Synthesis and structure determination of novel hexasubstituted cyclohexadienes

Article abstract of DOI:10.1016/j.cclet.2012.09.004

The linear trienes were obtained in high yields by copper-mediated cycloaddition of 2,5-bis(trimethylsilyl)zirconacyclo-pentadienes with dimethyl acetylenedicarboxylate (DMAD) which can be quantitatively converted to novel asymmetric hexasubstituted cyclo

Full text of DOI:10.1016/j.cclet.2012.09.004

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1137–1140
www.elsevier.com/locate/cclet
Synthesis and structure determination of novel
hexasubstituted cyclohexadienes
a
a
a
a
Hong Mei Qu a, , Xin Hui Niu , Juan Li , Jun Liu , Li Li Jiang ,
*
Jian Ke Tang a, Li Shan Zhou b
a Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin Key Laboratory of Biological and Pharmaceutical Engineering,
Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
b Tianjin Research and Design Institute of Chemical Industry, Tianjin 300131, China
Received 20 June 2012
Available online 23 September 2012
Abstract
The linear trienes were obtained in high yields by copper-mediated cycloaddition of 2,5-bis(trimethylsilyl)zirconacyclo-
pentadienes with dimethyl acetylenedicarboxylate (DMAD) which can be quantitatively converted to novel asymmetric hex-
asubstituted cyclohexadienes with high (E)-stereoselectivity. The structure of cyclohexadienes was determined via X-ray analysis.
# 2012 Hong Mei Qu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2,5-Bis(trimethylsilyl)zirconacyclopentadiene; Linear triene; Hexasubstituted cyclohexadiene; Cycloaddition
Six-membered carbocycles and cyclohexadienes are highly important classes of compounds. These compounds
have received enormous attention from organic chemists and have encouraged the development of new synthetic
pathways [1,2]. It has also been demonstrated that thermal hexatriene electrocyclization is indeed an enabling
approach for the construction of 1,3-cyclohexadiene from 1,3,5-hexatriene [3]. This type of reaction has been
widely used in the synthesis of complex natural products. For example, Miller and his co-workers have published the
total synthesis of pyrones from placobranchus using the thermal hexatriene electrocyclization [4]. A
diastereoselective 6p-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote
asymmetric induction has been reported [5]. However, only limited attention was paid on the preparation of
hexasubstituted cyclohexadienes via thermal 6e-p electrocyclization. It is uncommon to synthesize asymmetric
hexasubstituted cyclohexadienes with high (E)-stereoselectivity [6]. Yu et al. [7] showed an extraordinarily rapid
electrocyclization could occur for certain patterns of captodative substituted hexatrienes, including 2-acceptor–3-
donor hexatrienes, 2-acceptor–5-donor hexatrienes, and 3-acceptor–5-donor hexatrienes. In this context, we
envisaged that certain groups could be introduced to an appropriate position in the linear triene molecule to
facilitate the thermal hexatriene electrocyclization. Zirconocycles were synthetically useful building blocks. The
pioneering studies with zirconocene chemistry from Takahashi et al. groups are very significant [8]. We have
* Corresponding author.
E-mail address: ququhongmei@126.com (H.M. Qu).
1001-8417/$ – see front matter # 2012 Hong Mei Qu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.09.004

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H.M. Qu et al. / Chinese Chemical Letters 23 (2012) 1137–1140
TMS
TMS
R
R
R
a
b
H
E
H
(E=COOMe)
R
TMS
ZrCp2
TMS
E
R
TMS
.
3a: R = Pr (51%)
1
2
3
3b: R = Me (45%)
Scheme 1. Trienes formation mediated by zirconocene. (a) Cp2ZrBu2, THF, rt, 6 h; (b) DMAD, CuCl, À78 8C, 2 h.
TMS
Me
TMS
Me
H
E
H
I
H
E
H
ICl
(E=COOMe)
E Me
E Me
3b
TMS
4 (64%)
Scheme 2. Iodination of TMS-substituted triene.
exploited benzenes and polyacenes formation mediated by zirconocene as reported earlier [9]. These useful and
interesting results promoted us to further investigate the scope of these novel reactions.
In this communication, 2,5-bis(trimethylsilyl)zirconacyclopentadienes 2 were formed from 2 equiv of TMS-
substituted alkynes 1 mediated by zirconocene. When the coupling reaction of zirconacyclopentadienes 2 with DMAD
in the presence of copper chloride was carried out at À78 8C, linear trienes 3 were obtained in high yields after
hydrolysis (Scheme 1).
Silyl-substituted conjugated trienes were versatile synthetic precursors. It can be readily transformed into other
functional compounds. The TMS group of linear triene is easy to be removed, so the nucleophilic substitution may
occur. To investigate the reaction activity of linear triene, ICl was added at 0 8C to a THF solution of 3b, and
monoiodized triene 4 was obtained (Scheme 2). The preparation of monoiodized triene may be useful to produce some
asymmetric compounds by further reactions.
Then the thermal electrocyclization of linear triene was investigated. When linear triene 3a was heated in toluene at
100 8C for 1 h, interestingly, a new hexasubstituted cyclohexadiene 5 was obtained with highly stereoselectivity in
quantitative yield (Scheme 3).
This hexasubstituted cyclohexadiene was asymmetric. The stereochemistry of compound 5 was confirmed by
single crystal X-ray crystallography (Fig. 1). The compound had a torsional envelop conformation, with one ester
group at the equatorial position and the TMS group at the axial position. And the C2, C3, C4, C5 formed one plane.
The trimethylsilyl group can be further modified to afford functionalized cyclohexadienes. By this means, it is
possible to prepare various cyclohexadiene derivatives. Desilylation of hexasubstituted cyclohexadiene 5 could be
occurred. Using tetrabutylammonium fluoride trihydrate as desilylation reagent, hexasubstituted cyclohexadiene 5
converted to the compound 6 in high yield. No mono-silyl-substituted cyclohexadiene was detected (Scheme 4).
So, this reaction may be useful for the utilization of hexatriene electrocyclization in target-oriented organic
synthesis.
Pr
TMS
TMS
Pr
H
E
H
toluene
Pr
E
(E=COOMe)
H
100 °C, 1h
E Pr
TMS
H
E
TMS
3a
5 (quantitatively)
Scheme 3. Electrocyclization of linear trienes.

H.M. Qu et al. / Chinese Chemical Letters 23 (2012) 1137–1140
1139
Fig. 1. The molecular structure and labeling scheme of 5.
Pr
TMS
E
Pr
H
E
TBAF
rt,1h
Pr
Pr
E
H
H
(E=COOMe)
H
TMS
E
6 (89%)
5
Scheme 4. Desilylation of TMS-substituted hexadienes.
In summary, we developed a convenient method to synthesize novel hexasubstituted cyclohexadienes in
quantitative yields by the thermal electrocyclization of linear trienes. All of the trienes and the substituted
1
cyclohexadienes are new compounds and have been fully characterized by means of H NMR and 13C NMR. The
structure of hexasubstituted cyclohexadienes was also determined via X-ray crystal diffraction studies.
1. Experimental
All reactions were carried out at nitrogen atmosphere using standard of Schlenk technique. THF and toluene were
distilled from sodium and benzophenone. 1-Trimethylsilyl-1-pentyne was prepared according to the literature [10].
All the other reagents were purchased from TCI Co. Ltd. and ALDRICH Co. Ltd.
Synthesis of compound 3: To a solution of Cp2ZrCl2 (1.2 mmol, 350.8 mg) in 8 mL THF was added 1.76 mol/L n-
BuLi (2.4 mmol, 1.36 mL) at À78 8C (dry ice/acetone bath), the mixture was stirred for 20 min. Then the solution was
warmed to À40 8C for 40 min and then re-cooled to À78 8C. After 20 min, TMS-substituted alkyne 1 (2.0 mmol) was
added to the solution, and it was warmed to room temperature by removal of the cooling bath. After stirring for 6 h, the
reaction mixture was re-cooled to À78 8C again, CuCl (297 mg, 3.0 mmol) and dimethyl acetylenedicarboxylate
(426 mg, 3.0 mmol) were added to the mixture, and it was stirred for 2 h, and then the mixture was quenched with
3 mol/L HCl and extracted with ethyl acetate. The combined organic phase was washed with water, saturated aqueous
NaHCO3 solution, and brine. The solution was dried over anhydrous Na2SO4. The solvent was evaporated in vacuo.
Column chromatography on silica gel (hexane:ethyl acetate = 10:1) afforded the compound 3. 3a: light yellow liquid.
Isolated yield 51%. 1H NMR (300 MHz, CDCl3/Me4Si): d 0.06 (s, 9H), 0.17 (s, 9H), 0.88 (t, 6H, J = 7.3 Hz), 1.23–
1.34 (m, 4H), 2.04–2.09 (m, 2H), 2.16–2.21 (m, 2H), 3.67 (s, 3H), 3.69 (s, 3H), 5.09 (s, 1H), 5.56 (s, 1H). 13C NMR
(75 MHz, CDCl3/Me4Si,): d 0.00, 0.76, 13.98, 14.71, 21.75, 21.92, 36.82, 37.46, 51.63, 51.74, 123.22, 130.36, 132.85,
148.12, 157.00, 160.39, 166.12, 167.62; HRMS calcd. for C22H40O4Si2: 424.2465. Found: 424.2476. 3b: yellow
viscous liquid. Isolated yield 45%. 1H NMR (300 MHz, CDCl3/Me4Si,): d 0.06 (s, 9H), 0.18 (s, 9H), 1.77 (s, 3H), 1.93
(s, 3H), 3.70 (s, 6H), 5.08 (s, 1H), 5.58 (s, 1H); 13C NMR (75 MHz, CDCl3/Me4Si,): d À0.16, 0.44, 20.99, 22.16, 51.76,
51.93, 122.61, 127.34, 130.73, 148.91, 155.86, 157.84, 166.11, 167.74; HRMS calcd. for C18H32O4Si2: 368.1839.
Found: 368.1847.

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H.M. Qu et al. / Chinese Chemical Letters 23 (2012) 1137–1140
Synthesis of compound 4: 1.0 mol/L ICl (2.4 mL, 2.4 mmol) was added at 0 8C to a THF solution of 3b (368 mg,
1.0 mmol). After stirring for 6 h at 0 8C, the reaction mixture was quenched with saturated aqueous NaOH solution and
extracted with chloroform. The extract was then washed with water, saturated brine, and then dried over MgSO4. The
solvent was evaporated in vacuo. Column chromatography on silica gel (hexane:ethyl acetate = 10:1) afforded 4 as
1
yellow viscous liquid (64% isolated yield). H NMR (300 MHz, CDCl3/Me4Si): d 0.19 (s, 9H), 1.82 (s, 3H), 1.91
(s, 3H), 3.70 (s, 3H), 3.71 (s, 3H), 5.51 (s, 1H), 5.94 (s, 1H); 13C NMR (75 MHz, CDCl3/Me4Si): d 0.00, 21.77, 23.59,
51.58, 51.92, 79.63, 121.35, 134.48, 148.86, 149.43, 152.63, 165.22, 167.33; HRMS calcd. for C15H23IO4Si:
422.0410. Found: 422.0401.
Synthesis of compound 5: When linear triene 3a was heated in toluene at 100 8C for 1 h, the hexasubstituted
cyclohexadiene 5 was obtained quantitatively. 1H NMR (300 MHz, CDCl3/Me4Si): d 0.04 (s, 9H), 0.17 (s, 9H), 0.87 (t,
3H, J = 7.3 Hz), 0.96 (t, 3H, J = 7.3 Hz), 1.15–1.69 (m, 5H), 1.90–1.92 (m, 1H), 2.00–2.20 (m, 1H), 2.37–2.47 (m,
2H), 3.43–3.44 (m, 1H), 3.65 (s, 3H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3/Me4Si): d 1.00, 1.14, 14.07, 14.76,
23.97, 25.10, 31.74, 33.18, 36.20, 47.38, 51.49, 51.54, 134.79, 136.39, 142.65, 148.09, 168.59, 173.19; HRMS calcd.
for C22H40O4Si2: 424.2465. Found: 424.2457.
Synthesis of compound 6: To a THF solution (8 mL) of 5 (170 mg, 0.4 mmol), tetrabutylammonium fluoride
trihydrate (316 mg, 1.0 mmol) was added under nitrogen atmosphere at room temperature. The reaction was stirred for
1 h. The mixture was quenched with 3 N HCl and extracted with ethyl acetate. The combined organic phase was
washed with water, saturated aqueous NaHCO3 solution, and brine. The solution was dried over MgSO4. The solvent
was removed in vacuo. Column chromatography on silica gel (hexane:ethyl acetate = 10:1) afforded 6 as yellow liquid
(89% isolated yield). 1H NMR (300 MHz, CDCl3/Me4Si): d 0.85 (t, 3H, J = 7.5 Hz), 0.87 (t, 3H, J = 7.5 Hz), 1.32–
1.49 (m, 4H), 1.97–2.25 (m, 4H), 2.36–2.45 (dd, 1H, J = 17.4 Hz, 8.4 Hz), 2.68–2.75 (dd, 1H, J = 17.4 Hz, 3.3 Hz),
3.56–3.60 (dd, 1H, J = 8.4 Hz, 3.3 Hz), 3.60 (s, 3H), 3.75 (s, 3H), 7.06 (s, 1H); 13C NMR (75 MHz, CDCl3/Me4Si): d
13.53, 13.96, 21.08, 22.42, 31.33, 32.59, 34.80, 37.66, 51.62, 51.94, 122.73, 129.52, 139.41, 139.49, 167.15, 173.71;
HRMS calcd. for C16H24O4:280.1675. Found: 280.1669.
Acknowledgments
This work was funded by National Natural Science Foundation of China (No. 21102099). We thank Professor
Tamotsu Takahashi in Hokkaido University for his kind suggestions and help.
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