Thianthrene as a source of the 1,2-benzene dianion

Article abstract of DOI:10.1016/S0040-4039(02)01661-1

The lithiation of thianthrene 1 with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 4% molar) in THF at -90°C, followed by reaction with a carbonyl compound [Bu^tCHO, Me₂CO, Et₂CO, (CH₂)₅CO] at the same temperature, gives an intermediate, which was lithitated again and reacted with a second carbonyl compound [Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO] to give, after the final hydrolysis, the expected diols 2. Compounds 2 are easily cyclised under acidic conditions (85% H₃PO₄) to yield the expected phthalans in almost quantitative yields. Finally, when after the reaction with the first carbonyl compound (PhCHO, Me₂CO), carbon dioxide was used as the second electrophile, the expected substituted phthalides 3 were obtained after acidic work-up.

Full text of DOI:10.1016/S0040-4039(02)01661-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7205–7207
Thianthrene as a source of the 1,2-benzene dianion†
Miguel Yus,* Francisco Foubelo* and Jose´ V. Ferra´ndez
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 30 July 2002; accepted 8 August 2002
Abstract—The lithiation of thianthrene 1 with lithium and a catalytic amount of 4,4%-di-tert-butylbiphenyl (DTBB, 4% molar) in
THF at −90°C, followed by reaction with a carbonyl compound [ButCHO, Me2CO, Et2CO, (CH2)5CO] at the same temperature,
gives an intermediate, which was lithitated again and reacted with a second carbonyl compound [ButCHO, PhCHO,
Ph(CH2)2CHO, Me2CO, Et2CO, (CH2)5CO] to give, after the final hydrolysis, the expected diols 2. Compounds 2 are easily
cyclised under acidic conditions (85% H3PO4) to yield the expected phthalans in almost quantitative yields. Finally, when after the
reaction with the first carbonyl compound (PhCHO, Me2CO), carbon dioxide was used as the second electrophile, the expected
substituted phthalides 3 were obtained after acidic work-up. © 2002 Elsevier Science Ltd. All rights reserved.
Carbanion chemistry is commonly associated with
organometallic reagents, especially derived from elec-
tropositive metals belonging to main groups. Although
Grignard compounds played an important role at the
begining of the former century,1 in the last 50 years
organolithium derivatives have been shown to be more
versatile due to their high reactivity under very mild
reaction conditions, both as bases and as nucleophiles.2
Concerning organolithium intermediates, the corre-
sponding dilithio derivatives belong to a special family3
because they are, in general, very unstable species com-
pared to their monometallic congeners. However, from
a synthetic point of view, these dilithio compounds are
interesting intermediates because by reaction with elec-
trophiles they are able to introduce two electrophilic
fragments in the structure, so polyfunctionalised
molecules can be eventually prepared in only one reac-
tion step. One inherent problem related to dilithiated
materials is the impossibility of discriminating between
both carbonꢀlithium bonds, so the same electrophilic
fragment is introduced at both carbanionic centers. For
this reason, it would be interesting to be able to differ-
entiate the two carbonꢀlithium bonds in order to intro-
duce two different electrophiles in the organodimetallic
intermediates. In the last few years we have applied an
arene-catalysed lithiation4 to lithiate successively in situ
two different carbonꢀheteroatom bonds (usually car-
bonꢀchlorine and carbonꢀoxygen bonds), making pos-
sible the corresponding mentioned discrimination.5 On
the other hand, the application of the arene-catalysed
lithiation4 to the reductive ring opening of some hetero-
cyclic systems6 allows the generation of different func-
tionalised organolithium compounds,7 interesting
intermediates to prepare polyfunctionalised molecules.
In this paper we apply this last methodology to the ring
opening of thianthrene in order to generate a 1,2-
dilithiobenzene synthon.
The reaction of thianthrene 1 with a blue suspension of
an excess of lithium (1:14 molar ratio) and a catalytic
amount of DTBB (1:0.15 molar ratio; ca. 4%) in THF
at −90°C for 45 min led to a solution of intermediate I,8
which was treated with different carbonyl compounds
as electrophiles [E1=ButCHO, Me2CO, Et2CO,
(CH2)5CO; 1:1.05 molar ratio] at the same temperature
for 45 min, yielding the new intermediate II.8 This
compound was then lithiated with the excess of the
lithiation mixture present in the reaction medium and
allowed to react with a second carbonyl compound9
[E2=ButCHO, PhCHO, Ph(CH2)2CHO, Me2CO,
Scheme 1. Reagents and conditions: (i) Li, DTBB cat. (4%),
THF −90°C, 45 min; (ii) E1=ButCHO, Me2CO, Et2CO,
(CH2)5CO (1.05 equiv.), −90°C, 45 min; (iii) E2=ButCHO,
PhCHO, Ph(CH2)2CHO, Me2CO, Et2CO, (CH2)5CO (1.2
equiv.), −90 to −78°C, 30 min; (iv) H2O, −78 to 20°C.
Keywords: heterocycle reductive opening; DTBB-catalysed lithiation;
dianionic synthon; cyclisation.
* Corresponding authors. Fax: +34 965 903549; e-mail: yus@ua.es
†
Dedicated to Professor W. Adam on the occasion of his 65th
birthday.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01661-1

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M. Yus et al. / Tetrahedron Letters 43 (2002) 7205–7207
In conclusion, we have reported here the generation of
a dianionic synthon of type V (or VI), making it
possible to discriminate between both carbanionic cen-
ters, so two different (or identical) electrophiles can be
used. We have used carbonyl compounds or carbon
dioxide as electrophiles so diols 3 or lactones 4 can be
Et2CO, (CH2)5CO; 1:1.2 molar ratio] at temperatures
ranging between −90 and −78°C for 10 min. In this
second step a functionalised organolithium intermediate
III is formed in situ,10 which after condensation with
the second electrophile affords the dialkoxide IV. The
final hydrolysis with water at −78 to 20°C led to the
formation of diols 2 (Scheme 1, Chart 1 and Table 1).
When a prochiral carbonyl compound such as pivalde-
hyde was used in both steps, a ca. 1:1 mixture of
diastereomers was obtained, which could be separated
by column chromatography (Table 1, entry 1 and foot-
note c).
Some diols 2 (2d,e,h,i) were cyclised under acidic condi-
tions (85% H3PO4 under toluene reflux),11 so substi-
tuted phthalans 3 were obtained practically with
quantitative yields (Scheme 2).
Scheme 2. Reagents and conditions: (i) 85% H3PO4, PhMe
reflux, 2 h.
Finally, we studied the use of carbon dioxide as the
second electrophile in order to synthetise lactones.12
Thus, when the reaction shown in Scheme 1 was carried
out with benzaldehyde or acetone as the first elec-
trophile and next, the reaction was allowed to warm to
−70°C for 45 min, a solution of the corresponding
intermediates of type III was generated. After bubbling
carbon dioxide at the same temperature for 15 min,
and final hydrolysis under acidic conditions, the
expected substituted phthalides 4a,b were isolated
(Scheme 3).
Scheme 3. Reagents and conditions: (i) Li, DTBB cat. (4%),
THF −90°C, 45 min; (ii) E1=PhCHO, Me2CO (1.05 equiv.),
−90°C, 45 min; (iii) CO2, −70°C, 15 min; (iv) H2O, −70 to
20°C, then 3 M HCl.
Chart 1. Intermediates I–IV proposed.
Table 1. Preparation of compounds 2 from thianthrene 1
Entry
Electrophile E1
Electrophile E2
Product 2a
No.
X1
X2
Yield (%)b
1
2
3
4
5
6
7
8
9
ButCHO
Me2CO
Me2CO
Me2CO
Me2CO
Me2CO
Me2CO
Et2CO
ButCHO
ButCHO
PhCHO
Ph(CH2)2CHO
Me2CO
Et2CO
(CH2)5CO
Et2CO
2a
2b
2c
2d
2e
2f
2g
2h
2i
ButCHOH
Me2COH
Me2COH
Me2COH
Me2COH
Me2COH
Me2COH
Et2COH
ButCHOH
ButCHOH
PhCHOH
Ph(CH2)2CHOH
Me2COH
Et2COH
(CH2)5COH
Et2COH
68c
81
76
58
64
55
71
47
60
(CH2)5CO
(CH2)5CO
(CH2)5COH
(CH2)5COH
a All compounds 2 were >95% pure (GLC and for 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C
NMR, and MS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting material 1.
c A ca. 1:1 mixture of diastereomers was obtained (GLC), which was separated by column chromatography (silica gel, hexane/ethyl acetate) giving
35+33% of both diastereomers.

M. Yus et al. / Tetrahedron Letters 43 (2002) 7205–7207
7207
easily prepared. In addition, cyclization of some diols 2
under acidic conditions affords substituted phthalans 3.
3. For reviews, see: (a) Maercker, A. In Ref. 2b, Chapter 11;
(b) Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7,
1–26.
4. For the first account of this topic from our group, see: (a)
Yus, M.; Ramo´n, D. J. J. Chem. Soc., Chem. Commun.
1991, 398–400. For reviews, see: (b) Yus, M. Chem. Soc.
Rev. 1996, 25, 155–161; (c) Ramo´n, D. J.; Yus, M. Eur. J.
Org. Chem. 2000, 225–237; (d) Yus, M. Synlett 2001,
1197–1205; (e) Yus, M.; Ramo´n, D. J. Latv. J. Chem.
2002, 79–92. For mechanistic studies, see: (f) Yus, M.;
Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2001, 42,
3455–3458; (g) Yus, M.; Herrera, R. P.; Guijarro, A.
Chem. Eur. J. 2000, 8, 2574–2584. For a polymer sup-
ported arene-catalysed version of this reaction, see: (h)
Go´mez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39,
1397–1400; (i) Go´mez, C.; Ruiz, S.; Yus, M. Tetrahedron
1999, 55, 7017–7026; (j) Arnauld, T.; Barrett, A. G. M.;
Hopkins, B. T. Tetrahedron Lett. 2002, 43, 1081–1083; (k)
Yus, M.; Go´mez, C.; Candela, P. Tetrahedron 2002, 58,
6207–6210. From a previous paper on this topic from our
laboratory, see: (e) Yus, M.; Ramo´n, D. J.; Go´mez, I.
Tetrahedron 2002, 58, 5163–5172.
Typical procedure for compounds 2: To a blue suspen-
sion of lithium powder (100 mg, 14 mmol) an DTBB
(40 mg, 0.15 mmol) in THF (4 mL) was added thi-
anthrene (430 mg, 2 mmol) at −90°C, and the resulting
mixture was stirred for 45 min at the same temperature.
Then a carbonyl compound (2.1 mmol) was added and
it was stirred for 45 min at −90°C. The second carbonyl
compound (2.4 mmol) was then added allowing the
temperature to rise to −78°C for 30 min, the resulting
mixture was then hydrolysed with water (10 mL). After
extracting with ether (3×20 mL), the organic layer was
dried over Na2SO4 and evaporated (15 Torr) giving a
residue, which was purified by column chromatography
(silica gel, hexane/ethyl acetate) to yield the pure title
compounds 2.
5. See, for instance: (a) Alonso, F.; Lorenzo, E.; Yus, M.
Tetrahedron Lett. 1998, 39, 3303–3306; (b) Foubelo, F.;
Yus, M. Tetrahedron Lett. 1999, 40, 743–746; (c)
Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron Lett. 2000,
41, 1661–1665; (d) Foubelo, F.; Saleh, S. A.; Yus, M. J.
Org. Chem. 2000, 65, 3478–3483; (e) Foubelo, F.; Yus,
M. Tetrahedron Lett. 2000, 41, 5047–5051.
Acknowledgements
6. For a review, see: (a) Yus, M.; Foubelo, F. Rev. Het-
eroatom Chem. 1997, 17, 73–107. For a previous paper on
this topic from our laboratory, see: (b) Yus, M.; Foubelo,
F.; Ferra´ndez, J. V. Chem. Lett. 2002, 726–727.
7. For reviews, see: (a) Na´jera, C.; Yus, M. Trends Org.
Chem. 1991, 2, 155–181; (b) Na´jera, C.; Yus, M. Recent
Res. Devel. Org. Chem. 1997, 1, 67–96; (c) Na´jera, C.;
Yus, M. Curr. Org. Chem., in press. For a more general
review, see: (d) Boudier, A.; Bromm, L. O.; Lotz, M.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414–4435.
8. The formation of intermediates I and II was demon-
strated by hydrolysis of both systems giving the expected
compounds resulting from a lithium–hydrogen exchange
(see Ref. 6b).
9. The reaction with the second electrophile could take
place either in a two-step process (tandem lithiation–SE
reaction) or in a Barbier-type process (lithiation in the
presence of the electrophile). For a monograph, see: (a)
Blomberg, C. The Barbier Reaction and Related Pro-
cesses; Springer: Berlin, 1993. For a review, see: (b)
Alonso, F.; Yus, M. Recent Res. Devel. Org. Chem. 1997,
1, 397–436.
This work was generously supported by the Direccio´n
General de Investigacio´n of the current Spanish Minis-
terio de Educacio´n, Cultura y Deportes (MECD; grant
no. PB97-0133). J.V.F. thanks the Generalitat Valen-
ciana for a scholarship.
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