Reductive lithiation of alkyl phenyl sulfides in diethyl ether. A ready access to α,α-dialkylbenzyllithiums

Article abstract of DOI:10.1016/S0040-4039(03)01371-6

Diethyl ether is a convenient solvent for the conversion of benzylic phenyl sulfides to the corresponding organolithiums by an uncatalyzed reductive metalation, while catalysis by naphthalene is required to achieve the same reaction for alkyl phenyl sulfides. The addition of magnesium 2-ethoxyethoxide to solutions of unstable alkyllithiums prepared in this way provides storable reagents.

Full text of DOI:10.1016/S0040-4039(03)01371-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5633–5635
Reductive lithiation of alkyl phenyl sulfides in diethyl ether. A
ready access to a,a-dialkylbenzyllithiums
Constantinos G. Screttas,* Georgios A. Heropoulos, Maria Micha-Screttas, Barry R. Steele and
Dimitrios P. Catsoulacos
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou Avenue 48,
Athens 116 35, Greece
Received 6 May 2003; revised 22 May 2003; accepted 30 May 2003
Abstract—Diethyl ether is a convenient solvent for the conversion of benzylic phenyl sulfides to the corresponding organolithiums
by an uncatalyzed reductive metalation, while catalysis by naphthalene is required to achieve the same reaction for alkyl phenyl
sulfides. The addition of magnesium 2-ethoxyethoxide to solutions of unstable alkyllithiums prepared in this way provides storable
reagents.
© 2003 Elsevier Ltd. All rights reserved.
In a recent paper by Cohen et al.,1 it was reported that
the synthetically useful reaction of reductive lithiation1,2
can be carried out in the absence of tetrahydrofuran
(THF). The method involves generation of the radical
anion in dimethyl ether, reductive lithiation of the
sulfide in this medium and subsequent replacement of
the medium by a more appropriate solvent, e.g. diethyl
ether. Indeed, THF has conventionally been the solvent
of choice for carrying out reductive lithiations either
stoichiometrically3–5 or by arene catalysis,4 the reason
for this preference being that, in THF, concentrated
solutions of aromatic hydrocarbon radical anions can
be generated.
sulfide) 1, with lithium chips at 3–5°C for 2 h gave a
73% yield of a,a-dimethylbenzyllithium (cumyllithium)
(see Table 1, entry 3). Given that a,a-dimethylbenzyl
phenyl sulfide, when cleaved by lithium naphthalene
radical anion or by lithium metal in THF, gives the
dicumene almost exclusively,6 the above result repre-
sents a remarkable solvent effect. Cohen has very rea-
sonably attributed the failure of the reductive lithiation
in THF solvent to the coupling between the cumyl-
lithium and the cumyl phenyl sulfide,7 an explanation
that agrees with the statement that the phenylthio
group behaves like a pseudohalogen.4 In view of this
interpretation, the successful conversion of 1 to cumyl-
lithium in diethyl ether implies that, in this medium, the
coupling reaction does not become very competitive
with the lithiation reaction. Generally, sulfides of the
type ArC(R1R2)SPh, where Ar=aryl, R1,R2=aryl,
alkyl or hydrogen as well as ArCHꢀCHCH2SPh may be
reductively lithiated in diethyl ether (Eq. (1); see Table
1, entries 1–9).8
In view of Cohen’s report, the question arises as to
whether the suitability of a solvent as a medium for
carrying out reductive lithiations depends on its suit-
ability or not for generating stable solutions of, for
example, aromatic hydrocarbon radical anions. In this
letter we wish to present experimental evidence, which
demonstrates that reductive lithiation of alkyl phenyl
sulfides can be conducted in diethyl ether, i.e. in a
solvent unsuitable for generating radical anions, at least
in synthetically useful concentrations.
(1)
Rapid magnetic stirring of a diethyl ether solution of
a,a-dimethylbenzyl phenyl sulfide (cumyl phenyl
Alkyl phenyl sulfides, RSPh, however, failed to react
with lithium chips in diethyl ether, at least at a synthet-
ically convenient rate. This prompted us to try to carry
out the reaction with naphthalene catalysis. When a 1
M solution of naphthalene in anhydrous argon-satu-
rated diethyl ether was stirred with an excess of lithium
chips, a red–purple coloration developed rapidly. Titra-
Keywords: lithiation; reduction; thioethers; radical anion; magnesium
alkoxide.
* Corresponding author. Tel.: +30 210 7273876; fax: +30 210
7273877; e-mail: kskretas@eie.gr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01371-6

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C. G. Screttas et al. / Tetrahedron Letters 44 (2003) 5633–5635
Table 1. Reductive lithiation of alkylphenyl sulfides in
tuted benzyllithiums, whereas in THF styrenes undergo
anionic oligo- or polymerization.1,12
diethyl ethera
Entry
Sulfide
RLi
Yield (%)
It is of importance to note that, under naphthalene
catalysis in the presence of an excess of lithium, the
reaction leads to a mixture containing, besides the
organolithium derived from the sulfide, lithiated species
derived from naphthalene as well, the amount of which
depends on the quantity of naphthalene used. This is
somewhat puzzling since naphthalene and lithium in
diethyl ether and in the absence of sulfide, as has
already been mentioned, react only to a very small
extent. It appears, therefore, that some sort of syner-
gism is operable in the system sulfide, lithium and
naphthalene. The contamination of the desired organo-
lithium product by lithiated naphthalenes can be
avoided either by keeping the amount of catalytic naph-
thalene as low as possible or by employing a stoichio-
metric quantity of lithium. In the latter case, the
amount of naphthalene may be increased without seri-
ous problems.
1
2
3
4
5
6
7
8
PhCH(CH3)SPh
PhCH(CH3)SPh
PhC(CH3)2SPh
PhCH(CH3)Li
PhCH(CH3)Li
PhC(CH3)2Li
PhC(i-Pr)(Me)Li
PhC(i-Pr)(Me)Li
Ph2C(CH3)Li
PhCHꢀCHCH2Li
c-(CH2)4C(Ph)Li
c-(CH2)5C(Ph)Li
PhCH2CH2Li
68
83b
73
PhC(i-Pr)(Me)SPhc
PhC(i-Pr)(Me)SPhc
Ph2C(CH3)SPh
78d
90b
78
PhCHꢀCHCH2SPh
c-(CH2)4C(Ph)SPhc
c-(CH2)5C(Ph)SPh
PhCH2CH2SPh
PhCH2CH2SPh
PhCH(CH3)CH2SPh PhCH(CH3)CH2Li
73
55
60
9
10
11
12
13
14
15
89b
80b,e,f
85b
88b
80e
PhCH2CH2Li
Ph2CHCH2SPh
PhCH2SPh
Ph2CHCH2Li
PhCH2Li
p-CH3OC6H4CH2SPh p-CH3OC6H4CH2Li 84b,d,e,g
a Unless otherwise noted all sulfides and carboxylic products are
known compounds. Standard conditions: 5–10 mmol of sulfide, 40%
excess of lithium metal chips, 15–30 mL of solvent, ice–water bath
cooling, i.e. 3–8°C, reaction time 2 h. Yields are based on the
amount of isolated carboxylic acids after carboxylation.8
b In the presence of 25% naphthalene as a catalyst, stoichiometric
amount of lithium chips.
Solutions of the organolithiums prepared in diethyl
ether should be used immediately after their prepara-
tion. In order to make them storable, we studied briefly
their possible stabilization by adding magnesium 2-
ethoxyethoxide.14 In this way, carrying out the reduc-
tive lithiation of p-methoxbenzyl phenyl sulfide at room
temperature under naphthalene catalysis and in the
presence of an equimolar amount of magnesium 2-
ethoxyethoxide, an 84% yield of p-methoxyphenylacetic
acid was obtained by carboxylating the reaction mix-
ture which had subsequently been left to stand for 2.5
days. Similarly, the sulfide PhCH2CH2SPh gave an 80%
yield of 3-phenylpropionic acid after 8 days at room
temperature. In this context, the stabilization of an
otherwise unstable carbanion such as p-methoxybenzyl
is rather remarkable. Cumyl phenyl sulfide, on the
other hand, under the same conditions gave ultimately
bicumyl, although in the early stages of the reaction the
mixture was reddish colored. Even when magnesium
alkoxide is added to preformed cumyllithium the latter
is destroyed within about 1 h at room temperature as
deduced from the discharge of the color and the failure
to produce any carboxylic acid upon carboxylation. It
is of interest to note that in both cases the decay of
cumyllithium in the presence of magnesium alkoxide
leads to the formation of bicumyl. The latter compound
c New compounds, see Ref. 13.
d Reaction time: 3 h.
e In the presence of 1 mol equiv. of magnesium 2-ethoxyethoxide.
f Carboxylation after standing for 8 days at room temperature.
g Carboxylation after standing for 2.5 days at room temperature.
tion of an aliquot of such a solution indicated only a
minute (0.05 M) total alkalinity, regardless of the dura-
tion of stirring. Despite the very low concentration of
the lithium containing species, namely the dilithium
naphthalene dianion,10 it is effective in catalyzing the
conversion of alkyl phenyl sulfides to the corresponding
alkyllithiums (Eq. (2); Table 1, entries 10–13). The
greater ease of cleavability of the benzylic type sulfides
as compared to that of the alkyl phenyl sulfides, can be
reasonably attributed to the relative thermochemical
stabilities of the radicals Ar(R)2C and R which are
most probably involved in the reductive process,11 these
stabilities being a reflection of the respective CꢁSPh
bond strengths.
’
’
is obviously produced by homolysis of
a weak
(2)
carbonꢁmetal bond, probably of PhC(CH3)2ꢁ
MgOCH2CH2OEt. Cumyllithium also reacts with mer-
curic chloride and again affords bicumyl, as should be
expected. It should also be mentioned that reductive
lithiation of benzyl phenyl sulfide in diethyl ether
should be conducted in the presence of 1 equiv. of
magnesium 2-ethoxyethoxide (Table 1, entry 14). Oth-
erwise, the final product is lithiated benzyl phenyl
sulfide (Eq. (3)). The same holds for p-methoxbenzyl
phenyl sulfide (Table 1, entry 15).
The generation of organolithium reagents in diethyl
ether may provide a number of additional advantages
over THF. Alkyllithiums are more stable in diethyl
ether than in THF, thus permitting higher reaction
temperatures for their preparation. Also, the propensity
of ketones to enolize is diminished on going from THF
to Et2O, and thus higher yields of addition products
with organolithium reagents in diethyl ether may be
realized. In addition, in diethyl ether styrenes undergo
efficient addition reactions with primary, secondary and
tertiary organolithium reagents to produce a,a-substi-
(3)

C. G. Screttas et al. / Tetrahedron Letters 44 (2003) 5633–5635
5635
In summary, diethyl ether is found to be a convenient
solvent for the conversion of benzylic type phenyl
sulfides to the corresponding organolithiums by an
uncatalyzed reductive metalation. Alkyl phenyl sulfides,
however, require catalysis by naphthalene in order to
undergo reductive lithiation in the same medium.
Unstable alkyllithiums prepared in this way can be
stabilized by the addition of magnesium 2-ethoxyethox-
ide and thus be used as storable reagents.
speed for 2 h with ice–water bath cooling. The dark
orange–red solution was then carboxylated by transfer-
ring it via cannula to a large beaker containing crushed
solid CO2 and anhydrous ether. Water (150 mL) was
added to the carboxylation mixture at room temperature,
followed by 1 mL of Me2SO4 and 2 mL of 50% NaOH
solution to convert the lithium thiophenoxide to thioan-
isole. The resulting mixture was stirred for 2 h. Hexane
(100 mL) was added and the water layer separated and
washed with another 100 mL of hexane. The volume of
the water layer was reduced by rotary evaporation to ca.
50 mL, acidified with concentrated HCl and extracted
with CH2Cl2 (3×100 mL). The combined extracts were
filtered through a pad of Na2SO4 and evaporated to
constant weight. Yield 1.20 g, 73%, of a,a-
dimethylphenylacetic acid, recryst. H2O/i-PrOH, mp 77–
79°C (Lit.9 79–80°C).
Acknowledgements
The investigation was supported by the Greek General
Secretariat of Research and Technology.
For the reactions in which Mg(OCH2CH2OEt)2 was also
used, the volume of water added after the carboxylation
step was increased to 250 mL and then subsequently
reduced as above in order to ensure complete removal of
the 2-ethoxyethanol formed by hydrolysis of the alkoxide.
9. Brown, H. C.; Kim, C. J. J. Am. Chem. Soc. 1968, 90,
2082.
References
1. Cohen, T.; Kreethadumrongdat, T.; Liu, X.; Kulkarni, V.
J. Am. Chem. Soc. 2001, 123, 3478.
2. For reviews, see: (a) Yus, M.; Herrera, R. P.; Guijarro,
A. Chem. Eur. J. 2002, 8, 2574; (b) Ramon, D. J.; Yus,
M. Eur. J. Org. Chem. 2000, 225; (c) Cohen, T.; Bhupa-
thy, M. Acc. Chem. Res. 1989, 22, 152.
10. Levin, G.; Holloway, B. E.; Szwarc, M. J. Am. Chem.
Soc. 1976, 98, 5706.
11. Screttas, C. G. J. Chem. Soc., Chem. Commun. 1972, 869.
12. Wei, X.; Johnson, P.; Taylor, R. J. K. J. Chem. Soc.,
Perkin Trans. 1 2000, 1109.
3. Screttas, C. G. J. Chem. Soc., Chem. Commun. 1972, 752.
4. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978,
43, 1064.
13. New compounds gave satisfactory elemental analyses:
PhC(i-Pr)(Me)SPh: mp 52–54°C, 1H NMR (CDCl3): l
0.80 (d, 3H, C-CH3), 1.30 (d, 3H, C-CH3), 2.53 (m, 1H,
CHMe2), 7.05–7.45 (m, 10H, 2Ph); c-(CH2)4C(Ph)SPh:
1H NMR (CDCl3): l 1.83 (m, 2H, CH2), 2.03–2.26 (m,
6H, 3CH2), 6.99–7.30 (10H, 2Ph).
14. (a) Screttas, C. G.; Micha-Screttas, M. Organometallics
1984, 3, 904; (b) Screttas, C. G.; Steele, B. R. J. Org.
Chem. 1989, 54, 1013; (c) Salteris, C. S.; Kostas, I. D.;
Micha-Screttas, M.; Heropoulos, G. A.; Screttas, C. G.;
Terzis, A. J. Org. Chem. 1999, 64, 5589; (d) Kostas, I. D.;
Screttas, C. G. J. Org. Chem. 1997, 62, 5575.
5. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1979,
44, 713.
6. A report from this laboratory (Ref. 5) that cumyl phenyl
sulfide gives an 80% yield of cumyllithium, was in error
due to the erroneous transfer of data from the Table of
alkylsodium and alkylpotassium compounds to that for
alkyllithiums. See also Ref. 7.
7. Kulkarni, V.; Cohen, T. Tetrahedron 1997, 56, 12089.
8. Under an atmosphere of argon, a mixture of cumyl
phenyl sulfide (2.28 g, 10 mmol), lithium chips (0.20 g, 29
mmol) and 30 mL of anhydrous argon-saturated diethyl
ether was magnetically stirred at the maximum possible