1,3-bis(phenylmercapto)propane and 1-chloro-3-(phenylmercapto)propane: Useful precursors for 1,3-dilithiopropane synthons in the preparation of 1,5- diols

Article abstract of DOI:10.1016/S0040-4039(00)00764-4

Treatment of 1,3-bis(phenylmercapto)propane (1) with an excess of lithium and a catalytic amount of DTBB (3.5 mol%) at -78°C followed by reaction with a carbonyl comPOund [BuCHO, PhCHO, (PhCH₂)₂CO, Et₂CO, (CH₂)₇CO, [(CH2)7CO])-menthone, Ph₂CO] leads, after hydrolysis with water, to symmetrically substituted 1,5-diols (2). Starting from 1-chloro-3- (phenylmercapto)propane (3) and by successive treatment with: (a) lithium- naphthalene at -78°C; (b) a carbonyl compound {Me₂CO, (CH₂)₅CO, (CH₂)₇CO, (-)-menthone, [CH₃(CH₂)₄]₂CO] at the same temperature; (c) lithium powder at -50°C; and (d) a second carbonyl compound ['BuCHO, PhCHO] at the same temperature and final hydrolysis with water yields unsymmetrically substituted 1,5-diols (4). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00764-4

Tetrahedron Letters 41 (2000) 5047±5051
1,3-Bis(phenylmercapto)propane and
1-chloro-3-(phenylmercapto)propane: useful precursors for
1,3-dilithiopropane synthons in the preparation of 1,5-diols
Francisco Foubelo* and Miguel Yus*
Â
Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Â
Received 20 March 2000; accepted 10 May 2000
Abstract
Treatment of 1,3-bis(phenylmercapto)propane (1) with an excess of lithium and a catalytic amount of
DTBB (3.5 mol%) at ^78ꢀC followed by reaction with a carbonyl compound [tBuCHO, PhCHO,
(PhCH2)2CO, Et2CO, (CH2)5CO, (CH2)7CO, (^)-menthone, Ph2CO] leads, after hydrolysis with water, to
symmetrically substituted 1,5-diols (2). Starting from 1-chloro-3-(phenylmercapto)propane (3) and by
successive treatment with: (a) lithium±naphthalene at ^78ꢀC; (b) a carbonyl compound {Me2CO, (CH2)5CO,
(CH2)7CO, (^)-menthone, [CH3(CH2)4]2CO} at the same temperature; (c) lithium powder at ^50ꢀC; and (d)
a second carbonyl compound [tBuCHO, PhCHO] at the same temperature and ®nal hydrolysis with water
yields unsymmetrically substituted 1,5-diols (4). # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 1,3-dilithiopropane synthon; sulfur-lithium exchange; DTBB-catalysed lithiation.
Among the methodologies to generate organolithium reagents,1 one of the most important uses
halogenated starting materials,2 mainly chlorinated and brominated compounds. An alternative
to this general method consists of using a phenylthioether:3,4 in this case it is necessary to use
lithium±arene5 as the lithiation reagent in order to get the formation of the corresponding alkyl-
lithium compound in a regioselective manner. A catalytic version6,7 of this procedure has been
recently used8 for the preparation of functionalised organolithium compounds.9 On the other
hand, when two phenylmercapto units are present in the same molecule, the stoichiometric
lithium±arene reaction works only for dibenzylic derivatives3b in order to prepare dilithium
reagents.10 In the case of aliphatic di(phenylthio) ethers only one sulfur/lithium exchange took
place.3 For the above-mentioned reasons, we decided to apply the more potent catalytic version
of the arene-promoted lithiation6,7 to this type of compound, and to study the same reaction with
chlorinated phenyl thioethers in order to discriminate both carbon/lithium bonds, so making
possible the introduction of two di€erent electrophlic fragments.11
* Corresponding authors. Fax: +34 965 903549.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00764-4

5048
The reaction of 1,3-bis(phenylmercapto)propane (1) with an excess of lithium powder and a
catalytic amount of 4,4'-di-tert-butylbiphenyl (DTBB, 3.5 mol%) in THF at ^78ꢀC for 2 h, followed
by treatment with a carbonyl compound at the same temperature and ®nal hydrolysis with water,
led to the formation of the corresponding 1,5-diols 2a±h, containing the same substituents at both
sides of the molecule (Scheme 1 and Table 1). When a prochiral carbonyl compound such as an
aldehyde was used, a 1/1 diastereomeric mixture of the corresponding diols was obtained (Table 1,
entries 1±3). However, only one diastereoisomer was isolated from (^)-menthone, resulting
probably from attack of the organolithum compound to the less hindered face of the ketone
(Table 1, entry 7).11b
Scheme 1. (i) Li, DTBB cat. (3.5 mol%), THF, ^78ꢀC; (ii) R1R2CO, ^78ꢀC; (iii) H2O, ^78 to 20ꢀC
Table 1
Preparation of compounds 2

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Concerning a possible mechanistic pathway, two alternatives are: (a) a step-by-step lithiation±
SE reaction involving intermediates I±IV; or (b) generation of a dilithiated intermediate of type V.
Since the whole process is carried out in a two-step reaction (®rst lithiation and then addition of
the electrophile in the presence of the excess of lithium), both processes can be possible. In order
to clarify this question we tried to introduce two di€erent electrophiles using the protocol shown
in Scheme 1. Thus, using pivalaldehyde and cyclohexanone, and allowing the temperature to rise
to ^50ꢀC in the second lithiation±SE process, we obtained, together with the expected `mixed'
product 4a, an important amount (34%) of the corresponding 1,5-diol 2a resulting from the
double introduction of the ®rst electrophile (Scheme 2). From this result we can conclude that both
pathways can occur simultaneously. Pathway (a) can also explain this result if cyclohexanone is
more reactive than pivalaldehyde.
Scheme 2. (i) Li, DTBB cat. (3.5 mol%), THF, ^78ꢀC; (ii) ButCHO, ^78 to ^50ꢀC; (iii) (CH2)5CO, ^50ꢀC; (iv) H2O,
^50 to 20ꢀC
Just to take advantage of the monolithiation of bis(phenylthioethers),3a we performed the
lithiation of the starting materials 1 with lithium±naphthalene at low temperature: using cyclo-
hexanone as electrophile we obtained the expected compound 5a (through the corresponding
intermediate of type II) in 40% yield (Scheme 3). In order to improve this yield we started from
the chlorinated thioether 3 and using the same protocol the yield rose to 88% (Scheme 3). The
last process is useful for the introduction of two di€erent electrophiles in the molecule of the
dianionic synthon of type V. Thus, compound 3 was lithiated with lithium±naphthalene and
reacted with a ®rst electrophile (R1R2CO) at temperatures ranging from ^78 to ^50ꢀC. Then the
Scheme 3. (i) LiC10H8, THF, ^78ꢀC; (ii) (CH2)5CO, ^78ꢀC; (iii) H2O, ^78 to 20ꢀC; (iv) R1R2CO, ^78 to ^50ꢀC; (v) Li,
^50ꢀC; (vi) R3R4CO, ^50ꢀC; (vii) H2O, ^50 to 20ꢀC

5050
reaction mixture was treated with an excess of lithium so that, under these reaction conditions
(rather similar to those of the catalytic version of the lithiation), a second lithiation occurred
giving an intermediate of type III, which, after successive treatment with a second carbonyl
compound (R3R4CO) at ^50ꢀC and hydrolysis with water at the same temperature, gave the
expected `mixed' 1,5-diols 4a±g (Scheme 3 and Table 2). Also in this case, the use of two prochiral
carbonyl compounds, such as (^)-menthone and pivalaldehyde a€orded a 4/1 diastereomeric
mixture of the corresponding diols 4e (Table 2, entry 5).
Table 2
Preparation of compounds 4
In conclusion, the use of starting materials 1 and 3 allows the generation of a dianionic synthon
of type III, which can be successfully used to generate symmetrically or unsymmetrically sub-
stituted 1,5-diols, respectively. Compounds of this type are appropriate starting materials for
cyclic ethers by intramolecular dehydration.12,13
Acknowledgements
This work was generously supported by the DGES (no. PB97-0133) from the Spanish Ministerio
de Educacion y Cultura (MEC) and by the Generalitat Valenciana (no. GV-C-CN-09-066-96).

5051
References
1. Jenkins, P. R. Organometallic Reagents in Synthesis; Oxford University Press: Oxford, 1997.
2. (a) For a recent review on the preparation of organolithium compounds from non-halogenated precursors, see:
Guijarro, D.; Yus, M. Recent Res. Devel. Org. Chem. 1998, 2, 713±744. (b) For a previous paper on this topic from
our laboratory, see: Alonso, E.; Guijarro, D.; Martõnez, P.; Ramon, D. J.; Yus, M. Tetrahedron 1999, 55, 11027±
11038.
3. For leading references, see: (a) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978, 43, 1064±1071. (b) Screttas,
C. G.; Micha-Screttas, M. J. Org. Chem. 1979, 44, 713±719. (c) Kustas, I. D.; Screttas, C. G. J. Org. Chem. 1997,
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5. For a review, see: Holy, N. L. Chem. Rev. 1974, 74, 243±277.
6. For a ®rst account, see: Ramon, D. J.; Yus, M. J. Chem. Soc., Chem. Commun. 1991, 398±400.
7. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 155±161. (b) Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2000,
225±237.
8. (a) Foubelo, F.; Gutierrez, A.; Yus, M. Synthesis 1999, 503±514 (feature article). (b) Foubelo, F.; Gutierrez, A.;
Yus, M. Tetrahedron Lett. 1999, 40, 8173±8176. (c) Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett. 1999,
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9. For reviews, see: (a) Najera, C.; Yus, M. Trends Org. Chem. 1991, 1, 155±181. (b) Najera, C.; Yus, M. Recent Res.
Devel. Org. Chem. 1997, 1, 67±96. (c) Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73±107.
10. For a recent review, see: Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1±26.
11. For a related lithiation of chlorinated phenyl ethers, see: (a) Foubelo, F.; Yus, M. Tetrahedron Lett. 1999, 40, 743±
746. (b) Foubelo, F.; Saleh, S. A.; Yus, M. J. Org. Chem. submitted.
12. See, for instance: (a) Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1995, 51, 3351±3364. (b) Almena, J.; Foubelo,
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13. (a) Typical procedure for 2a: To a cooled (^78ꢀC) blue suspension of lithium powder (105 mg, 15.0 mmol) and a
catalytic amount of DTBB (40 mg, 0.15 mmol) in THF (3 ml) was added dropwise 1,3-bis(phenylmercapto)propane
(1, 260 mg, 0.17 ml, 1.0 mmol) under nitrogen and the mixture was stirred at the same temperature for 40 min.
Then pivalaldehyde (189 mg, 0.245 ml, 2.2 mmol) was added dropwise. The mixture was stirred at the same
temperature for 1.5 h and cyclohexanone (107 mg, 0.113 ml, 1.1 mmol) was added dropwise and after 15 min it
was hydrolysed with water (5 ml). The resulting mixture was extracted with ethyl acetate (3Â15 ml). The organic
layer was dried over anhydrous sodium sulfate and evaporated (15 torr). The residue was then puri®ed by column
chromatography (silica gel: hexane:ethyl acetate) to yield 74 mg (34%) of compound 2a as a 1:1 diastereomeric
mixture and 125 mg (55%) of compound 4a. (b) Typical procedure for 4a: To a cooled (^78ꢀC) solution of 1-chloro-
3-(phenylmercapto)propane (3, 190 mg, 0.15 ml, 1.0 mmol) in THF (2 ml) was added dropwise a 0.7 M THF
solution (3.2 ml, 2.2 mmol) of lithium±naphthalene and the mixture was stirred at the same temperature for 20
min. Then cyclohexanone (107 mg, 0.113 ml, 1.1 mmol) was added dropwise at ^78ꢀC and after 10 min, lithium
powder (28 mg, 4.0 mmol) was also added at once. The reaction mixture was stirred for 1.5 h at around ^50ꢀC and
pivalaldehyde was added dropwise (95 mg, 0.123 ml, 1.1 mmol) at the same temperature. The mixture was stirred
at the same temperature for 15 min and hydrolysed and work up as for 2a to yield 168 mg (74%) of compound 4a.