Concise synthesis of multiply substituted stereodefined cis,cis-2,4-diene-1,6-dials, cis,cis-2,4-diene-1,6-diols and further applications

Article abstract of DOI:10.1016/j.tetlet.2005.06.003

Reactions of 1,4-dilithio-1,3-dienes with DMF afforded multiply substituted stereodefined cis,cis-2,4-diene-1,6-dials in high yields. Treatment of these 1,6-dials with LiAlH₄ or RLi resulted in the formation of their corresponding 1,6-diols. These bifunctional compounds, cis,cis-2,4-diene-1,6- dials and -1,6-diols are otherwise not readily available. Further reaction of these 1,6-diols with an aldehyde catalyzed by strong acids led to the formation of oxacycles of novel structures.

Full text of DOI:10.1016/j.tetlet.2005.06.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5369–5372
Concise synthesis of multiply substituted stereodefined
cis,cis-2,4-diene-1,6-dials, cis,cis-2,4-diene-1,6-diols
and further applications
Guoliang Mao,a Congyang Wang,a Jinglong Chen,a Ayako Muramatsub and
Zhenfeng Xia,c,
*
aKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry,
Peking University, Beijing 100871, China
bDepartment of Chemistry, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received 12 April 2005; revised 30 May 2005; accepted 1 June 2005
Abstract—Reactions of 1,4-dilithio-1,3-dienes with DMF afforded multiply substituted stereodefined cis,cis-2,4-diene-1,6-dials in
high yields. Treatment of these 1,6-dials with LiAlH4 or RLi resulted in the formation of their corresponding 1,6-diols. These bifunc-
tional compounds, cis,cis-2,4-diene-1,6-dials and -1,6-diols are otherwise not readily available. Further reaction of these 1,6-diols
with an aldehyde catalyzed by strong acids led to the formation of oxacycles of novel structures.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Conjugated organic systems have attracted much atten-
tion since new materials and functional structures can be
expected. 2,4-Diene-1,6-bis-electrophile (Fig. 1), which
contains a butadienyl conjugated skeleton and two ter-
minal functional groups to be manipulated, represents
one of the useful building units for preparation of both
cyclic and linear conjugated compounds.1–7 As part of our
continuing interest in synthetic applications of 1,3-buta-
dienyl 1,4-dilithio reagents,8–16 we began to investigate
reactions of these dilithio compounds with easily avail-
able organic substrates, expecting development of syn-
thetic methods for 2,4-diene-1,6-bis-electrophiles,
which are very useful but otherwise not readily avail-
able. In this communication, we would like to report
preliminary results obtained from reactions of 1,4-di-
lithio-1,3-dienes with DMF, which afforded multiply
Electrophile
Electrophile
substituted
stereodefined
cis,cis-2,4-diene-1,6-dials
(1, Fig. 1) in high yields. Further transformation of
these 1,6-dials afforded multiply substituted stereo-
defined cis,cis-2,4-diene-1,6-diols (2, Fig. 1), and furan
derivatives of novel structure.
cis,cis-2,4-diene-1,6-bis-electrophiles
H
R
O
OH
O
HO
H
R
1
2
Reaction of N,N-disubstituted amides, such as N,N-
dimethylformamide (DMF), with organolithium
reagents has been of significant interest since it provides
an alternative method for preparation of carbonyl com-
pounds.17 However, this reaction is somewhat unpre-
dictable.17 Deniau and Enders reported that reaction
of a dilithium reagent with DMF afforded, instead of
linear carbonyl compounds, a cyclic product.18 When
1,4-dilithio-1,3-dienes 3a–e were treated with DMF,19
cis,cis-2,4-diene-
1,6-dials
cis,cis-2,4-diene-
1,6-diols
Figure 1.
Keywords: Multi-substituted cis,cis-2,4-diene-1,6-dials; Multi-substi-
tuted cis,cis-2,4-diene-1,6-diols; 1,4-Dilithiobutadienes.
*
Corresponding author. Tel.: +86 (10) 6275 9728; fax: +86 (10) 6275
1708; e-mail: zfxi@pku.edu.cn
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.003

5370
G. Mao et al. / Tetrahedron Letters 46 (2005) 5369–5372
R1
R2
R1
R
1) 2.5 DMF
- 78 oC, 1h
R
1) 2.5 DMF
- 78 oC, 1h
R
R
CHO
CHO
R2
R3
R
R
R
R3
R4
R
R
R
R
R
R
Li
Li
Li
Li
CHO
CHO
O
O
O
2) aq. NaHCO3
2) aq. NaHCO3
R
NMe2
R4
R
R
NMe2
ð1Þ
4
5
3f: R1 = R2 = Me
R3 = R4 = Ph
5a: R1 = R2 = Me, R3 = R4 = Ph
combined isolated yield 55%
5b: R1 = R4 = SiMe3
3
1
not observed
Scheme 1.
3g: R1 = R4 = SiMe3
R2 = R3= Me
R2 = R3= Me, 39% isolated yield
Table 1. Reaction of dillithiobutadienes 3 with DMF affording multi-
substituted cis,cis-2,4-diene-1,6-dials 1a
Dilithio reagent 3
Product 1
Yield/%b
Et
Et
Et
Et
Table 2. Preparation of multi-substituted cis,cis-2,4-diene-1,6-diols 2
a
from 1,6-dials 1 and LiAlH4
Li
CHO
CHO
61
3a
Li
1a
1b
Et
Et
R
R
R
1) 0.5 LiAlH4
0 oC, 1h
Et
Pr
Et
Pr
R
R
R
R
CHO
CHO
CH2OH
CH2OH
Pr
Pr
Pr
ð2Þ
Li
CHO
CHO
2) H+
51
44
3b
Li
R
Pr
1
2
Pr
Pr
Pr
Yield/%b
Pr
1,6-Dials 1
Product 2
Li
CHO
CHO
Et
Et
Et
3c
Li
1c
Et
Et
CHO
CHO
CH2OH
CH2OH
82
81
1a
1b
2a
2b
Pr
Et
Pr
Et
Et
Et
Et
Pr
Et
Pr
Et
83
77
3d
1d
CHO
Li
Li
Pr
Pr
Pr
Pr
CHO
Pr
CHO
CHO
CH2OH
CH2OH
Pr
Pr
Pr
Pr
Pr
1e
3e
CHO
Li
Li
Pr
Pr
CHO
a Reaction conditions are given in Scheme 1.
b Isolated yields.
CHO
CHO
CH2OH
CH2OH
77
1c
2c
Pr
Et
Pr
Et
Et
Et
the reaction proceeded smoothly, affording their corre-
sponding 1,6-dials 1 (Scheme 1). Results are given in
Table 1.
86
93
1d
1e
2d
2e
CH2OH
CH2OH
Pr
CHO
CHO
Pr
Unlike reactions between 3 and other substrates,8–16 no
cooperative action of the two alkenyllithio moieties to-
wards one molecule of DMF was observed in these reac-
tions, thus no formation of 4 was observed.20 Instead, a
small amount of compounds 5, which were obviously
formed from one molecule of 3 and two molecules of
DMF, was obtained in a few cases when 3a–e was used.
Interestingly, although the reason is not clear yet, di-
lithio reagents 3f and 3g reacted with DMF to give 5a
and 5b as the sole products, respectively (Eq. 1). No for-
mation of their corresponding 1,6-dials was observed.
Product 5a was obtained as a mixture of more than five
isomers with two major ones. The stereochemistry of
both 5a and 5b has not been determined.
Pr
Pr
CH2OH
CH2OH
CHO
CHO
a Reaction conditions are given in Eq. 2.
b Isolated yields.
have been reported to prepare a variety of complex
structures.5–7 Treatment of 1,6-dials 1 with n-BuLi also
result in formation of different types of 1,6-diols in good
isolated yields (Eq. 3).5–7,13,15
A novel application of 1,6-diols was developed. Thus
reaction of 1,6-diol 2h with 4-fluorobenzaldehyde in
the presence of high concentrated H2SO4 afforded the
fused ring oxacycle 6 in 68% isolated yield (Eq. 4).
The structures of the starting 1,6-diol 2h13 (Fig. 2) and
Reduction of thus formed 1,6-dials 1 with LiAlH4 affor-
ded their corresponding 1,6-diols 2 cleanly in excellent
isolated yields (Table 2).21 These types of 1,6-diols 2

G. Mao et al. / Tetrahedron Letters 46 (2005) 5369–5372
5371
HO
R
R
1) 2.2 n-BuLi
R
R
n-Bu
- 78 oC, 1h
Ar
R
R
R
R
Ar
CHO
CHO
OH
OH
Ar
H+
O
2) aq. NaHCO3
2h
OH
Ar
n-Bu
ð3Þ
H2O
Ar
H
O
1a: R = Et
1b: R = Pr
2f: R = Et
Ar
combined isolated yield 77%
2g: R = Pr
H
H
OH
Ar
combined isolated yield 83%
Ar
Ar
6
H2O
H+
Ar
Ar
Ar
Ar
O
O
Ar
Ar
O
Scheme 2.
Given in Scheme 2 is a proposed reaction mechanism for
the formation of 6 from 2h and 4-fluorobenzaldehyde in
the presence of high concentrated H2SO4. Further appli-
cation of these otherwise unavailable stereodefined 2,4-
diene-1,6-bis-electrophiles is in progress.
Figure 2. X-ray structure of 2h.
Acknowledgments
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. A.M. thanks the 21st Century COE Pro-
grams for Frontiers in Fundamental Chemistry for
financial support. Cheung Kong Scholars Program,
Qiu Shi Science & Technologies Foundation, and BASF
are gratefully acknowledged.
References and notes
1. (a) Walsh, J. G.; Furlong, P. F.; Gilheany, D. G. J. Chem.
Soc., Chem. Commun. 1994, 67–68; (b) Walsh, J. G.;
Furlong, P. F.; Gilheany, D. G. J. Chem. Soc., Perkin
Trans. 1 1999, 3657–3665, and references cited therein.
2. Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125–
4149.
Figure 3. X-ray structure of 6.
3. Zeng, X.; Qian, M.; Hu, Q.; Negishi, E. Angew. Chem.,
Int. Ed. 2004, 43, 2259–2263.
4. Kasatkin, A.; Whitby, R. J. J. Am. Chem. Soc. 1999, 121,
7039–7049.
the product 6 (Fig. 3) have been determined by single
crystal X-ray structural analysis.22,23
5. (a) Ramachandran, P. V.; Rudd, M. T.; Reddy, M. V. R.
Tetrahedron Lett. 2005, 46, 2547–2549; (b) Martin, M. E.;
Planchenault, D.; Huet, F. Tetrahderon 1995, 51, 4985–
4990; (c) Rigby, J. H.; Ateeq, H. S.; Charles, N. R.;
Cuisiat, S. V.; Ferguson, M. D.; Henshilwood, J. A.;
Krueger, C.; Ogbu, C. O.; Short, K. M.; Heeg, M. J.
J. Am. Chem. Soc. 1993, 115, 1382–1396.
6. (a) Foubelo, F.; Saleh, S. A.; Yus, M. J. Org. Chem. 2000,
65, 3478–3483; (b) Huang, Y.; Mo, X. Tetrahedron lett.
1995, 36, 3539–3542; (c) Hill, J. E.; Balaich, G.; Fanwick,
P. E.; Rothwell, I. P. Organometallics 1993, 12, 2911–2924;
(d) Reich, H. J.; Shah, S. K.; Chow, F. J. Am. Chem. Soc.
1979, 101, 6648–6656.
F
1.2 equiv.
Me
F
Me
Me
F
C
HO
Me
Me
Me
OH
OH
Me
9N H2SO4
r.t., 1h
O
F
F
6: 68% isolated yield
F
7. (a) Bols, M.; Skrydstrup, T. Chem. Rev. 1995, 95, 1253–
1277; (b) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114,
1087–1088; (c) Stork, G.; Chan, T. T.; Breault, G. A.
2h
ð4Þ

5372
G. Mao et al. / Tetrahedron Letters 46 (2005) 5369–5372
J. Am. Chem. Soc. 1992, 114, 7578–7579; (d) Sieburth, S.
M.; Fensterbank, L. J. Org. Chem. 1992, 57, 5279–5281.
Isolated yield 61% (271 mg). IR (neat) 1673 cmꢀ1 (C@O);
1H NMR (CDCl3, TMS): d 1.01–1.09 (m, 12H), 2.26–2.49
(m, 6H), 2.66–2.79 (m, 2H), 9.59 (s, 2H); 13C NMR
(CDCl3, TMS): d 11.8, 13.7, 18.5, 25.7, 143.5, 157.4, 192.3;
HRMS calcd for C14H22O2 222.1620, found 222.1611.
20. Xi, Z.; Song, Q. J. Org. Chem. 2000, 65, 9157–9159.
21. Typical procedure for the preparation of 1,6-diol 2a. To a
50 mL Schlenk tube containing 2.0 mmol of 1a in 20 mL
of ethyl ether, 1.0 mmol of LiAlH4 was added at 0 ꢁC.
After the reaction mixture was stirred at 0 ꢁC for 1h, the
reaction was quenched with 6 N H2SO4 and extracted with
ether. The extract was washed with NaHCO3, water and
brine and dried over Na2SO4. The solvent was then
evaporated in vacuo and the residue was purified by
column chromatograph (silica gel, diethyl ether/petroleum
ether in 1:3) to afford the product 2a. White solid. Isolated
yield 82% (371mg). Mp 70–71 ꢁC; 1H NMR (CDCl3,
TMS): d 0.84 (t, J = 7.5 Hz, 6H), 1.04 (t, J = 7.5 Hz, 6H),
1.74–1.97 (m, 2H), 2.08–2.48 (m, 6H), 3.61–3.83 (m, 2H),
3.91–4.20 (m, 4H); 13C NMR (CDCl3, TMS): d 12.2, 13.5,
22.4, 23.2, 61.9, 136.1, 138.6; HRMS calcd for
[C14H26O2Na]+ 249.1825, found 249.1821.
8. For a recent account on reaction chemistry of 1,4-dilithio-
1,3-dienes, see: Xi, Z. Eur. J. Org. Chem. 2004, 2773–2781;
see also: Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9,
459–490; Varela, J. A.; Saa, C. Chem. Rev. 2003, 103,
3787–3801.
9. Xi, Z.; Song, Q.; Chen, J.; Guan, H.; Li, P. Angew. Chem.,
Int. Ed. 2001, 40, 1913–1916.
10. Song, Q.; Chen, J.; Jin, X.; Xi, Z. J. Am. Chem. Soc. 2001,
123, 10419–10420.
11. Chen, J.; Song, Q.; Xi, Z. Tetrahedron Lett. 2002, 43,
3533–3535.
12. Song, Q.; Li, Z.; Chen, J.; Wang, C.; Xi, Z. Org. Lett.
2002, 4, 4627–4629.
13. Chen, J.; Song, Q.; Li, P.; Guan, H.; Jin, X.; Xi, Z. Org.
Lett. 2002, 4, 2269–2271.
14. Li, G.; Fang, H.; Xi, Z. Tetrahedron Lett. 2003, 44, 8705–
8708.
15. (a) Fang, H.; Li, G.; Mao, G.; Xi, Z. Chem. Eur. J. 2004,
10, 3444–3450; (b) Fang, H.; Song, Q.; Wang, Z.; Xi, Z.
Tetrahedron Lett. 2004, 45, 5159–5162.
16. Wang, C.; Song, Q.; Xi, Z. Tetrahedron 2004, 60, 5207–
5214.
17. Wakefield, B. J. Organolithium Methods; Academic Press:
London, 1988, pp 82–88.
18. For a reaction of dilithio reagents with DMF affording
cyclic compounds, see: Deniau, E.; Enders, D. Tetra-
hedron Lett. 2002, 43, 8055–8058.
19. Typical procedure for the preparation of 1,6-dial 1a. To a
50 mL Schlenk tube containing 2.0 mmol of 1,2,3,4-
tetraethyl-1,4-dilitho-1,3-diene 3a in 20 mL diethyl ether
at ꢀ78 ꢁC was added 5.0 mmol of DMF. After the
reaction mixture was stirred at ꢀ78 ꢁC for 1h, the
reaction was quenched with saturated aqueous NaHCO3
and extracted with ether. The extract was washed with
water and brine and dried over MgSO4. The solvent was
then evaporated in vacuo and the residue was purified by
column chromatograph (silica gel, diethyl ether/petroleum
ether in 1:30) to afford the product 1a. Colourless liquid.
22. X-ray crystallographic data for 2h: A colourless crystal
having approximate dimensions of 0.40 · 0.35 · 0.08 mm
was mounted on a glass fibre. X-ray data were collected on
a Rigaku RAXIS RAPID IP diffractometer with graphite-
˚
monochromated Mo/Ka radiation (k = 0.71073 A).
C22H24F2O2, fw = 358.41, triclinic, space group P-1,
˚
˚
˚
a = 12.061(1) A, b = 13.239(2) A, c = 6.963(1) A, V =
965.6(2) A ; Z = 2; Dcalcd = 1.233 g cmꢀ3
; R1 = 0.0595,
3
˚
wR2 = 0.1389. CCDC 268480.
23. X-ray crystallographic data for 6: A colourless crystal
having approximate dimensions of 0.40 · 0.30 · 0.15 mm
was mounted on a glass fibre. X-ray data were collected
on a Rigaku RAXIS RAPID IP diffractometer with grap-
˚
hite-monochromated Mo/Ka radiation (k = 0.71073 A).
C29H25F3O, fw = 446.49, triclinic, space group P-1,
˚
˚
˚
a = 10.728(1) A, b = 12.137(2) A, c = 9.271(1) A, V =
1140.2(3) A ; Z = 2; Dcalcd = 1.301 g cmꢀ3; R1 = 0.0486,
3
˚
wR2 = 0.1133. CCDC 268382.