A convenient route towards novel H8-1,1'-bis-(dibenzofuran-2-ol) derivatives and evaluation of their use as chiral auxiliaries

Article abstract of DOI:10.1016/j.tet.2011.03.077

A novel bidentate ligand, H₈-BIFOL, was successfully prepared and resolved starting from readily available reagents. The reactivity and selectivity was evaluated in the alkynylation of benzaldehyde, resulting in ee's up to 56%.

Full text of DOI:10.1016/j.tet.2011.03.077

Tetrahedron 67 (2011) 3685e3689
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convenient route towards novel H8-1,10-bis-(dibenzofuran-2-ol) derivatives and
evaluation of their use as chiral auxiliaries
a
a
b
a,
*
ꢀ
Hans Kelgtermans , Liliana Dobrzanska , Luc Van Meervelt , Wim Dehaen
a Molecular Design and Synthesis, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Heverlee, Belgium
b Biomolecular Architecture, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Heverlee, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel bidentate ligand, H8-BIFOL, was successfully prepared and resolved starting from readily avail-
able reagents. The reactivity and selectivity was evaluated in the alkynylation of benzaldehyde, resulting
in ee’s up to 56%.
Received 8 February 2011
Received in revised form 17 March 2011
Accepted 22 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 30 March 2011
Keywords:
Bidentate ligand
Chiral catalysis
Alkynylation
Dibenzofuran
1. Introduction
Another class of C2-symmetric bidentate ligands based on the
dibenzofuran (BIFOL) or carbazole (BICOL) unit was introduced by
After the introduction of 1,10-binaphthyl-2,20-diol (BINOL) as
a chiral agent in asymmetric synthesis, numerous publications
appeared reporting newor more efficient synthetic routes using this
ligand.1 The excellent ee’s and yields of many reactions using BINOL
led tothe developmentofa broadselectionof new, substituted chiral
auxiliaries, which dramatically improved the enantioselectivity of
certain reactions.2 A common modification of the classic binaphthyl
structure is made by partial hydrogenation of the naphthalene units,
providing the corresponding H4- and H8-BINOL ligands.3 Their in-
creased bulkiness and dihedral angle often give improved results
regarding the selectivity of several asymmetric reactions.4
Hiemstra et al.6 Despite their promising activity in asymmetric
catalysis, no other reports appeared using these new auxiliaries,
which is probably caused by the rather tedious and lengthy syn-
thetic route needed towards them.7 Nevertheless, the presence of
the electron-donating heteroatoms, which allow a more direct
functionalization, and the different bite-angle due to the increased
steric hindrance, are advantages that motivated us to look for an-
other synthetic approach allowing to further explore the scope and
applicability of these interesting ligands.
Besides altering the structure of the naphthyl skeleton, it is also
possible to vary the building block itself. A well known example of
these kind of ligands is 2,20-diphenyl-(3,30-biphenanthrene)-4,40-
diol (VAPOL), which is for instance capable of providing previously
unseen enantioselectivities in the synthesis or ring-opening of
aziridines.5
Keeping in mind further derivatization of the 3- and 30-positions
and the increased solubility in common organic solvents, we
decided to investigate the synthesis of the previous unknown hy-
drogenated derivative of 1,10-bis-(dibenzofuran-2-ol) (BIFOL).8
Thus, in this paper we wish to present an efficient and large-scale
synthesis of a novel C2-symmetric bidentate ligand; 1,10-bis-
(6,7,8,9-tetrahydro-dibenzofuran-2-ol) or H8-BIFOL 2, and its
application in the asymmetric alkynylation of aromatic aldehydes.
* Corresponding author. Tel.: þ32 16 327418; fax: þ32 16 327990; e-mail address:
wim.dehaen@chem.kuleuven.be (W. Dehaen).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.077

3686
H. Kelgtermans et al. / Tetrahedron 67 (2011) 3685e3689
2. Discussion and results
the copper-mediated dimerizations provided the best results until
now, further optimalizations were carried out using similar con-
ditions (Table 2).
2.1. Synthesis
The field of the BINOL based ligands has been studied exten-
sively, resulting in numerous amounts of synthetic approaches. The
best known route is the oxidative coupling of 2-naphthol, which is
based on the dimerization of two radical species produced by the
one electron oxidation under the influence of an oxidant. Recently,
increased attraction has gone out to copper9 or vanadium10 medi-
ated dimerizations as they allow the use of chiral inducers,
resulting in an enantiomeric excess of one of the two possible
isomers. As these methodologies are the most straightforward
approach towards C2-symmetric biphenols, we envisioned to apply
these to the known compound 6,7,8,9-tetrahydro-dibenzofuran-2-
ol 1, which was prepared on a large scale according to a slightly
modified literature procedure.11 In order to find the appropriate
conditions for the dimerization of 1, a variety of commonly
employed oxidants was screened (Table 1).
Table 2
Optimalization of the oxidative coupling of 3. DACH¼rac(-trans)diaminocyclohexane,
TMEDA¼N,N,N,N-tetramethylethylenediamine, MBA¼(rac)-
a-methylbenzylamine
Entrya
1
Oxidant/Ligand
Solvent
CH2Cl2
Time (h)
24
Yield (%)b
62
CuCl2 (100 mol %),
Benzylamine (200 mol %)
CuCl2 (100 mol %),
Benzylamine (200 mol %)
CuI (100 mol %),
Benzylamine (200 mol %)
CuCl (100 mol %),
Benzylamine (200 mol %)
CuCl (100 mol %),
TMEDA (200 mol %)
CuSO4 (100 mol %),
Benzylamine (200 mol %)
Cu(NO3)2 (100 mol %),
Benzylamine (200 mol %)
Cu(NO3)2 (10 mol %),
Benzylamine (20 mol %), O2
Cu(NO3)2 (10 mol %),
Benzylamine (20 mol %), O2
Cu(NO3)2 (10 mol %),
DACH (10 mol %), O2
Cu(NO3)2 (10 mol %),
MBA (10 mol %), O2
2
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
42
20
63
3
dc
33
4
22
Table 1
5
0.75
163
24
33
Study towards dimerization of H4-dibenzofuranol. TMEDA¼N,N,N,N-tetramethyl
-ethylenediamine
6
66
7
82
8
17
93 (84)d
56
9
50
10
11
26
dc
86
Entrya Oxidant/Ligand
Solvent Time (h) Yield (%)
18
1
2
K3[Fe(CN)6], KOH
CH2Cl2
CH2Cl2
20
115
db
Cu(NO3)2 (10 mol %)/
Benzylamine (20 mol %), O2
CuCl (100 mol %)/
Benzylamine (200 mol %)
CuCl2 (100 mol %)/
16
a
Reactions were carried out at room temperature with 0.5 mmol of 3 in 5 mL
3
4
CH2Cl2
CH2Cl2
67
67
d
d
solvent under N2 atmosphere (unless otherwise mentioned).
b
Isolated yields.
Starting material was recovered.
Yield in parentheses is after recrystallization (EtOH).
c
d
Benzylamine (200 mol %)
FeCl3/Al2O3
VO(acac)2 (10 mol %), O2
CuCl (100 mol %)/TMEDA (200 mol %) CH2Cl2
Mn(acac)3 MeCN
5c
6
Toluene
CH2Cl2
17
70
140
24
dd
b
Traces
31
Traces
7
This time we were pleased to see that tBu2-H8-BIFOL 4 was
formed in moderate to excellent yields. Several copper sources
were examined of which copper(II) nitrate seemed to be the best
choice (Table 2, entry 7). Lowering the amount of copper by using
oxygen as the stoichiometric oxidant resulted in higher yields,
which made it feasible to scale up the reaction. Changing the sol-
vent to acetonitrile (MeCN) did not improve the reaction, nor did
the use of other amines. Notable was the use of the CuCl/TMEDA
reagent (Table 2, entry 5), which decreased the reaction time sig-
nificantly, however at the cost of inferior yield.
8e
a
All reactions were carried out at room temperature with 1.0 mmol of 1 in 10 mL
degassed solvent under an atmosphere of N2 (unless otherwise mentioned).
b
Starting material was recovered.
c
Reaction carried out at 70 ꢀC.
d
Traces of product were detected by MS.
Reaction carried out at reflux temperature.
e
Unfortunately, none of the conditions provided satisfactory re-
sults, mostly due to the formation of over-oxidized compounds or to
unreactedstartingmaterial. Noteworthyhoweveristheuseofcopper
(II) nitrate/benzylamine (Table 1, entry 2), whichyielded the targeted
compound 2, albeit in low yield. Somewhat better results were ob-
served with CuCl/TMEDA, but prolonged reaction times were nec-
essary. As these findings were not very promising for the further
development of the ligand, we were obliged to modify our approach.
Preliminary research in our laboratory has showed that the
oxidative coupling can be significantly improved by the in-
troduction of a tert-butyl substituent at the ortho-position. This
bulky alkyl-group prevents the formation of the unwanted 1,30 and
3,30 dimerization products and stabilizes the radical intermediates
that are present during the reaction. Also it has been showed by
Schrock et al. that the presence of these sterically demanding
substituents on bidentate ligands can, for example, improve the
selectivity of enantioselective olefin metathesis.12 Thus, the alky-
lated H4-dibenzofuranol 3 was prepared in an almost quantitative
yield starting from 1 under general FriedeleCrafts conditions. Since
2.2. Resolution
In order to be useful as a chiral auxiliary, the separation (or
enantioselective synthesis) of the two isomers is essential. Several
methods, including oxidative coupling with chiral amines and in-
clusion crystallization using N-benzylcinchoninium chloride13
were examined, however, none resulted in a notable enantio-
meric excess of the ligand (according to HPLC analysis).
More satisfactory results were obtained with the formation of
diastereoisomers by employing 1-(S)-camphorsulfonyl chloride as
chiral substrate, allowing near quantative separation by means of
standard column chromatography followed by alkaline hydrolysis.
All efforts to obtain the two diastereoisomers (S,S)-5 or (R,S)-5 by
crystallization were unsuccessful. Finally, the alkyl substituents
were removed to obtain H8-BIFOL 2 in excellent yields without any
measurable racemization (Scheme 1).

H. Kelgtermans et al. / Tetrahedron 67 (2011) 3685e3689
3687
O
O
O
tBu
O
tBu
OH
i
ii
OH
OH
iii
OH
OH
4
(rac)-
OSO2R
+ separation
tBu
O
tBu
O
(-)-(S,S)-5 (42%)
(-)-(S)-4 (97%) ee: >99%
(+)-(S)-2 (95%) ee: >99%
R =
5
4
2
(+)-(R,S)- (41%)
(+)-(R)- (96%) ee: >99%
(-)-(R)- (96%) ee: >99%
O
Scheme 1. Resolution of the enantiomers using camphorsulfonyl chloride. (i) 1-(S)-camphorsulfonyl chloride, Et3N, DMF. (ii) NaOH (3 M), THF/MeOH (3:1). (iii) AlCl3, PhOH,
Toluene. Enantiomeric excess was calculated using HPLC analysis (Chiralpak IB). The absolute configuration was determined using X-ray analysis.
Suitable crystals for X-ray analysis of 4 were obtained via slow
evaporation out of methanol and showed (S)-configuration for the
first fraction (Fig. 1).
3. Conclusion
In summary, we reported a novel up scalable route towards
a new bidentate ligand starting from cheap, commercially available
reagents. A copper catalyzed oxidative coupling was used as the
key-step in the synthesis. The resolution was achieved by separa-
tion of diastereoisomers, which were prepared using (1)-(S)-cam-
phorsulfonyl chloride as a chiral substrate. The usefulness of the
new ligands as chiral auxiliary was screened through the alkyny-
lation of benzaldehyde, resulting in moderate ee’s up to 56%.
Although similar experiments using BINOL resulted in a higher
selectivity, optimalization studies regarding this reaction will be
continued. Further investigation of the use of H8-BIFOL or its de-
rivatives in other asymmetric reactions is currently ongoing and
will be reported in due course.
4. Experimental section
4.1. General
All commercial products were used without further purification.
Fig. 1. Representation of two independent molecules in the asymmetric unit with
partial atom labelling and 50% probability displacement ellipsoids; H-atoms as well as
disorder on the cyclohexene rings are omitted for clarity.
All solvents that were used were stored on oven dried molecular
ꢁ
sieves (4 A). All reactions were carried out under an inert atmosphere
(nitrogen) unless other conditions are specified. 1H and 13C NMR
spectra are recorded on a 300 or 400 MHz (75 MHz and 100 MHz for
13C, respectively) Bruker Avance spectrometer with CDCl3 as solvent
and TMS as internal standard. Melting points are uncorrected. HRMS
spectra were recorded on a Kratos HRMS system, EI and CI spectra
were recorded on an HP system. For the resolution on chiral HPLC
a Chiralpak IB column (kept at 20 ꢀC) was used. All chromatographic
separations were performed on a Buchi MPLC system.
2.3. Screening of the catalyst activity
Since several years now, the well established procedure for the
alkynylation of aromatic or aliphatic aldehydes using titanium-
binolate species has become a benchmark system for the evaluation
of newly synthesized bidentate ligands.14 Different parameters
were evaluated using (ꢁ)-(R)-H8-BIFOL, however, the average en-
antiomeric excess of 10 remained moderate (Table 3). Lowering the
temperate to 0 ꢀC increased the selectivity to 56% (Table 3, entry 2).
Changing the amount of ligand did not have any substantial in-
fluence on the enantiomeric excess.
4.1.1. 6,7,8,9-Tetrahydro-2-hydroxydibenzofuran (1). N-Morpholino-
1-cyclohexene (56.48 g, 0.338 mol) was added dropwise over a 1 h
period to a solution of benzoquinone (33.21 g, 0.307 mol) in toluene
Table 3
Screening of the new ligands in alkynylation of benzaldehyde
OH
*
H
1. Et2Zn
2. (R)-H8-BIFOL
Ti(iPrO)4
3. PhCHO
10
Entry
Ligand (mol %)
Alkyne (mol %)
Et2Zn (mol %)
Ti(iPrO)4 (mol %)
T (ꢀC)
Solvent
Time (h)
Yield (%)
ee (%)a
1
2
10
10
5
10
10
20
10
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0.25
0.25
0.25
0.25
0.50
0.25
0.25
RT
0
0
0
0
THF
THF
THF
THF
THF
THF
Toluene
20
19
21
20
20
22
19
69
67
50
53
71
66
63
42
56
52
50
46
52
24
3
4b
5
6
7
0
RT
a
Enantiomeric excess was calculated using HPLC analysis (Chiralpak IB). The main isomer of 10 was determined to be (S).
Benzaldehyde was dissolved in 1 mL THF.
b

3688
H. Kelgtermans et al. / Tetrahedron 67 (2011) 3685e3689
(800 mL) at 0 ꢀC. After addition, stirring at 0 ꢀC was continued for
another 7 h. The precipitate was collected by filtration, washed
thoroughly with toluene and dried overnight in vacuo. The resulting
white, beige solid was mixed well with water (600 mL) and under
mechanical stirring, HCl (100 mL, 5 M) was added dropwise
(30 min). After 6 h the precipitate was collected again, washed well
with water and dried. The obtained slightly red solid was purified by
filtration over silica (CH2Cl2) yielding the pure compound as a white
solid (29.43 g, 51%). Using enamine of lesser quality resulted in
lower yields and required more purification. Mp 103e104 ꢀC (Lit:11
and finally dried in vacuo, yielding 7.35 g as a 1:1 mixture of the
two diastereoisomers. The separation was performed using column
chromatography (8/2:CH2Cl2/C7H16).
4.1.5. Fraction 1 (Rf¼0.29): (S)-20-(((1S,4R)-7,7-dimethyl-2-oxobicyclo
[2.2.1]heptan-1-yl)methanesulfonyloxy)-1,10-bis-(6,7,8,9-tetrahydro-3-
tert-butyldibenzofuran-2-ol) ((S,S)-5). Yield 2.95 g, 42%; mp 83 ꢀC;
½
a 2D0
(s, 1H),
ꢂ
ꢁ85 (c 1, CH2Cl2); 1H NMR (CDCl3, 300 MHz)
d 7.60 (s,1H), d 7.42
d
5.19 (s, 1H),
d
2.63 (m, 4H),
d
2.33e
d
2.08 (m, 4H), 1.96e
d
d
1.63 (m, 13H),
0.80 (m, 3H),
d
1.58 (s, 9H),
0.74 (s, 3H),
d
1.48 (s, 9H),
d
1.31 (m, 1H), d 0.98e
d
104 ꢀC); 1H NMR (CDCl3, 300 MHz)
d
7.23 (d, 1H, J¼9.1 Hz),
6.69 (dd, 1H, J1¼8.2 Hz, J2¼2.7 Hz), 4.64 (s, 1H),
2.56 (m, 2H),
1.87 (m, 4H) ppm; 13C NMR (CDCl3,
151.2, 149.4, 129.9, 112.9, 111.2, 104.1,
22.8,
20.6 ppm; MS (CI) m/z (MHþ) 189.
d
6.82 (d,
d
d
0.54 (s, 3H) ppm; 13C NMR (CDCl3,
1H, J¼1.8 Hz),
d
d
75 MHz)
d
212.9,
d
156.1,
d
154.9,
126.7,
d
152.1,
121.2,
d
149.2,
115.3,
d
148.5,
113.9,
d
144.6,
113.2,
d
2.71 (m, 2H),
d
d
d
d
d
d
139.6,
110.5,
d
133.8,
109.6,
d 128.0,
58.4,
d
d
d
d
d
75 MHz)
d
155.4,
23.0,
d
d
d
d
d
d
d
d
d
50.8,
d
47.9,
d
43.2,
d
42.5,
d
35.7,
22.6,
d
35.6,
22.8,
d
23.67,
d
d
d
35.3,
20.3,
d
31.5,
20.1,
d
30.0,
19.7,
d
26.9,
d
26.6,
d
26.1,
d
23.8,
d
22.7,
d
d
d
d
d
19.3 ppm; MS (EI) m/z (Mþ) 700; HRMS calcd
4.1.2. 6,7,8,9-Tetrahydro-2-hydroxy-3-tert-butyldibenzofuran (3). A
mixture of 1 (18.8 g, 0.1 mol), tert-butylchloride (27.77 g, 32.67 mL,
0.3 mol) and ZnCl2 (34.07 g, 0.25 mol) in CH2Cl2 (200 mL) was
refluxed for 9 h (after about 20 min the product started to pre-
cipitate). The reaction mixture was then hydrolyzed in water
(200 mL) and extracted with CH2Cl2. The organic layer was sepa-
rated, washed with saturated NaHCO3 and brine, dried over MgSO4
and evaporated under reduced pressure, yielding 23.4 g (96%) of
pure compound as a white solid. If necessary, the product can be
recrystallized from chloroform to remove small impurities. Mp
for [C42H52O7S] 700.34338, found 700.34234.
4.1.6. Fraction 2 (Rf¼0.19): (R)-20-(((1S,4R)-7,7-dimethyl-2-oxobicyclo
[2.2.1]heptan-1-yl)methanesulfonyloxy)-1,10-bis-(6,7,8,9-tetrahydro-3-
tert-butyldibenzofuran-2-ol) ((R,S)-5). Yield 2.85 g, 41%; mp 81 ꢀC;
a 20
½ ꢂD þ85 (c 1, CH2Cl2); 1H NMR (CDCl3, 300 MHz)
d
7.60 (s,1H),
2.17e
0.79 (m, 6H), 0.50 (s, 6H)
d
7.41
(s, 1H),
13H),
ppm; 13C NMR (CDCl3, 75 MHz)
d
5.34 (s, 1H),
d
2.65 (m, 5H),
d
2.23 (m, 1H),
d
d
d 1.66 (m,
d
1.55 (s, 9H),
d
1.48 (s, 9H),
d
1.40e
d
d
213.1,
134.5,
d
156.2,
128.3,
d
154.6,
126.5,
d
d
152.1,
121.5,
d
d
d
d
149.1,
115.3,
d
148.5,
d
144.4,
113.2,
35.6, 35.4,
22.6, 22.5,
d 139.5,
d
d
d
d
201e202 ꢀC; 1H NMR (CDCl3, 300 MHz)
4.65 (s, 1H), 2.69 (m, 2H), 2.53 (m, 2H),
9H) ppm; 13C NMR (CDCl3, 75 MHz)
154.6,
35.1,
d
7.32 (s, 1H),
d
d
6.67 (s, 1H),
1.85 (m, 4H), 1.44 (s,
132.6,
22.9,
d
113.9,
d
d
110.6,
d
109.7,
29.9,
d
58.4,
27.00,
19.3,
d
50.5,
26.6,
47.9,
25.3,
d
42.9,
23.8,
d
d
d
d
42.4,
22.9,
d
35.8,
22.8,
d
d
d
31.6,
d
d
d
d
d
d
d
d
150.3,
d
149.6,
d
d
d
d
d
20.5,
d
20.1,
d
18.5 ppm; MS (EI)
d
d
127.0,
d
112.3,
d
109.0,
d
105.0,
d
d
30.0,
d
23.7,
d
23.1,
d
m/z (Mþ) 700; HRMS calcd for [C42H52O7S] 700.34338, found
20.7 ppm; MS (EI) m/z (Mþ) 244, (eCH3) 229; HRMS calcd for
700.34446.
[C16H20O2] 244.14633, found 244.14606.
4.2. General procedure for the hydrolysis of the sulfonate
esters
4.1.3. Large scale preparation of 1,10-bis-(6,7,8,9-tetrahydro-2-hy-
droxy-3-tert-butyldibenzofuran) (rac-4). To a mixture of 3 (10.02 g,
0.0411 mol) and Cu(NO3)2.3H2O (0.993 g, 0.0041 mol) in CH2Cl2
(200 mL), benzylamine (0.881 g, 0.899 mL, 0.0082 mol) was added.
The resulting solution was stirred at room temperature under O2
atmosphere (ambient pressure) during 17 h after which it was
poured into water (300 mL), acidified with HCl and finally extracted
with CH2Cl2. The organic layer was dried over MgSO4 and con-
centrated in vacuo, yielding a dark red solid, which was dissolved in
refluxing EtOH (230 mL) and stored overnight at ꢁ18 ꢀC. The pre-
cipitate was collected by filtration, washed with cold ethanol and
dried, yielding a slightly pink solid (7.62 g, 76%), which was pure
enough for further reactions according to 1H NMR and TLC analysis.
The coloured impurities (o-quinone-like compounds) can be re-
A mixture of (S,S)-5 or (R,S)-5 (0.700 g, 1 mmol), NaOH (10 mL,
3 M) in THF/MeOH (30 mL:10 mL) was refluxed during 22 h. After
this period, the reaction mixture was cooled down to room tem-
perature, poured into water and neutralized (HCl). The organic
fraction was extracted using CH2Cl2, washed with brine and finally
dried over MgSO4. The resulting red oil after evaporation was pu-
rified using flash chromatography (7/3:C7H16/CH2Cl2) yielding the
ligands as a white solid.
4.2.1. (S)-1,10-Bis-(6,7,8,9-tetrahydro-2-hydroxy-3-tert-butyldi-
benzofuran) ((S)-4). Yield 97%, mp 259 ꢀC; ½a D20
ꢂ
e158 (c 0.5, CH2Cl2),
spectroscopic data were identical with that of rac-(4); ee >99%
(Chiralpak IB, hexane, flow rate¼0.5 mL/min, retention time¼11.9).
moved if necessary by flash column chromatography (9/1: C7H16
/
CH2Cl2). The filtrate after crystallization was concentrated in vacuo
and purified by column chromatography (9/1: C7H16/CH2Cl2),
yielding another 0.760 g (8%) of pure 4. Mp 194e195 ꢀC; 1H NMR
4.2.2. (R)-1,10-Bis-(6,7,8,9-tetrahydro-2-hydroxy-3-tert-butyldi-
benzofuran) ((R)-4). Yield 96%, mp 257 ꢀC; ½a D20
þ158 (c 0.5, CH2Cl2),
ꢂ
(CDCl3, 600 MHz)
(m, 2H), 1.78 (m, 4H),
NMR (CDCl3, 75 MHz)
d
7.44 (s, 2H),
d
5.08 (s, 2H),
1.47 (s, 18H) ppm; 13C
148.8, 132.6, 126.4,
23.8, 22.7, 22.7,
d
2.67 (m, 4H),
d
2.02
spectroscopic data were identical with that of rac-(4); ee >99%
(Chiralpak IB, hexane, flow rate¼0.5 mL/min, retention time¼11.5).
d
d
1.58 (m, br, 6H), d
d
155.0,
d
149.2,
d
d
d
d
112.8,
d
109.9,
d
109.1,
d
35.3,
d
29.9,
d
d
d
4.3. General procedure for the de-tert-butylation of (4)
d
20.1 ppm; MS (EI) m/z (Mþ) 486, (eCH3) 471, 415 (eC5H12); HRMS
calcd for [C32H38O4] 486.27701, found 486.27799.
To a solution of (S)-4 or (R)-4 (0.265 g, 0.545 mmol) and phenol
(0.359 g, 3.816 mmol) in toluene (10 mL), AlCl3 (0.218 g,1.636 mmol)
was added at room temperature. Stirring was continued under
ambient temperature during 4 h, after which the reaction mixture
was hydrolyzed in water. The organic fractions were extracted with
CH2Cl2, washed with saturated NaHCO3 and finally dried over
MgSO4. After evaporation and purification using column chroma-
tography (CH2Cl2), the compound was obtained as a white solid. 1H
4.1.4. Esterification and resolution of 1,10-bis-(6,7,8,9-tetrahydro-2-
hydroxy-3-tert-butyldibenzofuran). To a solution of rac-4 (4.86 g,
10 mmol) and 1(S)-camphorsulfonyl chloride (4.518 g, 18 mmol) in
dry DMF (60 mL) at 0 ꢀC, Et3N (10 mL) was added dropwise. After
the addition was complete the mixture was allowed to heat up to
room temperature and stirred for 3 h. The resulting suspension was
poured into water (400 mL) after which the precipitate was col-
lected by filtration, washed well with water and saturated NH4Cl
NMR (CDCl3, 300 MHz)
J¼8.6 Hz), 4.75 (s, 2H),
d
7.38 (d, 2H, J¼8.8 Hz), 6.92 (d, 2H,
d
d
d
2.69 (m, 4H), 2.01 (m, 2H), d 1.79 (m, 6H),
d

H. Kelgtermans et al. / Tetrahedron 67 (2011) 3685e3689
3689
d
d
d
1.57 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz)
129.2, 113.3, 112.4, 111.1, 109.1,
d
156.0,
23.8,
d
d
150.1, 148.9,
22.7, d 22.6,
d
a fellowship to H.K. We thank the Fonds voor Wetenschappelijk
Onderzoek (FWO), the ministerie voor Wetenschapsbeleid and the
K.U. Leuven for continuing financial support.
d
d
d
d
d
20.3 ppm; MS (EI) m/z (Mþ) 374; HRMS calcd for [C24H22O4]
374.15449, found 374.15371.
Supplementary data
4.3.1. (S)-1,10-Bis-(6,7,8,9-tetrahydro-2-hydroxy-dibenzofuran) ((S)-
2). Yield 95%, mp 57e61 ꢀC; ½a D20
þ58 (c 1, CH2Cl2); ee >99%
ꢂ
Copies of NMR spectra and chiral chromatograms. Supplemen-
tary data related to this article can be found online at doi:10.1016/
j.tet.2011.03.077. These data include MOL files and InChIKeys of the
most important compounds described in this article.
(Chiralpak IB, 50/50:CH2Cl2/hexane, flow rate¼1.2 mL/min, re-
tention time¼7.1).
4.3.2. (R)-1,10-Bis-(6,7,8,9-tetrahydro-2-hydroxy-dibenzofuran) ((R)-
2). Yield 96%, mp 59e62 ꢀC; ½a D20
ꢁ58 (c 1, CH2Cl2); ee >99%
ꢂ
References and notes
(Chiralpak IB, 50/50:CH2Cl2/hexane, flow rate¼1.2 mL/min, re-
tention time¼6.7).
1. For a general review on the use of BINOL, see: Brunel, J. M. Chem. Rev. 2007, 107
PR1ePR45.
2. For recent reviews on substituted BINOL derivatives, see: (a) Kocovsky, P.;
ꢂ
ꢀ
4.4. General procedureforthealkynylationofbenzaldehyde(10)
ꢂ
ꢂ
Vyskocil, S.; Smrcina, M. Chem. Rev. 2003, 103, 3213e3245; (b) Chen, Y.; Yekta,
S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155e3211.
3. For a review on the use of H8-BINOL based ligands, see: Au-Yeung, T. T.-L.; Chan,
S.-S.; Chan, A. S. C. Adv. Synth. Catal. 2003, 345, 537e555.
To a flame-dried flask containing THF (2 mL), phenylacetylene
(0.204 g, 0.220 mL, 2 mmol) and Et2Zn (2 mL, 1 M solution in
hexane) were added dropwise. After refluxing for 1 h, the reaction
mixture was cooled down to room temperature, and a solution
containing the ligand (10 mol %) and Ti(OiPr)4 (25 mol %) in THF
(2 mL) was added via cannula. The resulting yellow mixture was
stirred for another hour at room temperature (reactions performed
at 0 ꢀC were cooled before addition of benzaldehyde) after which
benzaldehyde (0.106 g, 0.101 mL, 1 mmol) was added. Stirring was
continued during the times indicated in Table 3. After the reaction
was complete (judged by TLC analysis), the solution was poured
into saturated NH4Cl, extracted with EtOAc and the organic frac-
tions dried over MgSO4. After evaporation of the solvent under
reduced pressure, compound 8 was obtained as a light yellow oil
after using column chromatography (15/85:EtOAc/C7H16). Enan-
tiomeric excess was determined by chiral HPLC using a Chiralpak IB
column (5/5:CH2Cl2/C7H16, flowrate 0.75 mL/min). 1H NMR (CDCl3,
4. For some recent publications on the use of H4- and H8-BINOL based ligands,
see: (a) Wang, B.; Feng, X.; Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org. Chem. 2002,
67, 2175e2182; (b) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002,
124, 10e11; (c) Lam, K. H.; Xu, L.; Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W.-H.; Chan,
A. S. C. Adv. Synth. Catal. 2005, 347, 1755e1758; (d) Kim, J. G.; Camp, E. H.;
Walsh, P. J. Org. Lett. 2006, 8, 4413e4416; (e) Harada, T.; Ukon, T. Tetrahedron:
Asymmetry 2007, 18, 2499e2502; (f) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song,
L.; Feng, Z.; Gong, L. Z. Org. Lett. 2009, 11, 4620e4623.
5. (a) Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.;
Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am.
Chem. Soc. 1996, 118, 3392e3405; (b) Loncaric, C.; Wulff, W. D. Org. Lett.
2001, 3, 3675e3678; (c) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130,
6922e6923; (d) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009,
11, 5186e5189.
6. (a) Gelpke, A. E. S.; Fraanje, J.; Goubitz, K.; Schenk, H.; Hiemstra, H. Tetrahedron
1997, 53, 5899e5908; (b) Gelpke, A. E. S.; Kooijman, H.; Spek, A. L.; Hiemstra, H.
Chem.dEur. J. 1999, 5, 2472e2482; (c) Botman, P. N. M.; Postma, M.; Fraanje, J.;
Goubitz, K.; Schenk, H.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem.
2002, 12, 1952e1955; (d) Botman, P. N. M.; Fraanje, J.; Goubitz, K.; Peschar, R.;
Verhoeven, J. W.; van Maarseveen, J. H.; Hiemstra, H. Adv. Synth. Catal. 2004,
346, 743e754.
7. BIFOL was prepared by Hiemstra in a four-step synthesis starting from di-
benzofuran-2-ol. Unfortunately, recent commercial sources of the latter are
expensive, but it can be prepared in a three-step process out of dibenzofuran in
a moderate yield. However, the overall seven-step route suffers from low yields,
which is surely the reason why BIFOL has not found wider application as
a chiral auxiliary.
300 MHz)
d
7.47e
d
7.29 (m, br, 10H),
d
5.69 (d, 1H, J¼6.0 Hz),
d
2.37
131.9,
d 65.24 ppm.
(d, 1H, J¼6.2 Hz) ppm; 13C NMR (CDCl3, 75 MHz)
d
140.8,
d
d
128.8,
d
128.7,
d
128.6,
d
128.4,
d
126.9,
d
88.8,
d
86.8,
4.4.1. Crystal data for (S)-4. C32H38O4, M¼486.62, colourless plate,
0.15ꢃ0.12ꢃ0.05 mm3, monoclinic, space group P21 (No. 4),
8. As with H8-BINOL, any electrophilic aromatic substitution happens exclusively
at the 3 and 30-position.
a¼10.6393(8), b¼21.6225(18), c¼11.6943(9) A,
b
¼91.397(5)ꢀ,
ꢁ
9. For some recent papers on copper-mediated oxidative coupling, see: (a) Na-
kajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S. J. Org. Chem. 1999, 64,
2264e2271; (b) Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. Organometallics
2002, 21, 4513e4522; (c) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Ko-
zlowski, M. C. J. Org. Chem. 2003, 68, 5500e5511.
10. For some recent papers on vanadium-mediated oxidative coupling, see: (a)
Guo, Q.-X.; Wu, Z.-J.; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo, S.-W.; Cun, L.-F.;
Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 13927e13938; (b) Takizawa, S.;
Katayama, T.; Kameyama, C.; Onitsuka, K.; Suzuki, T.; Yanagida, T.; Kawai,
T.; Sasai, H. Chem. Commun. 2008, 1810e1812; (c) Takizawa, S.; Katayama,
T.; Somei, H.; Asano, Y.; Yoshida, T.; Kameyama, C.; Rajesh, D.; Onitsuka, K.;
Suzuki, T.; Mikami, M.; Yamataka, H.; Jayaprakash, D.; Sasai, H. Tetrahedron
2008, 64, 3361e3371.
3
ꢁ
3
V¼2689.5(4) A , Z¼4, Dc¼1.202 g/cm , F000¼1048, Bruker SMART
6000, Cu Ka radiation, l
¼1.54178 A, T¼100(2) K, 2qmax¼142.8ꢀ,
ꢁ
23,148 reflections collected, 9521 unique (Rint¼0.0927). Final
GooF¼1.027, R1¼0.0647, wR2¼0.1340, R indices based on 7057 re-
flections with I>2sigma(I) (refinement on F2), 713 parameters, 42
restraints. Lp and absorption corrections applied,
m
¼0.612 mmꢁ1
.
Absolute structure parameter¼0.0(2).15 The structure was solved
and refined using the SHELX-97 suite of programs.16 The program
Mercury was used to prepare figures.17 All hydrogen atoms were
positioned geometrically and refined using a riding model with
11. Prado, S.; Janin, Y. L.; Saint-Joanis, B.; Brodin, P.; Michel, S.; Koch, M.; Cole, S. T.;
Tillequin, F.; Bost, P.-E. Bioorg. Med. Chem. 2007, 15, 2177e2186.
12. Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.; Hoveyda, A. H.;
Schrock, R. R. Angew. Chem., Int. Ed. 2001, 40, 1452e1456.
ꢁ
ꢁ
CeH¼0.99e0.95 A, OeH¼0.84 A and Uiso(H)¼1.2 Uequiv(C, O),
1.5 Uequiv (methyl C). The cyclohexene rings C7eC12, C43eC48 and
C61eC66 werepartially disordered and modelled overtwopositions
with site occupancy ratios of 71:29, 78:22 and 79:21, respectively.
The CeC bonds in the disordered moieties and the displacement
parameters were restrained to be approximately equal.
13. (a) Toda, F.; Tanaka, K. J. Org. Chem. 1994, 59, 5748e5751; (b) Wang, Y.; Sun, J.;
Ding, K. Tetrahedron 2000, 56, 4447e4451.
14. (a) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124,
12636e12637; (b) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855e1857; (c) Yang, F.;
Xi, P.; Jingbo, L.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457e5460; (d) Yue, Y.;
Turlington, M.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 8681e8689.
15. Flack, H. D. Acta Crystallogr. 1983, A39, 876e881.
Acknowledgements
16. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
17. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock,
E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crys-
tallogr. 2008, 41, 466e470.
The Instituut voor de aanmoediging van innovatie door Weten-
schap en Technologie in Vlaanderen (IWT) is acknowledged for