germany, 1993; (b)
Review: Alonso, F.; Yus, M. Review: Recentdevelopmenst in
Barbier-type reactions. Recent Res. Des. Org. Chem. 1997, 1, 397.
22. Watson, S.C.; Eastham, J.F. Colored indicators for simple direct
titration of magnesium and lithium reagents. J. Organomet.
Chem. 1967, 9, 165.

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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Yus, Martınez, and Guijarro
23. Nishio, T. Direct conversion of alcohols into thiols. J. Chem. Soc.,
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25. Barluenga, J.; Florez, J.; Yus, M. g-Substituted secondary orga-
noalkaline compounds and their chlorinated precursors. Synthetic
applications. Synthesis 1985, 846.
Received in the Netherlands October 15, 2002