Formation of 2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes or multiply substituted o-benzoquinones from reactions of 1,4-dilithio-1,3-dienes with dimethyl oxalate

Article abstract of DOI:10.1016/j.tetlet.2004.08.181

Reactions of 1,4-dilithio-1,3-dienes with dimethyl oxalates afforded multiply substituted o-benzoquinones or stereodefined 2,6-dioxabicyclo[3.3.0]- octa-3,7-dienes in good yields.

Full text of DOI:10.1016/j.tetlet.2004.08.181

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8095–8098
Formation of 2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes or
multiply substituted o-benzoquinones from reactions of
1,4-dilithio-1,3-dienes with dimethyl oxalate
Guoliang Mao,a Jiang Lua and Zhenfeng Xia,b,
*
aKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 23 July 2004; revised 18 August 2004; accepted 24 August 2004
Available online 21September 2004
Abstract—Reactions of 1,4-dilithio-1,3-dienes with dimethyl oxalates afforded multiply substituted o-benzoquinones or stereo-
defined 2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes in good yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
O
O
Bimetallic reagents 1,4-dilithio-1,3-dienes
1
show
R
R
R
R
unprecedented reaction patterns with organic sub-
strates.1–6 In addition to novel reaction patterns, experi-
mental results have demonstrated that these dilithio
reagents are synthetically useful building blocks.1–6 As
our continuous interest in synthetic applications of these
dilithio reagents for organic syntheses, we began to
investigate reactions of these dilithio compounds with
multi-functional substrates, expecting development of
synthetic methods for otherwise unavailable complex
structures. In this communication, we would like to re-
port preliminary results obtained from reactions of
1,4-dilithio-1,3-dienes 1 with dimethyl oxalates, which
afforded multiply substituted o-benzoquinones 2 or stereo-
defined 2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes 3 in good
yields (Scheme 1).
R
R
R
R
O
O
O
R'O
OR'
Li
Li
or
R'O2C
CO2R'
O
R
R
R
R
1
2
3
Scheme 1. Reaction of 1,4-dilithio-1,3-dienes 1 with dimethyl oxalates
affording multiply substituted o-benzoquinones 2 or stereodefined 2,6-
dioxabicyclo[3.3.0]-octa-3,7-dienes 3.
bicyclo[3.3.0]-octacycles have also been found in many
biologically active compounds, and development of
methods for the synthesis of this skeleton has been of
interest.12
The dilithio reagent 1 may react with dimethyl oxalates
in 1:1 molar ratio pattern or in 1:2 molar ratio pattern.
In case of 1:1 molar ratio reaction pattern, substituted o-
benzoquinones 2 might be expected (path a, Scheme 2).
If the reaction took place in a 1:2 molar ratio pattern,
products 4 might be formed (path b, Scheme 2). Addi-
tion of dimethyl oxalates to the diethyl ether solution
of 1, generated in situ from their corresponding 1,4-di-
iodobutadienes and t-BuLi,1–6 did afford the expected
substituted 1,2-benzoquinones in good isolated yields
(Eq. 1, Table 1).13 In cases of 1a and 1b, besides the sub-
stituted o-benzoquinones 2, a different product deter-
mined to be 2,6-dioxabicyclo[3.3.0]-octa-3,7-diene 3
was obtained in 14–20% isolated yields. These two
o-Benzoquinones are useful building blocks for synthesis
of a variety of functionalized compounds.7–10 Recently,
o-quinones have been proposed to be active carcinogenic
metabolites and have been reported to react with DNA
to form both stable and depurinating adducts.11 Thus,
increasing interest has been paid to the synthesis of sub-
stituted o-benzoquinones.7–11 On the other hand, dioxa-
Keywords: Substituted o-benzoquinones; Dioxabicyclo [3.3.0]-octa-
cycles; 1,4-Dilithiobutadienes; Dimethyl oxalate.
*
Corresponding author. Tel.: +86 10 6275 9728; fax: +86 10 6275
1708; e-mail: zfxi@pku.edu.cn
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.181

8096
G. Mao et al. / Tetrahedron Letters 45 (2004) 8095–8098
Table 2. Reaction of dilithiobutadienes 1 with carboxylates in 1:2
molar ratio pattern to afford stereodefined 2,6-dioxabicyclo[3.3.0]-
O
O
OR
OR
Li
Li
+
octa-3,7-dienes 3a
R
1
R
R
R
R
O
O
1
O
O
O
+
CO2R'
R'O2C
ð2Þ
- 78 oC, 1h
O
R'O
OR'
path a
path b
1:1
1:2
R
R
R
2
(4 equiv.)
3
OLi
OMe
CO2Me
OMe
OLi
OLi
Dilithio reagent 1 OR0 Product 3
Yield (%)b
OMe
OMe
Pr
CO2Me
Pr
CO2Me
O
Pr
Pr
Pr
OLi
Li
Li
1a
OMe
OEt
58
3a
Pr
MeO2C
O
Pr
2 LiOMe
Pr
Pr
CO2Et
O
O
Pr
1a
51
50
3b
O
O
CO2Me
CO2Me
Pr
EtO2C
O
Pr
Et
Et
Et
CO2Me
O
O
Et
Et
Et
Li
Li
2
4
1b
1d
OMe
3c
Et
MeO2C
O
Et
Scheme 2. Expected reaction patterns and products of 1,4-dilithio-1,3-
dienes 1 with dimethyl oxalates.
Me
Me
CO2Me
O
Me
Me
Me
Li
Li
OMe
OEt
52
3d
Me
MeO2C
O
Me
Table 1. Reaction of dilithiobutadienes 1 with carboxylates in 1:1
molar ratio pattern to afford 1,2-benzoquinones 2a
Me
Me
CO2Et
O
Me
EtO2C
O
O
1d
3e 52
Me
O
Me
R
R'O
OR'
R
R
(2 equiv.)
Bu
Li
Li
Bu
CO2Me
O
Bu
MeO2C
Bu
Bu
- 78 oC, 1h
Li
Li
OMe
62
1e
1f
3f
ð1Þ
R
1
Bu
Bu
O
R
R
R
R
Bu
Pr
R
R
O
O
+
R'O2C
CO2R'
O
O
CO2Me
O
Pr
R
3 R
Li
Li
OMe
3g 49
2
Pr
MeO2C
O
Pr
Dilithio reagent 1
OR0
Product 2
Yield (%)b
a Reaction conditions are given in Eq. 2.
b Isolated yields.
Pr
Pr
Pr
Pr
Pr
O
Li
1a
Li
OMe
OEt
2a
46
41
Pr
O
Pr
Pr
the reactions gave the same products, but in lower yields
with about 30% of 1 unreacted.
1a
2a
As shown in Scheme 2, products 4 might be formed if
the reaction of 1 with dimethyl oxalates proceeded in
1:2 molar ratio reaction pattern. However, even with
4equiv of dimethyl oxalates, no formation of products
4 was observed. Instead, interestingly, stereodefined
2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes 3 were obtained,
though in low yields. Since this type of compounds is
important and can not be readily prepared by other
methods, we tried to improve yields of products.
Et
Et
Et
Et
Et
Et
O
O
Li
1b
Li
OMe
OEt
2b
2c
49
45
52
Et
Et
1b
2b
Pr
Pr
Pr
Pr
1c
OMe
Li
Li
O
It is obvious that products 3 are formed from the reac-
tion pattern of 1:2 molar ratio, thus concentration of di-
methyl oxalates might be very important. Higher
concentration of dimethyl oxalates should be better for
the formation of 3. Therefore, we changed the addition
order of reagents. The diethyl ether solution of 1 was
added to dimethyl oxalates in diethyl ether solution.
Indeed, this was the right order to mix these reagents
and the reaction gave stereodefined 2,6-dioxabi-
O
a Reaction conditions are given in Eq. 1.
b Isolated yields.
products 2 and 3 could be easily separated using column
chromatography. For reaction of 1c, quinone 2c was
obtained as the only product in 52% isolated yield.
When one equivalent of dimethyl oxalates was used,

G. Mao et al. / Tetrahedron Letters 45 (2004) 8095–8098
8097
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˚
Figure 1. X-ray structure of 3d. Selected bond lengths [A]: C1–C2
8. (a) Barnard, G. M.; Brown, M. A.; Mabrouk, H. E.;
McGarvey, B. R.; Tuck, D. G. Inorg. Chem. Acta 2003,
349, 142–148; (b) Meiners, F.; Haase, D.; Koch, R.; Saak,
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1.330 (2), C1–C3A 1.502 (2), C3A–C3 1.557 (3), C3–O1 1.4692 (18),
O1–C2 1.377 (2).
O
OLi
CO2Me
OMe
expected
CO2Me
CO2Me
OMe
2 LiOMe
CO2Me
O
OLi
4
OMe
CO2Me
OLi
R
R
observed
O
R'O2C
CO2R'
OLi
O
2 LiOMe
R
R
CO2Me
OMe
3
Scheme 3. A proposed mechanism for the formation of 2,6-dioxabi-
cyclo[3.3.0]-octa-3,7-dienes 3.
11. (a) Harvey, R. G. Curr. Org. Chem. 2004, 8, 303–323; (b)
Harvey, R. G.; Dai, Q.; Ran, C.; Penning, T. M. J.
Org. Chem. 2004, 69, 2024–2032, and references cited
therein.
12. Nguyen, V.-H.; Nishino, H. Tetrahedron Lett. 2004, 45,
3373–3377, and references cited therein.
cyclo[3.3.0]-octa-3,7-dienes 3 in good isolated yields (Eq.
2, Table 2).14 In cases of 1a,b, and 1e, in addition to 3,
o-benzoquinones 2 were obtained in less than 20%
yields. These two products 2 and 3 could be easily sepa-
rated using column chromatography. For reactions of
1d and 1f, 2,6-dioxabicyclo[3.3.0]-octa-3,7-dienes 3d,e,
and 3g were obtained as the only products, respectively,
in 52%, 52%, and 49% isolated yield. The structure of 3d
has been determined by single-crystal X-ray structural
analysis (Fig. 1).15
13. Typical procedure for the preparation of 1,2-benzoqui-
none 2a. To a 50mL Schlenk tube containing 2.0mmol
of 1,2,3,4-tetrapropyl-1,4-dilitho-1,3-diene 1a in 20mL
diethyl ether at ꢀ78ꢁC was added 4.0mmol of dimethyl
oxalate. After the reaction mixture was stirred at ꢀ78ꢁC
for 1h, the reaction was quenched by pouring the mixture
into saturated aqueous NH4Cl solution and extracted with
ether. The extract was washed with water and brine and
dried over MgSO4. The solvent was then evaporated in
vacuo to give a red oil, which was purified by column
chromatograph (silica gel, diethyl ether/petroleum ether in
1: 30) to afford the product 2a. Deep red liquid. Isolated
yield 46% (254mg). IR (neat) 1652cmꢀ1 (C@O); 1H NMR
(CDCl3, TMS): d 0.95 (t, J = 7.3Hz, 6H), 1.06 (t,
J = 7.3Hz, 6H), 1.28–1.64 (m, 4H), 2.16–2.43 (m, 4H);
13C NMR (CDCl3, TMS): d 14.4, 14.6, 22.9, 23.4, 28.3,
32.4, 137.6, 151.7, 180.9.
A proposed mechanism is shown in Scheme 3. Further
application of this synthetically useful method involving
other multi-functionalized substrates is in progress.
Acknowledgements
14. Typical procedure for the preparation of 2,6-dioxabicy-
clo[3.3.0]-octa-3,7-diene 3a. To a 50mL Schlenk tube
containing the solution of 8.0mmol of dimethyl oxalates
in 10mL of ethyl ether at ꢀ78ꢁC, was added dropwise the
solution of 2.0mmol 1,2,3,4-tetrapropyl-1,4-dilitho-1,3-
diene 1a in 20mL ethyl ether via a syringe. After the
reaction mixture was stirred at ꢀ78ꢁC for 1h, the
reaction was quenched by pouring the mixture into
aqueous 3N HCl solution and extracted with ether. The
extract was washed with water and brine and dried over
MgSO4. The solvent was then evaporated in vacuo to give
yellow residue, which was purified by column chromato-
graph (silica gel, diethyl ether/petroleum ether in 1:30) to
afford the product 3a. White solid, isolated yield 58%
yield (456mg), mp 86–87ꢁC. IR (KBr) 1726cmꢀ1 (C@O);
This work was partially supported by the National Nat-
ural Science Foundation of China (20172003, 20232010,
20328201), the Major State Basic Research Develop-
ment Program (G2000077502-D), and Dow Corning
Corporation. Cheung Kong Scholars Program, Qiu
Shi Science & Technologies Foundation, and BASF
are gratefully acknowledged.
References and notes
1. For a recent account on reaction chemistry of 1,4-dilithio-
1,3-dienes, see: Xi, Z. Eur. J. Org. Chem. 2004, 2773–
2781.

8098
G. Mao et al. / Tetrahedron Letters 45 (2004) 8095–8098
1H NMR (CDCl3, TMS): d 0.69–1.03 (m, 12H), 1.07–1.64
0.35 · 0.30mm was mounted on a glass fiber. X-ray data
were collected on Rigaku RAXIS RAPID IP
(m, 8H), 1.75–2.22 (m, 6H), 2.45–2.77 (m, 2H), 3.81 (s,
6H); 13C NMR (CDCl3, TMS): d 14.3, 14.6, 17.3, 22.9,
26.2, 33.4, 51.9, 98.8, 129.3, 141.4, 161.3; HRMS calcd for
C22H34O6 394.2355, found 394.2357.
a
diffractometer with graphite-monochromated Mo/Ka
˚
radiation (d = 0.71073A). C14H18O6, fw = 282.28, mono-
˚
˚
clinic, space group C2/c, a = 19.329(4)A, b = 5.9661(12)A,
3
c = 13.218(3)A, V = 1465.5(5)A ; Z = 4; Dcalc
˚
˚
15. X-ray crystallographic data for 3d: A colorless block
crystal having approximate dimensions of 0.5 ·
=
1.279gcmꢀ3; R1 = 0.0422, wR2 = 0.0922. CCDC 240171.