Medium-dependent lithiated side products in the reductive lithiation of allylic phenyl thioethers. Diethyl ether versus tetrahydrofuran

Article abstract of DOI:10.1016/j.tetlet.2005.04.080

Diethyl ether is a convenient solvent for the reductive lithiation of allylic phenyl thioethers without the serious complications, which occur when the reaction is carried out in tetrahydrofuran.

Full text of DOI:10.1016/j.tetlet.2005.04.080

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4357–4360
Medium-dependent lithiated side products in the reductive
lithiation of allylic phenyl thioethers. Diethyl ether versus
tetrahydrofuran
Constantinos G. Screttas,* Georgios A. Heropoulos, Maria Micha-Screttas
and Barry R. Steele
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas., Constantinou Avenue 48,
Athens 116 35, Greece
Received 8 March 2005; revised 11 April 2005; accepted 20 April 2005
Available online 5 May 2005
Abstract—Diethyl ether is a convenient solvent for the reductive lithiation of allylic phenyl thioethers without the serious compli-
cations, which occur when the reaction is carried out in tetrahydrofuran.
ꢀ 2005 Elsevier Ltd. All rights reserved.
A recent report by Streiff et al.1 brought up an impor-
tant matter concerning the reductive lithiation of
allylic-type thioethers. They reported that, in an attempt
to reductively lithiate geranyl phenyl thioether under
DBB (4,40-di-tert-butylbiphenyl) catalysis and ultra-
sonic irradiation, extensive lithiation of the sulfide at
the allylic carbon occurred instead. It was shown that
the lithiated product arose from attack on the thio-
ether of 4-lithioxybutyllithium, which was derived
from the reductive ring opening of the THF solvent
(Eq. 1).
alternatively, as demonstrated by Streiff et al.,1 by 4-lithi-
oxybutyllithium. There is evidence that reductive ring
opening of THF can take place by a ꢀsilentꢁ reaction as
well. This can be inferred from the observation that
heating a solution of lithium naphthalene radical anion
in THF leads to the formation of 1- and 2-(4-hydroxy-
butyl)dihydronaphthalenes.7 This mode of attack on
THF differs from the well-known cleavage reaction
involving ordinary organolithiums. The latter reagents
react by proton abstraction from the a-position of
THF and the resulting unstable carbanion undergoes a
[2+2] retroaddition to give ethylene and the acetalde-
hyde enolate.8 We observed that, after prolonged stir-
ring of lithium metal and a catalytic amount of DBB
ð1Þ
Tetrahydrofuran, which is the conventional medium for
carrying out reductive lithiations,2–4 is a sufficiently
strong Lewis base to activate organolithiums towards
proton abstraction from carbon acids.5 Thus, in a num-
ber of instances it has been observed that benzylic2 or
allylic6 type phenyl thioethers, which exhibit consider-
able carbon acidity, may undergo metalation either by
the autogenously produced organolithium reagent or
Li+ DBB
Li
O
OLi
O
ð2Þ
n-BuOH
Keywords: Reduction; Organolithium; Metalation; Regioselectivity.
*
Li
Corresponding author. Tel.: +302107273876; fax: +30210
7273877; e-mail: kskretas@eie.gr
O
OLi
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.080

4358
C. G. Screttas et al. / Tetrahedron Letters 46 (2005) 4357–4360
in THF, all the lithium was eventually consumed and
that on hydrolysis acetaldehyde was produced along
with n-butanol. These results also imply that Li+DBBÆꢀ
decays by a ꢀsilentꢁ reductive ring opening of THF and
formation of 4-lithioxybutyllithium, which subsequently
decays by proton abstraction from THF (Eq. 2).
tion, which was a mixture of the two expected carboxylic
acids 1 and 2, (Eq. 3).
Et2O
Li
SPh
+
2Li
+
LiSPh
Li
THF
Li
SPh
2Li+C10H8
SPh
+
Cohen and co-workers have applied the reductive lithia-
tion method extensively to both a-substituted and cyclic
allylic phenyl thioethers using the lithium dimethylamino-
naphthalene radical anion in THF, apparently without
any complications.9 This lack of complications can be
reasonably explained by the higher reactivity of the
lithium dimethylaminonaphthalene radical anion as
+
ð3Þ
We also studied the reductive lithiation of carbocyclic
allylic-type phenyl thioethers and the results are summa-
rized in Table 1, (entries 8–11). The thioethers were syn-
thesized by adding PhSCH2Li to (ꢀ)-menthone, C6, C8
and C12 cycloalkanones and subsequent dehydration of
the resulting carbinols.6 In Table 1, besides the yields of
the carboxylic acids, the corresponding endo/exo ratios
are also included, following the terminology of Ref. 6
(Eq. 4).
compared to that of Li+C10H8 and the diminished
Æꢀ
carbon acidity of the thioethers used.
We have reported recently that alkyl phenyl thioethers
may be reductively lithiated in diethyl ether,10 thus
extending the range of solvents which can be used for
these reactions beyond THF and dimethyl ether.11 How-
ever, even in diethyl ether, the uncatalyzed reductive lith-
iation of benzyl phenyl thioether leads to a mixture of
PhCH2Li and PhCH(SPh)Li. Therefore, one can plausi-
bly assume that the metalated thioether derives solely
from the attack of benzyllithium on the starting thio-
ether. We reasoned that allylic phenyl thioethers, due
to their lower carbon acidity compared to the corre-
sponding benzylic compounds, as well as due to the
weaker Lewis basicity of diethyl ether, might be reduc-
tively lithiated in diethyl ether without the complications
observed when THF is employed as the reaction med-
ium. Here we report our results.
-H2O
PhSCH2Li
SPh
OH
SPh
O
E
E+
Li
2Li, Et2O
+
E
A solution of allyl phenyl sulfide in diethyl ether, on stir-
ring with an excess of lithium chips at ice bath temper-
ature (3–6 ꢁC), initially gave a yellow, cloudy and
milky mixture which eventually turned into a thick white
emulsion. Carboxylation of this mixture after 2 h affor-
ded 3-butenoic acid in up to 87% yield (see Table 1,
entry 1). High yields of allylated products were also
obtained with the electrophiles Ph2CO, Ph2SiCl2,
Bu2SnCl2 and Ph3SnCl, (entries 2–5). It is noteworthy
that the NMR spectrum of the acid indicated barely
detectable resonances in the aromatic region, implying
that the undesired metalation of the allyl phenyl sulfide
was not a competing reaction, at least to any appreciable
extent. Analogous results were obtained with geranyl
and neryl phenyl thioethers (entries 6 and 7). When
the reductive lithiation of allyl phenyl thioether was per-
formed in THF, the acid fraction after carboxylation
was found to be a very complex mixture. Even when
allyl phenyl sulfide was added to 2 equiv of preformed
lithium naphthalene radical anion at ꢀ75 to ꢀ70 ꢁC
and the mixture stirred for 10min at ꢀ80 ꢁC followed
by carboxylation, the acid fraction, in addition to 3-but-
enoic acid, contained acids derived from the lithiated
sulfide, namely CH2@CHCH(SPh)COOH, 1, and
PhSCH@CHCH2COOH, 2. In order to demonstrate
the ready metalation of the allyl phenyl sulfide by allyl-
lithium, we prepared allyllithium in diethyl ether and
added it to a THF solution of allyl phenyl sulfide. In-
deed, carboxylation of the mixture afforded an acid frac-
endo
exo
ð4Þ
In these allylic-type organolithiums, two of the three
carbon atoms that comprise the allylic system are incor-
porated into the carbocyclic ring, and therefore upon
derivatization the electrophile has two options: either
to form a bond with the exocyclic carbon giving the
so-called endo olefinic product or with the appropriate
ring carbon to afford the exo olefinic product. The ole-
finic proton(s) in the two isomers exhibit well-separated
resonances and an estimate of the ratio of isomers was
obtained by NMR analysis. More accurate endo/exo ra-
tios were obtained by GC analysis on the mixture of the
methyl esters.
It is also worth noting that it appears that, in the case of
the reductive lithiation of cycloalkenylmethyl phenyl
sulfides, the endo/exo ratio exhibits a rather marked sol-
vent dependency. In THF, the endo isomer increases lin-
early and rapidly from C5 to C8 and then less steeply
from C8 to C10, where it becomes almost the sole
product.6 If such a relationship were to hold also for
diethyl ether, then in the case of C12 we ought to have
obtained only the endo isomer. Instead, a 50–50 mixture
of the two isomers was obtained consistently over sev-
eral runs.

C. G. Screttas et al. / Tetrahedron Letters 46 (2005) 4357–4360
4359
Table 1. Products from the reductive lithiation of allylic sulfides in diethyl ether after reaction with electrophiles
Entry
1
Thioether
Electrophile
CO2
Yield (%)a
Product(s)
CO2H
SPh
87
Sn(n-Bu)2
2
2
n-Bu2SnCl2
82
SPh
C(OH)Ph2
3
4
Ph2CO
90
83
SPh
SPh
SnPh3
Ph3SnCl
SiPh2
2
5
6
7
Ph2SiCl2
CO2
94
85
60
SPh
CO2H
CO2H
SPh
SPh
CO2
CO2H
CO2H
8
CO2
85 (95/5)
SPh
CO2H
CO2H
9
CO2
71 (79/21)
SPh
CO2H
CO2H
10
CO2
77 (85/15)
SPh
CO2H
11
CO2
80 (50/50)
SPh
CO2H
a Figures in parentheses indicate the endo/exo ratio.
In conclusion, reductive lithiation of allyl phenyl sulfide
in diethyl ether provides an efficient route to high yields
of allyllithium. The reaction is devoid of complications
arising from metalation of the thioether by the organoli-
thium produced and, in addition, the procedure is less
experimentally demanding than that involving reductive
lithiation of allyl phenyl ether12 and certainly less expen-
sive than the one involving metal-metal interchange be-
tween allylstannanes and phenyllithium.13
argon, using standard vacuum line and Schlenk
techniques.
Allyl phenyl thioether was prepared by stirring at reflux
a mixture of allyl chloride, thiophenol and potassium
carbonate in ethanol for 1 h. Ethanol was removed
under vacuum, water was added to dissolve salts and the
product was taken up in CH2Cl2. The solution of the
thioether was filtered through a short pad of silica gel
covered with anhydrous sodium sulfate. Evaporation
of the solvent yielded the thioether (99% pure by GC).
Reported procedures were employed for the preparation
General experimental procedure: Reductive lithiation
reactions were carried out under an atmosphere of pure

4360
C. G. Screttas et al. / Tetrahedron Letters 46 (2005) 4357–4360
of geranyl phenyl thioether14 and neryl phenyl
thioether.15
All products are known compounds and were identi-
fied by comparison with authentic NMR spectroscopic
data.
The syntheses of 1-phenylthiomethyl-cyclohexene and
-cyclooctene and their reductive lithiation in THF have
been described previously6 and (ꢀ)-1-phenylthio-
methyl-p-menthene was prepared in an analogous
fashion.
Acknowledgements
This investigation was supported by the Greek General
Secretariat of Research and Technology.
Typical reductive lithiation and carboxylation procedure:
To 23 mL of anhydrous, argon-saturated diethyl ether
were added 1.50g, 10mmol of allyl phenyl sulfide and
0.2 g, 29 mmol of lithium chips. The resulting mixture
was stirred at ice-water bath temperature, 3–6 ꢁC, for
2 h. Within a few minutes, the mixture turned yellow,
then cloudy, milky and finally into a white thick slurry.
The slurry was forced by a stream of argon through a
cannula into a mixture of crushed solid carbon dioxide
and anhydrous ether. Water (150mL) was added to
the carboxylation mixture at room temperature, fol-
lowed by 1 mL of Me2SO4 and 2 mL of 50% aqueous
NaOH. The resulting mixture was stirred for 2 h and
then extracted with hexane (2 · 100 mL). The volume
of the water layer was reduced by rotary evaporation
almost to dryness, acidified with concentrated HCl
and the resulting slurry extracted with CH2Cl2
(3 · 300 mL). The combined extracts were filtered
through a pad of anhydrous sodium sulfate and the fil-
trate concentrated to a small volume by distilling the
solvent through a 40cm Vigreux column. Complete re-
moval of the solvent was effected by rotary evaporation
at room temperature. Yield 0.75 g, 87% (duplicate runs)
of 3-butenoic acid.
References and notes
´
1. Streiff, S.; Robeiro, N.; Desaubry, L. D. Chem. Commun.
2004, 346–347.
2. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978,
43, 1064–1071.
3. Cohen, T.; Daniewski, W. M.; Weisenfeld, R. B. Tetra-
hedron Lett. 1978, 4665–4668.
4. For reviews see: Clayden, J. In Organolithiums: Selectivity
for Synthesis, Tetrahedron Organic Chemistry Series, 2002;
Vol. 23, Chapter 4; Ramon, D. J.; Yus, M. Eur. J. Org.
Chem. 2000, 225–237; Yus, M.; Herrera, R. P.; Guijarro,
A. Chem. Eur. J. 2002, 8, 2574–2584.
5. Screttas, C. G.; Eastham, J. F. J. Am. Chem. Soc. 1965, 87,
3276–3277.
6. Screttas, C. G.; Smonou, I. C. J. Organomet. Chem. 1988,
342, 143–152.
7. Fugita, T.; Suga, K.; Watanabe, S. Synthesis 1972, 630.
8. Maercker, A.; Stumpe, R. W. Tetrahedron Lett. 1979,
3843–3846; Maercker, A. Angew. Chem., Int. Ed. Engl.
1987, 26, 972–989; Bartlett, P. D.; Tauber, C. W.; Weber,
W. P. J. Am. Chem. Soc. 1969, 91, 6362–6366; Spialter, L.;
Harris, C. W. J. Org. Chem. 1966, 31, 4263–4264; Screttas,
C. G.; Micha-Screttas, M. J. Org. Chem. 1983, 48, 153–
158.
9. Cohen, T.; Guo, B.-S. Tetrahedron 1986, 42, 2803–2808;
Guo, B.-S.; Doubleday, W.; Cohen, T. J. Am. Chem. Soc.
1987, 109, 4710–4711; Kulkarni, V.; Cohen, T. Tetrahe-
dron 1997, 56, 12089–12100.
10. Screttas, C. G.; Heropoulos, G. A.; Micha-Screttas, M.;
Steele, B. R.; Catsoulacos, D. P. Tetrahedron Lett. 2003,
44, 5633–5635.
11. Cohen, T.; Kreethadumrongdat, T.; Liu, X.; Kulkarni, V.
J. Am. Chem. Soc. 2001, 123, 3478–3483.
12. Eisch, J. J.; Jacobs, A. M. J. Org. Chem. 1963, 28, 2145–
2146.
For reactions with other electrophiles, the following typ-
ical procedure was followed: To allyllithium prepared
from 10mmol of allyl phenyl sulfide as described in
the previous paragraph was added 1.05 mL, 5 mmol,
of Ph2SiCl2 with ice bath cooling. After 0.5 h stirring,
the reaction mixture was hydrolyzed, the solvent was re-
moved by rotary evaporation and the product was taken
up in CH2Cl2. The extract was washed three times with
10% aqueous NaOH solution, filtered through a pad of
anhydrous sodium sulfate and the product freed from
solvent by rotary evaporation. The residue was re-dis-
solved in hexane, and the cloudy solution was filtered.
Hexane was removed under vacuum, leaving 1.25 g,
94%, of the title compound.
13. Yamamoto, Y.; Yatagai, H.; Maruyama, K. J. Am. Chem.
Soc. 1981, 103, 1969–1975.
14. Fukuda, T.; Irie, R.; Katsuki, T. Tetrahedron 1999, 55,
649–664.
15. Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc.
1999, 121, 6792–6797.