Synthesis of three-dimensionally arranged bis-biphenol ligand on hexaaryl benzene scaffold and its application for cross-pinacol coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2011.06.113

The three-dimensionally arranged bis-biphenol ligand on a hexaaryl benzene scaffold for a dinuclear complex was synthesized by the Diels-Alder addition-decarbonylation reaction as a key step. Its preliminary studies on the titanium-induced cross-pinacol c

Full text of DOI:10.1016/j.tetlet.2011.06.113

Tetrahedron Letters 52 (2011) 4567–4569
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Tetrahedron Letters
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Synthesis of three-dimensionally arranged bis-biphenol ligand on
hexaaryl benzene scaffold and its application for cross-pinacol coupling
reaction
⇑
Toru Amaya, Akihiro Miyasaka, Toshikazu Hirao
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The three-dimensionally arranged bis-biphenol ligand on a hexaaryl benzene scaffold for a dinuclear
complex was synthesized by the Diels–Alder addition–decarbonylation reaction as a key step. Its preli-
minary studies on the titanium-induced cross-pinacol coupling reaction were performed based on
step-by-step activation of two different aldehydes.
Received 6 May 2011
Revised 21 June 2011
Accepted 28 June 2011
Available online 2 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Dinuclear catalyst
Bimetallic catalyst
Biphenol ligand
Pinacol coupling
Dual reactive sites allow to position two substrates appropri-
ately for the reaction, activate them, and induce electrically cooper-
ating effect. Well-organized dinuclear transition metal complexes
are considered to permit such a system, which is also found some-
times in active sites of enzymes to catalyze the reactions.1 So far,
many dinuclear catalysts have been developed and applied to or-
ganic reactions.2 In this context, we envisioned that the controlled
arrangement of two metals on the rigid scaffold can provide spa-
tially regulated reaction sites. Based on this concept, the rigid bis-
biphenol ligand 1 on a hexaphenyl benzene scaffold was designed
(Scheme 1). The utility of our bis-biphenols depends on such con-
formationally regulated structure although there are various re-
ports of ligands possessing two biphenol moieties.2d,3 Here, we
report the synthesis of the bis-biphenol ligand 1 and its preliminary
studies on the ligand controlled cross-pinacol coupling reaction
based on step-by-step activation of two different aldehydes.
Structural optimization of ligand 1a was carried out using MM2
force field. The obtained structure showed the three-dimensionally
controlled arrangement of biphenol ligand moieties (see Supple-
mentary data, Fig. S1).
tolan 3 would arise from the two biphenol derivatives 4 and acety-
lene spacer through the repetitive Sonogashira coupling reaction.
Scheme 2 shows the synthesis of 1. The iodide 4 and the ethynyl
derivative 55 were coupled by the Sonogashira reaction to give 3a
and 3b in 80% and 52% yields, respectively. The thus-obtained 3a
and 3b were treated with 2 in diphenylether at 250 °C, followed
by deprotection of the methoxy group with BBr3 to give the bis-
biphenol ligand 1a and 1b as a mixture of diastereomers (two steps
63% for 1a and 57% for 1b, Scheme 2). The cis/trans ratios for 1a and
1b are 35:65 and 32:68, respectively, the assignment of which is
described in the next paragraph. Diastereomers were able to be
separated by silica-gel chromatography. The gram scale synthesis
was possible.
The structural assignment was studied by 1D ROESY experi-
ments of the trimethylsilyl derivative 6cis, which was prepared
6
by the reaction of 3TMS with 2, followed by the separation of the
cis/trans diastereomers by preparative thin-layer chromatography
(Scheme 3). The isomer, in which ROEs were observed between
the trimethylsilyl and methoxy groups, was assigned as a cis-iso-
mer. The trimethylsilyl derivative 6cis was transformed to 1acis by
treatment with BBr3 for the deprotection of the methoxy and tri-
methylsilyl groups. In this way, the structure of 1acis was deter-
mined. Similarly, the cis/trans determination of 1bcis was carried
out by the transformation to 1acis by deiodation.
Our synthetic strategy for ligand 1 is outlined retrosynthetically
in Scheme 1. We envisaged that 1 is constructed via the Diels–Alder
addition–decarbonylation reaction4 of tetraphenylcyclopentadie-
none (2) with the tolan 3 possessing two bis-biphenol moieties. Such
The desired cis-isomer is a minor product in the Diels–Alder
addition–decarbonylation reaction, which made us investigate
the isomerization equilibrium. The treatment of the demethylated
compound 1atrans in diphenylether at 150 °C for 12 h resulted in
the trans- and cis-isomers in 37:63 (Scheme 4). This finding
⇑
Corresponding author. Tel.: +81 6 6879 7413; fax: +81 6 6879 7415.
E-mail address: hirao@chem.eng.osaka-u.ac.jp (T. Hirao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.113

4568
T. Amaya et al. / Tetrahedron Letters 52 (2011) 4567–4569
R
Structural determination
ROEs
0.4%
Me3Si
0.4%
HO
HO
0.3%
MeO
HO
HO
Dields-Alder addition-
decarbonylation
MeO
MeO
Ph2O, 250 °C, 24 h
3
TMS+ 2
MeO
33%
6cis
+
6trans
1a (R = H)
1b (R = I)
O
1) BBr3, CH2Cl2,
rt, 20 min
Ph
Ph
Ph
Ph
2) aqueous
work-up
1) BuLi, THF, -78 °C to rt,
10 min
80%
2
1bcis
1aci s
R
2) aqueous work-up
96%
OMe
MeO
OMe MeO
Scheme 3. Structural determination of 1 based on 1D ROESY experiments of 6cis
.
3a (R = H)
3b
(R = I)
TMS (R = SiMe3)
3
Sonogashira coupling
reaction
HO
HO
HO
HO
Ph2O,150 °C,
12 h
R
HO
HO
OMe
OMe
MeO
MeO
HO
HO
I
I
+
+
1atrans
1acis
4a (R = H)
4b (R = I)
37
:
63
THF, reflux, 24 h
Scheme 1. Synthetic strategy for the ligand 1.
1atrans
1acis
Scheme 4. Trans/cis isomerization of 1a.
MeO
MeO
Furthermore, the derivatization is possible by using the iodo-
substituent of 1bcis. For example, the B-alkyl Suzuki–Miyaura
cross-coupling reaction with MeB(OH)2 allowed the introduction
of the methyl group with the formation of 7 (Scheme 5).
Pd(PPh3)2Cl2 (1 mol%)
4a,b +
3a,b
CuI (1.5 mol%), NEt3,
70 °C
80% for 3a
52% for
Complexation of 1acis with TiCl4 was studied by 1H NMR (see Sup-
plementary data, Fig. S2). The integral ratio for the hydroxyl protons
in the phenoxy group decreased by half by the addition of 1 equiv
TiCl4. On further addition of 1 equiv TiCl4, the peaks disappeared,
suggesting the formation of the corresponding dinuclear complex.
With such a complex in hand, the intermolecular cross-pinacol
coupling reaction was studied using the stoichiometric amount of
1acis (Scheme 6) because the sequential activation of two different
aldehydes and subsequent cross-coupling is envisioned to be al-
lowed due to the fixed bimetallic reactive sites. Although catalytic,
diastereoselective, and/or enantioselective methods have been
developed,7,8 the intermolecular cross-pinacol coupling reaction
is still a challenging issue due to the difficulty in the discrimination
of two aldehydes in the reaction. So far, there are only few exam-
ples for the cross-pinacol-type coupling, which strongly depend on
the combination of substrates.9 First, the ligand (100 mol %) was
mixed with 200 mol % of TiCl4 for complexation in toluene under
argon at room temperature. After 1 h, the solvent was changed to
THF. Then, activated Zn (1000 mol %) was added to the mixture
to generate a reduced Ti complex.10 o-Trifluoromethyl benzalde-
hyde was added to the reaction mixture at room temperature.
One minute later, 2-thienylaldehyde was added to the reaction
mixture at the same temperature. The cross-coupling product 8
5
3b
1) Ph2O, 250 °C, 24 h
3a,b
2
+
2) BBr3, CH2Cl2, rt,
10 min
R
R
HO
HO
HO
HO
HO
HO
+
HO
HO
1cis
1trans
1a (R = H) : 2 steps 63%, cis
1b (R = I) : 2 steps 57%, cis
/
trans = 35/65
/
trans = 32/68
Scheme 2. Synthesis of 1a and 1b.
permits the better conversion to 1acis. On the other hand, this
isomerization did not occur in THF at reflux temperature even after
24 h to indicate the conformational rigidity.
was obtained in 56% yield (syn/anti = 51:49)11
, where the

T. Amaya et al. / Tetrahedron Letters 52 (2011) 4567–4569
4569
the dinuclear titanium complex permitted preliminary investiga-
tion on the cross-pinacol coupling reaction utilizing step-by-step
activation of two different aldehydes by sterically controlled
arrangement of the biphenol ligand moieties. Further increase of
cross-selectivity is expected by the left–right asymmetric ligand
as shown in the concept in Figure 1, which can be synthesized
using the Pd-catalyzed cross-coupling reaction as demonstrated
by the synthesis of 7. Furthermore, such ligands will be applied
to other reactions that need dual activation by metals.
Me
HO
MeB(OH)2, Pd(dppf)Cl2,
K3PO4, THF/CH2Cl2
HO
HO
HO
1bcis
60 °C, 18 h
7
23%
Acknowledgment
Scheme 5. Derivatization to 7.
A.M. expresses his special thanks for The Global COE (center of
excellence) Program ‘Global Education and Research Center for
Bio-Environmental Chemistry’ of Osaka University.
TiCl4 (200 mol%)
toluene, rt,1 h
removal of toluene
1aci s
Supplementary data
CHO
S
CHO
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.113.
CF3
(100 mol%) (100 mol%)
Zn(1000 mol%)
References and notes
THF, rt, 20 min
rt, 1 min rt, 1 h
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S
OH
8 56%
OH
OH CF3
9
36%
:
without 1acis
8
9
,
0% for , 69% for
S
49% for 10
S
use of 2,2'-biphenol
OH
10 43%
1a
8
,
instead of cis: 0% for
77% for 9, 71% for 10
Scheme 6. Cross-pinacol coupling reaction based on step-by-step activation using
the ligand 1acis
.
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followed by the trapping with chlorotrimethylsilane, see Supplementary data
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homo-coupling products 9 and 10 were also formed in 36% (dl/
meso = 71:29)12 and 43% (dl/meso = 76:24)13 yields, respectively.
Here, yield was calculated as follows: (mol of product)/(maximal
mol of producible products)ꢀ100. On the other hand, the same
reaction using 2,20-biphenol instead of 1acis gave only the homo-
coupling products 9 and 10 in 77% (dl/meso = 48:52) and 71% (dl/
meso = 55:45) yields,14 respectively, without the formation of 8.
Similarly, the same reaction without 1acis led to only the homo-
coupling products 9 and 10 in 69% (dl/meso = 53:47) and 49% (dl/
meso = 71:29) yields,14 respectively. These results indicate a steric
effect of the bis-biphenol ligand 1acis toward the cross-pinacol
reaction.
In summary, the three-dimensionally arranged bis-biphenol li-
gand on the hexaaryl scaffold for the dinuclear complex was syn-
thesized to show the conformational stability. The formation of
R1
R2
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see Supplementary data for details.
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Knollmueller, M.; Gaertner, P. Tetrahedron: Asymmetry 2006, 17, 2413–2429;
(b) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481–8490.
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J.; Feng, Y.; Li, M.-J.; You, T.-P. Tetrahedron: Asymmetry 2004, 15, 1707–1710.
14. Dominant formation of homo-coupling products may be accounted for by the
completion of the coupling reaction of o-trifluoromethyl benzaldehyde before
addition of thienylaldehyde due to the higher reactivity of the former one.
M
M
Figure 1. Concept of next generation ligands.