1,3-Dilithio-2-(diphenylmethylene)propane

Article abstract of DOI:10.1016/j.tetlet.2008.06.065

The reaction of 2,2-diphenylmethylenecyclopropane (5) with an excess of lithium and a catalytic amount of DTBB (4 mol %) in THF at -78 °C leads to the formation of dilithiated species 6-8 by reductive opening of the cyclopropane ring. Further reaction of these intermediates with different electrophiles [E = H₂O, D₂O, CH₂{double bond, long}CMeCH₂Cl, Me₃SiCl, Me₃SiCH₂Cl, t-BuCHO, Me₂CO, Et₂CO, n-Pr₂CO, i-Pr₂CO, t-Bu₂CO, (CH₂)₅CO, Ph₂CO and adamantanone] is highly regioselective, yielding exclusively the corresponding products 9, after hydrolysis with water. However, when 3-chloro-2-(chloromethyl)propene (14) is used as a dielectrophile, the cyclisation to give a six-membered ring takes place through intermediate 6, giving compound 16 as the only reaction product.

Full text of DOI:10.1016/j.tetlet.2008.06.065

Tetrahedron Letters 49 (2008) 5182–5185
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1,3-Dilithio-2-(diphenylmethylene)propane
*
*
Victor J. Lillo, Cecilia Gómez , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2,2-diphenylmethylenecyclopropane (5) with an excess of lithium and a catalytic amount
of DTBB (4 mol %) in THF at ꢀ78 °C leads to the formation of dilithiated species 6–8 by reductive opening
of the cyclopropane ring. Further reaction of these intermediates with different electrophiles [E = H2O,
D2O, CH2@CMeCH2Cl, Me3SiCl, Me3SiCH2Cl, t-BuCHO, Me2CO, Et2CO, n-Pr2CO, i-Pr2CO, t-Bu2CO, (CH2)5CO,
Ph2CO and adamantanone] is highly regioselective, yielding exclusively the corresponding products 9,
after hydrolysis with water. However, when 3-chloro-2-(chloromethyl)propene (14) is used as a
dielectrophile, the cyclisation to give a six-membered ring takes place through intermediate 6, giving
compound 16 as the only reaction product.
Received 14 April 2008
Revised 10 June 2008
Accepted 13 June 2008
Available online 18 June 2008
Dedicated to Professor Gregorio Asensio on
occasion of his 60th birthday
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dilithiopropane derivative
Cyclopropane ring opening
DTBB-catalysed lithiation
Aliphatic SE reaction
Lithium
The world of dilithium intermediates,1 which can be considered
as functionalised organolithium compounds,2 has some similarities
with that of simple organolithium reagents.3 Most of the general
methods for their preparation, including deprotonation, halogen–
lithium exchange or metal–lithium transmetallation, can be ap-
plied to generate these dianionic synthons, the main problem
being their low stability even under very mild reaction conditions.
Amongst the different possible methodologies available, the dou-
ble chlorine–lithium exchange of an adequate dichlorinated mate-
rial using an arene-catalysed lithiation4 has shown to be a practical
procedure for the in situ generation of dilithium synthons. These
species are able to react with an electrophile present in the reac-
tion medium (Barbier-type reaction conditions)5 to give the ex-
pected difunctionalised products.6 As an example, Scheme 1
shows the 4,40-di-tert-butylbiphenyl (DTBB)-catalysed lithiation
of 2,3-dichloropropene (1) in the presence of different carbonyl
compounds to yield, after hydrolysis, the corresponding unsatu-
rated diols 2. These compounds are appropriate precursors for
dioxaspiroheptanones 3, which are present in many naturally
occurring compounds.7 The formation of compounds 2 would in-
volve a dilithiated species of type 4.
Concerning the generation of dilithio derivatives by reductive
ring opening of substituted cyclopropanes, and related to the
well-known topic of Y-aromaticity in the trimethylenemethane
dianion,8–10 Maercker11 and more recently our group12 have stud-
ied the formation of dilithiated species by reaction of substituted
cyclopropanes with lithium metal or lithium in the presence of a
catalytic amount of an arene,4 respectively. In general, these reac-
tions show a series of problems associated with (a) lithium migra-
tions, (b) lithium-hydride eliminations, (c) lithium–hydrogen
exchange (hydrogen abstraction), (d) ortho-lithiation in phenyl
derivatives, and (e) carbon–carbon coupling reactions through
OH
O
R
R
R
Li
R
i,ii
Cl
Li
R
R
Cl
R
R
O
O
OH
1
4
2
4
Scheme 1. Reagents and conditions: (i) Li, DTBB (4%), R2CO, THF, 0 °C to rt; (ii) H2O.
* Corresponding authors. Fax: + 34 965 903549.
E-mail addresses: cgomez@ua.es (C. Gómez), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.065

V. J. Lillo et al. / Tetrahedron Letters 49 (2008) 5182–5185
5183
Li
Li
Li
Li
i
Li
Ph
Li
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
8
7
6
ii,iii
OH OH
X
X
X
X
X
Ph
Ph
Ph
Ph
Ph
Ph
9n
Ph
Ph
9
9'
10
Scheme 2. Reagents and conditions: (i) Li (1:7 molar ratio), DTBB (4% molar), THF, ꢀ78 °C, 1.5 h; (ii) E = H2O, D2O, CH2@CMeCH2Cl, Me3SiCl, Me3SiCH2Cl, t-BuCHO, Me2CO,
Et2CO, n-Pr2CO, i-Pr2CO, t-Bu2CO, (CH2)5CO, Ph2CO and adamantanone (2.2 equiv), ꢀ78 to ꢀ65 °C, 30 min; (iii) H2O, ꢀ65 °C to rt, 1 h.
the initially formed radical-anions. Therefore, mixtures of different
products are frequently obtained, limiting the applicability of this
methodology from a synthetic point of view.
In this Letter, we report the generation of a 2-substituted 1,3-
dilithio compound through an arene-catalysed regioselective lithi-
ation of a substituted methylenecyclopropane.
Only for very reactive electrophiles, such as H2O and D2O, we
obtained a mixture of compounds 9 and 10, resulting from the
reaction of the electrophile with the intermediates 8 and 6, respec-
tively (Table 1, entries 1 and 2). In all the other cases, the formation
of compounds 10 was not detected in the reaction crudes. For
chlorinated electrophiles (Table 1, entries 3–5) and pivalaldehyde
(Table 1, entry 6), the best results were obtained by filtering off
the excess of lithium at the end of the first step (Table 1, footnote
d). In almost all cases [except for the diisopropylketone derivative
(Table 1, entry 10 and footnote g)] we detected small amounts
(<10%, GLC) of the monosubstituted product of type 90. This prod-
uct is formed by hydrogen abstraction,13 either from intermediate
8 or after the incorporation of the first electrophilic fragment, by
lithium–hydrogen exchange from the reaction medium.13 Chro-
matographic separation of compounds 90 during purification of
products 9 was easily performed, although in the case of the hin-
dered di(tert-butyl)ketone, compound 9k0 was the only reaction
product isolated, due probably to steric problems (Table 1, entry
11). Concerning the reaction conditions, the reaction gave lower
yields and not so clean reaction crudes when the process was per-
formed in the presence of the electrophile (Barbier conditions)5 or
at higher temperatures.
The reaction of 2,2-diphenylmethylenecyclopropane (5)11d with
an excess of lithium (1:7 molar ratio) and a catalytic amount of
DTBB (1:0.08, 4% molar) in THF at ꢀ78 °C for 1.5 h led to the initial
formation of a dilithio derivative 6, which is in equilibrium with
the intermediate 8 through the allyl-delocalised species 7. After
treatment of the reaction mixture with different electrophiles
[E = H2O, D2O, CH2@CMeCH2Cl, Me3SiCl, Me3SiCH2Cl, t-BuCHO,
Me2CO, Et2CO, n-Pr2CO, i-Pr2CO, t-Bu2CO, (CH2)5CO, Ph2CO and
adamantanone; 1:2.2 molar ratio] at temperatures ranging
between ꢀ78 and ꢀ65 °C for 30 min, followed by hydrolysis with
water at ꢀ65 °C to rt, compounds 9 were obtained (Scheme 2
and Table 1).
Table 1
The X-ray structure of compound 9h (Fig. 1) confirmed all the
analytical and spectroscopic data obtained for this selected exam-
ple and for all the members of the series.
Preparation of compounds 9
Entry
Electrophile E
Producta
No.
X
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H2O
D2O
9a + 10a
9b + 10b
9c
9d
9e
9f
9g
9h
9i
9j
9k0
9l
9m
9n
H
D
85 (3:2)
79 (3:2)c
49d
CH2@CMeCH2Cl
Me3SiCl
Me3SiCH2Cl
t-BuCHO
Me2CO
Et2CO
n-Pr2CO
i-Pr2CO
CH2@CMeCH2
Me3Si
Me3SiCH2
t-BuCHOH
Me2COH
Et2COH
n-Pr2COH
i-Pr2COH
t-Bu2COH
(CH2)5COH
Ph2COH
45d
53d
55d,e
44f
48
56f
42g
t-Bu2CO
(CH2)5CO
Ph2CO
58f
46
40
h
Adamantanone
—
76f
a
All products 9 (and 10) were fully characterised by analytical (microanalysis
and/or HRMS) and spectroscopic means (IR, 1H and 13C NMR, and MS).
b
Isolated yield of pure compounds (>95% from NMR and/or GLC) after column
chromatography (silica gel, hexane–EtOAc) unless otherwise stated.
c
The content of D was found to be >95% by MS.
The excess of lithium was removed by filtration at the same temperature after
d
the lithiation step.
e
A ca. 1:1 mixture of diastereomers (NMR) was obtained.
Yield after recrystallisation from hexane/Et2O.
A 16% of the corresponding monosubstituted product 9j0 was also obtained.
f
g
h
See Scheme 2.
Figure 1. X-ray structure of compound 9h.

5184
V. J. Lillo et al. / Tetrahedron Letters 49 (2008) 5182–5185
Li
ii,iii
Li
i
Li
X
5
Li
X
Ph
Ph
11
Ph
Ph
Ph
Ph
12
13a: X = H (90%)
13b: X = D (88%)
Scheme 3. Reagents and conditions: (i) Li (1:7 molar ratio), naphthalene (4% molar), Et2O, rt, 3 h; (ii) E = H2O, D2O, ꢀ78 °C, 1 h; (iii) H2O, ꢀ78 °C to rt, 1 h.
As regards the role of the catalyst, we observed that the process
could also be carried out in the absence of DTBB under the same
reaction conditions, but reaction times were slightly longer, the
reaction crudes were not clean and yields were lower. An interest-
ing effect was observed when naphthalene14 was used instead of
DTBB and ether as the solvent at room temperature: in this case,
compounds 13 were the reaction products when using water and
deuterium oxide as electrophiles, resulting from an initial addition
of two lithium atoms to the double bond (generally proposed by
Maercker in similar cases11) to form intermediate 11.15 This spe-
cies undergoes subsequent ring opening to give the most stable
benzylic derivative 12 (Scheme 3). Compounds 13a and 13b
(>95% D from MS) were obtained in good yields after quenching
with H2O or D2O. As it can be seen, the reaction results can be con-
trolled depending on the reaction conditions: in our case (THF, low
temperature, DTBB-catalysis), only compounds 9 were isolated,
whereas isomers 13 were obtained by using Maercker conditions
(and naphthalene as the electron carrier catalyst). Finally, since
the same results (compound 13) were obtained in the absence of
any arene, we conclude that the effects of temperature16 and/or
solvent are responsible of the different behaviour observed in
Schemes 2 and 3. However, even this case being, we do not have
any simple explanation for these facts.
In the last part of this study, we tried to take advantage of the
dianionic character of intermediates 6–8 in order to obtain cyclic
compounds by reaction with a dielectrophile. Thus, once the dian-
ionic species was generated as described above (Scheme 2), it was
treated with 3-chloro-2-(chloromethyl)propene (14) and hydroly-
sed with water. Surprisingly, we obtained exclusively the corres-
ponding di-exo olefin 16, resulting from the reaction of the
intermediate 6 with the electrophile, instead of the expected cyclic
product 15 (by cyclisation with intermediate 8), (Scheme 4). So far,
we do not have any explanation to rationalise the regiochemistry
shown in Scheme 4.
Acknowledgements
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; Grants CTQ2007-65218/BQU and
Consolider Ingenio 2010, CSD2007-00006). V.L. thanks the Univer-
sity of Alicante for a predoctoral fellowship. We also thank Medal-
chemy S.L. for a gift of chemicals, especially lithium powder.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.065.
References and notes
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Cl
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+
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10096–10107. For
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(3,4)
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7
14
Ph
Ph
15
(1,3)
i
3
1
Ph
16 (57%)
Ph
Scheme 4. Reagents and conditions: (i) ꢀ78 to ꢀ50 °C, 1 h and then H2O, ꢀ50 °C to
7. Alonso, F.; Meléndez, J.; Yus, M. Helv. Chim. Acta 2002, 85, 3262–3271.
rt, 1 h.

V. J. Lillo et al. / Tetrahedron Letters 49 (2008) 5182–5185
5185
8. See, for instance: (a) Klein, J. Tetrahedron 1983, 39, 2733–2759; (b) Klein, J.
Tetrahedron 1988, 44, 503–518; (c) See also Refs. 6a,b.
conversion was achieved after 3 h in the presence of naphthalene, whereas
only ca. 30% conversion was observed in its absence.
15. One referee suggested that intermediate 6 (Scheme 2) could also be generated
from intermediate 11 through a different b-elimination process as follows:
9. For X-ray structural determination9a and reactivity of a triphenyl derivative,
see: (a) Wilhelm, D.; Dietrich, H.; Clark, T.; Mahdi, W.; Kos, A. J.; von Ragué
Schleyer, P. J. Am. Chem. Soc. 1984, 106, 7279–7280; (b) Witt, O.; Mauser, H.;
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Li
10. For studies (mainly DFT calculations) of a radical anion10a or a radical cation10b
derivative from a diphenyl derivative, see: (a) Ikeda, H.; Namai, H.; Kato, N.;
Ikeda, T. Tetrahedron Lett. 2006, 47, 1501–1504; (b) Ikeda, H.; Namai, H.; Kato,
N.; Ikeda, T. Tetrahedron Lett. 2006, 47, 1857–1860.
Li
Li
Li
Ph
Ph
Ph
Ph
11. (a) Maercker, A.; Klein, K.-D. Angew. Chem., Int. Ed. Engl. 1989, 28, 83–84; (b)
Maercker, A.; Girreser, U. Angew. Chem., Int. Ed. Engl. 1990, 29, 667–669; (c)
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Oeffner, K. S.; Girreser, U. Tetrahedron 2004, 60, 8245–8256.
11
6
We thank the referee for this interesting suggestion.
12. Gómez, C.; Lillo, V. J.; Yus, M. Tetrahedron 2007, 63, 4655–4662.
16. The same process at room temperature gave the same results but with poorer
yield, and the reaction crude was not clean. Under these conditions a proton
abstraction from the solvent decomposed partially the lithiated intermediates
(see Ref. 13).
13. The proton abstraction can occur at the
a-position of THF. See, for instance:
Clayden, J.; Yasin, S. A. New J. Chem. 2002, 26, 191–192.
14. The reaction in the absence of naphthalene11 gave the same reaction products
but much slower. For instance, by using water as the electrophile, total