Selective Tandem Inter/intramolecular Eglington Coupling for Chiral Cyclophyne Synthesis

Article abstract of DOI:10.1080/00397910902730945

Tandem inter- and intramolecular Eglington couplings take place with good selectivity to afford an enantiopure three-dimensional cyclophyne with a large cavity.

Full text of DOI:10.1080/00397910902730945

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Selective Tandem Inter/
intramolecular Eglington
Coupling for Chiral Cyclophyne
Synthesis
De-Lie An a , Qiang Chen a , Zhi-Yang Zhang a , Hong
Yan a , Jing-Kun Fang a , Qiong Su a , Wan-Rong Dong
a , Akihiro Orita b & Junzo Otera b
a Department of Chemistry , College of Chemistry
and Chemical Engineering, Hunan University ,
Changsha, China
b Department of Applied Chemistry , Okayama
University of Science , Ridai-cho, Okayama, Japan
Published online: 03 Aug 2009.
To cite this article: De-Lie An , Qiang Chen , Zhi-Yang Zhang , Hong Yan , Jing-Kun
Fang , Qiong Su , Wan-Rong Dong , Akihiro Orita & Junzo Otera (2009) Selective
Tandem Inter/intramolecular Eglington Coupling for Chiral Cyclophyne Synthesis,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:17, 3092-3100, DOI: 10.1080/00397910902730945
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Synthetic Communications1, 39: 3092–3100, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730945
Selective Tandem Inter/intramolecular Eglington
Coupling for Chiral Cyclophyne Synthesis
De-Lie An,1 Qiang Chen,1 Zhi-Yang Zhang,1 Hong Yan,1 Jing-Kun
Fang,1 Qiong Su,1 Wan-Rong Dong,1 Akihiro Orita,2 and Junzo Otera2
1Department of Chemistry, College of Chemistry and Chemical
Engineering, Hunan University, Changsha, China
2Department of Applied Chemistry, Okayama University of Science,
Ridai-cho, Okayama, Japan
Abstract: Tandem inter- and intramolecular Eglington couplings take place with
good selectivity to afford an enantiopure three-dimensional cyclophyne with a
large cavity.
Keywords: Chiral cyclophyne, Eglington coupling, intramolecular, intermolecular,
tandem
Cyclophynes, an acetylenic family of cyclophanes, have been the subject of
extensive attention in terms of providing carbon-rich materials and persis-
tent molecular architectures.[1] We have long been involved in chemistry of
cyclophynes with the arylene–ethynylene unit connected by binaphthyl
groups as chiral stereogenic hinges.[2] During this study, we explored a
facile route to monosilylated diethynyl binaphthyl 1, which was success-
fully employed as a starting block for enantiopure arylene ethynylene
double helices.[3] Then, we became interested in applying 1 to construction
of three-dimensional cyclophyne architectures with a large cavity.
Our strategy is shown in Scheme 1. Sonogashira coupling between 1
and 1,3,5-tribromobenzene afforded 2 in good yield. Desilylation of this
Received October 11, 2008.
Address correspondence to Akihiro Orita, Department of Applied Chemistry,
Okayama University of Science, Ridai-cho, Okayama 700-0005, Japan. E-mail:
orita@high.ous.ac.jp
3092

Eglington Coupling for Chiral Cyclophyne Synthesis
3093
Scheme 1. Tandem synthesis of 5.
compound provided terminal acetylene 3. Subjection of 3 to Eglington
coupling[4] induced tetramerization exclusively to give 5 in 61% yield
(Fig. 1). We had anticipated a possible competing dimerization reaction
to give 6, which actually was never detected in the product. These results
can be interpreted by initial intermolecular coupling between one of acet-
ylenic functions in the respective molecules of 3 followed by intramolecu-
lar coupling between one of the remaining acetylenic functions to arrive

3094
D.-L. An et al.
Figure 1. MALDI-TOF MS spectrum of 5.
at dimeric intermediate 4. Then, further coupling of 4 induced another
mode of dimerization to give 5, a tetramer of 3. This last step was con-
firmed by preparation of 4 by a separate route (Scheme 2). Subjection
of 4 to Eglington coupling afforded 5 in 74% yield. No intramolecular
reaction leading to 6 occurred. Apparently, the reaction course from 3
to 5 is kinetically controlled by a sequence of highly selective inter-,
intra-, and intermolecular couplings. The second intramolecular step plays
a key role in the fate of the sequential couplings. If the reaction had
occurred intermolecularly in this step, higher oligomers should have
appeared, but no such products were produced. The 74% yield of the last
step as revealed in Scheme 2 suggests that the intermediate 4 was produced
in 82% yield in Scheme 1. Suppose that intermolecular Eglington coupling
in the first step proceeded in 90–95% yield as usual; then the yield of the
second intramolecular coupling can be estimated to be about 90%.
Furthermore, intermolecular coupling also took place with good selectivity
in the third step. At the moment, we have no explicit explanation for these
remarkable differentiations between inter- and intramolecular modes. It
may be said, however, that the orientation of rigid acetylene moieties in
the respective intermediate molecules controls the reaction course.
In contrast to these results, in which 3 failed to give dimer 6, a larger
block 17, upon Eglington coupling, provided dimer 18, albeit with poor

Eglington Coupling for Chiral Cyclophyne Synthesis
3095
Scheme 2. Stepwise synthesis of 5.
yield (Scheme 3, Fig. 2). In this case, three terminal acetylenic moieties
undergo sequential inter-, intra-, and intramolecular couplings, and the
final intramolecular coupling is allowed to proceed to some extent, pos-
sibly because of the decrease in the steric demand arising from insertion
of the phenylethynyl spacers.
In summary, arylene–ethynylene building blocks with binaphthyl
hinges can undergo Eglington coupling in an inter- or intramolecular
fashion selectively, depending on the molecular size. This procedure

3096
D.-L. An et al.
Scheme 3. Tandem synthesis of 18.
provides structurally unique, enantiopure cyclophynes. Applications of
these compounds to chiral hosts in supramolecular chemistry are now
in progress in our laboratories.

Eglington Coupling for Chiral Cyclophyne Synthesis
3097
Figure 2. MALDI-TOF MS spectrum of 18.
EXPERIMENTAL
General
All reactions were carried out under an atmosphere of nitrogen with
freshly distilled solvents unless otherwise noted. Melting points were
determined with a Taike XT-4 micro-melting-point apparatus and are
uncorrected. Tetrahydrofuran (THF) was distilled from sodium=
benzophenone. Other solvents such as toluene and diisopropylamine
were distilled from CaH2. Pd(PPh3)2Cl2 was purchased from Merck.
NMR spectra were recorded on Varian Inova-400 instruments with tetra-
methylsilane (TMS) as an internal reference. Mass spectra (MS) were
recorded on an LCQ-Advantage LC=MS (atmospheric pressure chemical
ionization [APCI], Thermo-Finnigan) mass spectrometer. Optical
rotations were obtained on a Jasco P-1010 polarimeter.
Typical Procedure: Preparation of 2
A 100-ml flask was charged with 1 (420 mg, 1.12 mmol), 1,3,5-tribromo-
benzene (110 mg, 0.35 mmol), Pd(PPh3)2Cl2 (37 mg, 0.053 mmol), CuI
(10 mg, 0.053 mmol), diisopropylamine (6 mL), and toluene (30 mL).

3098
D.-L. An et al.
After the mixture had been stirred at 75ꢀC for 12 h, the reaction mixture
was filtered at room temperature. The filtrate was poured into aqueous
NH4Cl and extracted with ethyl acetate. The combined organic layer
was washed with brine, dried over MgSO4, and evaporated in vacuo.
The residue was subjected to column chromatography on silica gel
(hexane=CH2Cl2 ¼ 4:1) to give 293 mg of 2 (70%) as pale yellow foam.
1
Compound 2: mp 96.0–97.0ꢀC; H NMR (CDCl3, 400 MHz) d ꢁ0.26
(s, 27H), 5.91 (s, 3H), 7.22–7.32 (m, 12H), 7.40 (td, J ¼ 7.2, 1.2 Hz,
3H), 7.46–7.50 (m, 3H), 7.67 (d, J ¼ 8.4 Hz, 3H), 7.70 (d, J ¼ 8.4 Hz,
3H), 7.85–7.96 (m, 12H); 13C NMR (CDCl3, 100 MHz) d ꢁ0.64, 89.91,
91.87, 98.83, 104.72, 121.06, 121.37, 122.90, 126.42, 126.46, 126.58,
126.63, 126.68, 127.83, 127.85, 127.97, 128.00, 128.09, 128.13, 132.35,
132.58, 132.96, 132.98, 133.05, 140.34, 141.00.
Preparation of 3
A 50-mL flask was charged with 2 (293 mg, 0.25 mmol), K2CO3 (676 mg,
5.00 mmol), THF (15 mL), and methanol (15 mL). The mixture was stir-
red at room temperature for 5 h. The reaction mixture was poured into
water and extracted with ethyl acetate. The combined organic layer
was dried over MgSO4 and evaporated. The residue was subjected to col-
umn chromatograph on silica gel (hexane=CH2Cl2 ¼ 3:1) to give 237 mg
1
of 3 (97%) as white foam. Compond 3: mp 162.0–163.0ꢀC; H NMR
(CDCl3, 400 MHz) d 2.81 (s, 3H), 6.07 (s, 3H), 7.16 (d, J ¼ 8.4 Hz, 3H),
7.22–7.26 (m, 6H), 7.32 (t, J ¼ 8.4 Hz, 3H), 7.41 (t, J ¼ 7.6 Hz, 3H),
7.49 (t, J ¼ 7.6 Hz, 3H), 7.71 (d, J ¼ 8.4 Hz, 3H), 7.75 (d, J ¼ 8.4 Hz,
3H), 7.86–7.98 (m, 12H); 13C NMR (CDCl3, 100 MHz) d 80.68, 82.80,
89.65, 91.89, 120.40, 121.14, 122.94, 126.37, 126.3, 126.63, 126.75,
126.82, 126.85, 128.06, 128.09, 128.14, 128.16, 128.89, 132.33, 132.44,
132.98, 133.10, 133.17, 139.97, 140.50.
Preparation of 5
A 100-mL flask was charged with Cu(OAc)2 (536 mg, 2.40 mmol) and
pyridine (50 mL). A solution of 3 (237 mg, 0.24 mmol) in pyridine
(10 mL) was added to the suspension over 4 h at 60ꢀC by a syringe pump.
After the mixture had been stirred at 60ꢀC for 2 h, pyridine was removed
in vacuo, and the residue was extracted with dichloromethane (DCM).
After the organic layer was dried over MgSO4 and evaporated, the resi-
due was subjected to column chromatography on silica gel (hexane=
CH2Cl2 ¼ 2:1) to give 140 mg of 5 (61%). Compound 5: mp > 192ꢀC

Eglington Coupling for Chiral Cyclophyne Synthesis
3099
(decomp.); 1H NMR (CDCl3, 400 MHz) d 6.42 (s, 8H), 6.84 (d,
J ¼ 8.4 Hz, 8H), 6.90 (d, J ¼ 8.4 Hz, 8H), 6.96–7.76 (m, 112H), 7.88 (d,
J ¼ 8.0 Hz, 8H), 7.93 (d, J ¼ 8.4 Hz, 8H), 8.11 (s, 4H); 13C NMR (CDCl3,
100 MHz) d 77.35, 78.81, 81.40, 84.76, 89.62, 91.81, 92.09, 93.32, 120.31,
120.38, 121.17, 121.50, 123.47, 123.64, 126.08, 126.35, 126.53, 126.67,
126.78, 126.85, 128.01, 128.19, 128.34, 128.70, 129.27, 130.42, 130.57,
132.09, 132.19, 132.72, 132.81, 132.91, 133.02, 133.12, 137.79, 138.88,
6:4
138.99, 141.16; (R)-isomer: ½aꢂD þ99.2 (c 0.1, CHCl3); MALDI-TOF
MS: m=z calcd. for C312H156 (Mþ): 3901.2; found: 3902.7.
Compound 4
Mp> 186.0ꢀC (decomp.); 1H NMR (CDCl3, 400 MHz) d 2.74 (s, 2H), 6.56
(s, 4H), 6.85 (d, J ¼ 8.0 Hz, 4H), 6.90 (d, J ¼ 8.4 Hz, 4H), 7.09 (d, J ¼ 8.4 Hz,
2H), 7.17–7.22 (m, 12H), 7.26–7.48 (m, 14H), 7.62–8.01 (m, 36H), 8.08 (s,
2H); 13C NMR (CDCl3, 100 MHz) d 78.77, 80.54, 82.76, 84.59, 89.61,
92.14, 92.19, 93.10, 120.38, 121.12, 121.43, 123.32, 123.78, 126.29, 126.36,
126.59, 126.67, 126.76, 126.84, 126.91, 128.04, 128.14, 128.20, 128.39,
128.77, 129.17, 130.48, 130.60, 132.25, 132.39, 132.84, 132.94, 133.04,
9:3
133.16, 137.82, 138.95, 139.30, 140.40, 141.44; (R)-isomer: ½aꢂD þ236.4
(c 0.1, CHCl3); MS (APCI): 1952.5 (Mþ, 37), 1953.9 (Mþ þ 1, 100).
Compound 18
Mp > 216ꢀC (decomp.); 1H NMR (CDCl3, 400 MHz) d 6.91 (d,
J ¼ 8.0 Hz, 12H), 6.99 (d, J ¼ 8.4 Hz, 6H), 7.02 (d, J ¼ 8.8 Hz, 6H),
7.15–7.23 (m, 24H), 7.36 (s, 6H), 7.38–7.44 (m, 12H), 7.68 (d, J ¼ 8.4 Hz,
6H), 7.78 (d, J ¼ 8.4 Hz, 6H), 7.85–7.88 (m, 18H), 7.94 (d, J ¼ 8.4 Hz,
6H); 13C NMR (CDCl3, 100 MHz) d77.56, 81.42, 89.52, 90.28, 91.17,
92.87, 120.59, 121.41, 121.20, 123.31, 123.54, 126.24, 126.44, 126.58,
126.88, 128.01, 128.10, 128.33, 129.31, 131.30, 131.33, 132.42, 132.96,
18:5
133.08, 133.86, 139.33, 140.87; (R)-isomer: ½aꢂD þ387.4 (c 0.1, CHCl3);
MALDI-TOF MS: m=z calcd. for C204H102 (Mþ): 2550.8; found 2552.2.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (Grant Nos. 20272012 and 20672033), Hunan Natural Science
Foundation (Grant No. 07JJ3026), and a Grant-in-Aid (Grant No.
17065020) from Ministry of Education, Sports, Science and Technology
(MEXT), Japan.

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D.-L. An et al.
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