A novel class of bidentate ligands with a conformationally flexible biphenyl unit built into a planar chiral [2.2]paracyclophane backbone

Article abstract of DOI:10.1016/S0040-4039(03)00711-1

We report the synthesis of a novel class of planar chiral bidentate aryl[2.2]paracyclophane ligands. For the first time in the [2.2]paracyclophanyl series the Pd-catalyzed Suzuki cross-coupling was employed for the formation of the arylparacyclophanyl skeleton. From the two possible approaches: (a) cross-coupling of [2.2]paracyalophanylboronic acids with aryl halides; (b) cross-coupling of [2.2]paracyclophanyl halides with arylboronic acids, the latter was found to be more efficient. This approach was successfully used for the synthesis of a wide range of aryl[2.2]paracyclophanes with different types of substitution patterns (ortho-, pseudo-ortho- or pseudo-gem-arrangement of the functionally-substituted aryl fragment with respect to the substituent in the paracyclophane ring).

Full text of DOI:10.1016/S0040-4039(03)00711-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3801–3804
A novel class of bidentate ligands with a conformationally
flexible biphenyl unit built into a planar chiral
[2.2]paracyclophane backbone
V. I. Rozenberg,* D. Yu. Antonov, R. P. Zhuravsky, E. V. Vorontsov and Z. A. Starikova
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow,
Russia
Received 30 January 2003; revised 5 March 2003; accepted 14 March 2003
Abstract—We report the synthesis of a novel class of planar chiral bidentate aryl[2.2]paracyclophane ligands. For the first time
in the [2.2]paracyclophanyl series the Pd-catalyzed Suzuki cross-coupling was employed for the formation of the arylparacy-
clophanyl skeleton. From the two possible approaches: (a) cross-coupling of [2.2]paracyalophanylboronic acids with aryl halides;
(b) cross-coupling of [2.2]paracyclophanyl halides with arylboronic acids, the latter was found to be more efficient. This approach
was successfully used for the synthesis of a wide range of aryl[2.2]paracyclophanes with different types of substitution patterns
(ortho-, pseudo-ortho- or pseudo-gem-arrangement of the functionally-substituted aryl fragment with respect to the substituent in
the paracyclophane ring). © 2003 Elsevier Science Ltd. All rights reserved.
an ortho-position (Type I), a pseudo-ortho-position
(Type II) or a pseudo-gem-position (Type III) towards
the aryl substituent to allow chelation with a metal
atom (Fig. 1).
One general strategy in the field of asymmetric synthe-
sis is based on the application of catalysts constructed
from chirally rigid ligands. A new powerful conceptual
approach for asymmetric catalysis involves the design
and application of catalysts, combining conformation-
ally flexible ligands and a chirally stable stereogenic
part.1,2 These self-organized diastereomeric catalysts
can provide better stereocontrol due to dynamic con-
formational behavior and, as a result, superior fine-tun-
For the synthesis of these types of bifunctional
arylparacyclophanes5 we used Suzuki cross-coupling,
the most versatile, pragmatic and extensively utilized
method for the synthesis of functionally substituted
unsymmetrical biaryls.6
ing of the chiral environment. As
a rule, the
conformationally flexible part of these catalysts is
played by a biphenyl unit or derivatives thereof.2,3
Synthesis of ortho-substituted aryl[2.2]paracyclophanes
Earlier4 we reported a number of effective approaches
to the synthesis of a series of chiral bidentate ligands
constructed from one or two [2.2]paracyclophane moi-
eties and possessing not only planar chiral elements but
also central ones (multichirality). In this study we
describe a novel class of planar chiral bidentate ligands,
with a conformationally flexible biphenyl unit built into
a configurationally stable [2.2]paracyclophane back-
bone. In these ligands the biphenyl unit is formed by
one aromatic ring of the [2.2]paracyclophane and the
ortho-substituted benzene ring. The second functional
We considered two possible synthetic routes to aryl-
paracyclophanes of Type I, namely, cross-coupling of
paracyclophanylboronic acid (obtained from 4-
hydroxy[2.2]paracyclophane 1) with bromoanisole and
paracyclophanyl halides (from 1) with arylboronic
acids.
group
Y
can be placed in any ring of the
[2.2]paracyclophane backbone, but must be located in
* Corresponding author. Tel.: +7-095-135-9268; fax: +7-095-135-5085;
e-mail: lera@ineos.ac.ru
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00711-1

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V. I. Rozenberg et al. / Tetrahedron Letters 44 (2003) 3801–3804
(a) Cross-coupling of paracyclophanylboronic acid and
ortho-bromoanisole. Lithiation of MOM-protected
paracyclophanol 27 with n-BuLi in Et2O followed by
treatment of the reaction mixture with B(OMe)3
resulted in the corresponding paracyclophanylboronic
acid 3 which was then used in cross-coupling without
isolation. The yield of 3 (50%) was estimated from the
preparative yield of 5-hydroxy-4-methoxymethylene-
oxy[2.2]paracyclophane 4 obtained by oxidation of 3 in
situ with hydrogen peroxide in a basic medium (Scheme
1).
paracyclophane 5 was isolated by preparative chro-
matography on SiO2 in 44% yield. The unreacted
iodophenol 7 was recovered from the reaction mixture
in 51% yield. The structure of 5 (CCDC 202651) was
studied by X-ray diffraction analysis (Fig. 2).
In order to prepare the biphenol ligand 1211 from 5 we
first removed the MOM protective group by hydrolysis
using HCl/MeOH. The resulting 11 was obtained in
quantitative yield; however, numerous Me-deprotection
attempts under various conditions were unsuccessful.
For instance, the cyclic [2.2]paracyclophano[4,5-
b]benzofuran (55%) as the only product was obtained
in the case of demethylation in HBr/AcOH (1:1) mix-
ture. For this reason target 12 was synthesized by the
Cross-coupling of 3 and ortho-bromoanisole (2 equiv.)
was carried out by refluxing the reagents in a toluene/
MeOH/H2O mixture in the presence of Na2CO3 as base
and Pd(dppf)Cl2 as catalyst (10 mol%) to produce the
desired biaryl 5 in up to 20% yield (Scheme 1).
cross-coupling
reaction
of
7
and
ortho-
methoxymethyleneoxyphenylboronic acid (instead of
10) followed by hydrolysis of the intermediate double
MOM-protected cyclophane (Scheme 3).
(b) Cross-coupling of [2.2]paracyclophanyl halides and
arylboronic acids. For the regioselective introduction of
a halogen substituent into the molecule of phenol 1, its
derivatives 27 and 68 were ortho-lithiated and then Li
was replaced with iodine (Scheme 2). Thus 4-iodo-5-
methoxymethyleneoxy[2.2]paracyclophane 7 (80% as a
mixture with 5% of unreacted 2) and 5-diethylcar-
In principle, the three ortho-substituted biphenyl units
in arylparacyclophanes of Type I can be either flexible
1
or enantiomerically stable. Thus in the H NMR spec-
trum of 5 only one set of the signals detected in the
temperature range 293–383
K can probably be
bamoyloxy-4-iodo[2.2]paracyclophane
8 (98%) were
attributed to a chirally rigid structure. In the spectrum
of the sterically less hindered 11 a double set of signals
indicated the existence of two rapidly interconverting
diastereomers. The energy barrier to rotation for 11
(17–18 kcal mol−1) was estimated from the coalescence
temperature (390 K) for the methoxy signals using the
synthesized. Removal of the MOM protecting group in
7 with HCl/MeOH resulted in 5-hydroxy-4-iodo[2.2]-
paracyclophane 9 in 80% yield.
Cross-coupling of halide 7 and ortho-anisylboronic acid
10 was performed under anhydrous conditions (tolu-
ene/K3PO4/Pd(dppf)Cl2)9 (Scheme 3). The aryl[2.2]-
1
variable-temperature H NMR technique.
Scheme 3. Reagents and conditions: (i) 10, Pd(dppf)Cl2 (2
mol%) and K3PO4 in toluene, 100°C, 44%; (ii) HCl/MeOH,
40°C, >98%; (iii) 2-B(OH)2-C6H4OMOM, Pd(dppf)Cl2 (2
mol%), K3PO4, toluene, 100°C; then HCl/MeOH, reflux,
39%.10
Scheme 1. Reagents and conditions: (i) NaH, DMF, rt; then
MOMCl, 95%; (ii) n-BuLi, Et2O, 0°C; then B(OMe)3; (iii)
H2O2, NaOH/H2O, Et2O, 50%; (iv) 2-BrC6H4OMe,
Pd(dppf)Cl2 (10 mol%), toluene/MeOH/H2O, Na2CO3, reflux,
up to 20%.
Scheme 2. Reagents and conditions: (i) Z=MOM: n-BuLi,
Et2O, 0°C; then I2, 75%; Z=CONEt2: n-BuLi, TMEDA,
THF, −78°C; then I2, 98%; (ii) HCl/MeOH, reflux, 80%.
Figure 2. The X-ray crystal structures of 5 and 21.

V. I. Rozenberg et al. / Tetrahedron Letters 44 (2003) 3801–3804
3803
Thus we have found that both routes (a) and (b) can be
used for the synthesis of disubstituted aryl[2.2]-
paracyclophanes, however, the cross-coupling of para-
cyclophanyl halides with arylboronic acids is more
effective. It should be noted that, arylparacyclophanes
of Type I can be obtained from the enantiomers of 1,
the efficient resolution of which has recently been
reported by us.12
Synthesis of pseudo-ortho-substituted aryl[2.2]paracyclo-
phanes
For the synthesis of pseudo-ortho-substituted aryl[2.2]-
paracyclophanes (Type II) we chose pseudo-ortho-
dibromo[2.2]paracyclophane 13 because of its easy syn-
thetic access13 and the possibility of obtaining it in
optically pure form.14
Scheme 5. Reagents and conditions: (i) 10, Pd(dppf)Cl2 (2
mol%), K3PO4, toluene, 105°C, 80%; (ii) LiAlH4, Et2O, rt,
>98%; (iii) DDQ, dioxane, rt, 98%; (iv) HBr (48%), AcOH,
reflux, 98%; (v) LiAlH4, Et2O, rt, 98%; (vi) DDQ, dioxane, rt,
84%.
Cross-coupling of 13 with 10 resulted in two products,
14 and 15 (Scheme 4), which were separated by prepar-
ative chromatography on SiO2. The minor 4,12-bis(2-
methoxyphenyl)[2.2]paracyclophane 15 (37%) resulted
from cross-coupling at both bromine atoms. In contrast
to ortho-substituted aryl[2.2]paracyclophane 11,
removal of the methyl groups in compound 15 with
HBr/AcOH occurred smoothly and led to biphenol 16
in 80% yield (Scheme 4). This biphenol is the first
example of a unique bidentate ligand with not only one,
but two conformationally flexible ortho-functionally-
substituted biphenyl units built into the chiral
[2.2]paracyclophane skeleton.
paracyclophanyl-4-carboxylic acid, whose efficient reso-
lution has been reported many times.16
Cross-coupling of 17 and 10 led to 4-methoxycarbonyl-
13-(2-methoxyphenyl)[2.2]paracyclophane 18 (80%),
while the unreacted bromide 17 was recovered from the
reaction mixture in 15% yield (Scheme 5).
The major reaction product was 4-bromo-12-(2-
methoxyphenyl)[2.2]paracyclophane 14, isolated in 51%
yield. The presence of a bromine substituent in 14
opens up considerable prospects for obtaining a series
of pseudo-ortho-substituted arylparacyclophanes with
various donor functional groups (-OH, -CHO, -SR,
-PR2, -NR2, etc.).
It should be noted that aryl[2.2]paracyclophane 18 has
vast synthetic potential due to the possibility of modifi-
cation at the methoxycarbonyl group, which allows the
synthesis of e.g. oxazoline, amino, hydroxy as well as
many other functionalised ligands. Scheme 5 illustrates
the first examples of the application of 18 as a new
ligand precursor. Reduction of the ester group of 18
with LiAlH4 resulted in methoxyarylcarbinol 19 in
quantitative yield. Subsequent oxidation of 19 under
mild conditions (DDQ, dioxane, room temperature)
gave methoxyarylaldehyde 20. Refluxing of compound
18 in a HBr/AcOH mixture led to a high yield of
hydroxyarylcarboxylic acid 21. The structure of 21
(CCDC 202652) was studied by X-ray diffraction anal-
ysis (Fig. 2). Reduction of 21 with LiAlH4 in ether
resulted in arylhydroxycarbinol 22 (98%). Oxidation of
22 with DDQ occurred analogously to the oxidation of
carbinol 19 and gave hydroxyarylaldehyde 23 in 84%
yield.
Synthesis of pseudo-gem-substituted aryl[2.2]paracyclo-
phanes
The 4-bromo-13-methoxycarbonyl[2.2]paracyclophane
1715 was used as starting compound for the synthesis
aryl[2.2]paracyclophanes of Type III, because optically
active 17 can be readily obtained from enantiomers of
In summary, a number of planar chiral bidentate
aryl[2.2]paracyclophane ligands of different types were
obtained by Suzuki cross-coupling reactions. Since this
method tolerates a broad range of functional groups it
will be possible to synthesize a variety of aryl[2.2]
paracyclophane ligands bearing different pairs of donor
groups. Preparation of aryl[2.2]paracyclophanes in
enantiomerically pure forms and their application in
asymmetric catalysis are currently being investigated.
Scheme 4. Reagents and conditions: (i) 10, Pd(dppf)Cl2 (2
mol%), K3PO4, toluene, 105°C, 51% of 14 and 37% of 15; (ii)
HBr (48%), AcOH, reflux, 80%.

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V. I. Rozenberg et al. / Tetrahedron Letters 44 (2003) 3801–3804
was extracted with toluene/THF (1/1) mixture, the com-
Acknowledgements
bined organic layers were dried over Na2SO4, concentrated
under reduced pressure and purified by preparative chro-
matography on SiO2. Analytical data for key compounds
5, 14 and 18 are as follows: Compound 5: Rf=0.3
(CH2Cl2). Mp 106.5–107°C. Anal. calcd for C25H26O3: C,
80.18; H, 7.00. Found C, 80.14; H, 7.11. 1H NMR (400.13
MHz, CDCl3; l, ppm; J, Hz): 2.65–2.95 (m, 5H, -CH2-
CH2-); 2.94 (s, 3H, -OCH2OCH3 or -OCH3); 3.03–3.12 (m,
1H, -CHHCH2-); 3.14–3.24 (m, 1H, -CHHCH2-); 3.31–
3.40 (m, 1H, -CHHCH2-); 3.65 (s, 3H, -OCH2OCH3 or
-OCH3); 4.47 (d, 2J=5.9, 1H, -OCHHOCH3); 4.56 (d,
2J=5.9, 1H, -OCHHOCH3); 6.39 (d, 3J=7.8, 1H, PC-
arom-H); 6.47 (d, 3J=7.8, 1H, PC-arom-H); 6.69 (m, 3H,
Financial support of this work by the Russian Founda-
tion for Basic Research (Project Nos. 03-03-32214 and
00-03-32807) and by funds provided by the EU
Descartes Prize is gratefully acknowledged.
References
1. (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.;
Pham, T.; Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495;
(b) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997,
53, 9541; (c) Miura, K.; Katsuki, T. Synlett 1999, 783; (d)
Balsells, J.; Walsh, P. J. Am. Chem. Soc. 2000, 122, 1802;
(e) Mikami, K.; Aikava, K. Org. Lett. 2002, 4, 99.
2. (a) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K.
Angew. Chem., Int. Ed. 2002, 41, 1551; (b) Reetz, M. T.;
Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38, 179; (c)
Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 8737.
3. (a) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda,
I. J. Org. Chem. 2000, 65, 3326; (b) Mikami, K.; Aikava,
K.; Yusa, Y.; Hatano, M. Org. Lett. 2002, 4, 91; (c)
Mikami, K.; Aikava, K.; Yusa, Y. Org. Lett. 2002, 4, 95.
4. For example, see recent papers: (a) Rozenberg, V.;
Danilova, T.; Sergeeva, E.; Vorontsov, E.; Starikova, Z.;
Lysenko, K.; Belokon’, Y. Eur. J. Org. Chem. 2000, 3295;
(b) Rozenberg, V.; Antonov, D.; Zhuravsky, R.;
Vorontsov, E.; Khrustalev, V.; Ikonnikov, N.; Belokon’,
Yu. Tetrahedron: Asymmetry 2000, 11, 2683; (c) Rozen-
berg, V.; Danilova, T.; Sergeeva, E.; Vorontsov, E.;
Starikova, Z.; Korlyukov, A.; Hopf, H. Eur. J. Org. Chem.
2002, 3, 468; (d) Sergeeva, E.; Rozenberg, V.; Antonov, D.;
Vorontsov, E.; Starikova, Z.; Hopf, H. Tetrahedron: Asym-
metry 2002, 13, 1121.
5. The synthesis of some arylparacyclophanes bearing an
alkylsubstituted aromatic fragment by the cross-coupling
reaction of paracyclophanyl halides and arylmagnesium
halides has already been described: (a) Dickerman, S. C.;
Milstein, N. J. Org. Chem. 1967, 32, 852; (b) Rozenberg,
V. I.; Sergeeva, E. V.; Kharitonov, V. G.; Vorontsova, N.
V.; Vorontsov, E. V.; Mikul’shina, V. V. Russ. Chem. Bull.
1994, 43, 1018; (c) Kus, P.; Dalley, N.; Kuo, X.; Rogers,
R.; Bartsch, R. Pol. J. Chem. 2001, 75, 1351 and previous
papers by these authors.
6. Recent reviews: (a) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633; (b) Hassan, J.; Sevignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359.
7. Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.;
Pizzo, F. J. Org. Chem. 1997, 62, 3744.
3
PC-arom-H); 6.87 (br d, J=7.8, 1H, PC-arom-H); 6.94
3
(br d, J=8.1, 1H, arom-H); 7.15 (m, 1H, arom-H); 7.33
(m, 1H, arom-H); 7.82 (dd, 3J=8.1, 4J=1.8, 1H, arom-H).
MS (EI, 70 eV), m/z: 374 (29, M+), 239 (17), 238 (23), 225
(78), 195 (17), 165 (15), 105 (11), 104 (26). Compound 14:
Rf=0.14 (CCl4). Mp 172–173°C. Anal. calcd for
C23H21BrO: C, 70.24; H, 5.38; Br, 20.32. Found: C, 70.34;
H, 5.49; Br, 20.44. 1H NMR (400.13 MHz, CDCl3; l, ppm;
J, Hz): 2.36–2.50 (m, 1H, -CHHCH2-); 2.79–2.94 (m, 3H,
-CH2CH2-); 3.07–3.23 (m, 3H, -CH2CH2-); 3.47–3.58 (m,
3
1H, -CHHCH2-); 3.72 (s, 3H, -OCH3); 6.51 (dd, J=7.8,
4J=1.8, 1H, PC-arom-H); 6.61 (d, 3J=7.8, 1H, PC-arom-
H); 6.65 (m, 2H, PC-arom-H); 6.71 (d, 4J=1.8, 1H,
PC-arom-H); 6.94 (d, 3J=8.1, 1H, arom-H); 6.99 (d,
4J=1.8, 1H, PC-arom-H); 7.21 (m, 1H, arom-H); 7.37 (m,
1H, arom-H); 7.99 (dd, 3J=7.5, 4J=1.6, 1H, arom-H). MS
(EI, 70 eV), m/z: 394 (4, M+), 392 (4, M+), 313 (12, M+−Br),
210 (42), 209 (100), 196 (10), 195 (41), 179 (24), 178 (17),
165 (12). Compound 18: mp 182.5–183.5°C. Anal. calcd for
C25H24O3: C, 80.62; H, 6.49. Found: C, 80.57; H, 6.59. 1H
NMR (400.13 MHz, CDCl3; l, ppm; J, Hz): 2.72–2.83 (m,
1H, -CHHCH2-); 2.94–3.09 (m, 3H, -CH2CH2-); 3.12–3.34
(m, 3H, -CH2CH2-); 3.51 (s, 3H, -OCH3); 3.72 (s, 3H,
-OCH3); 3.89–3.99 (m, 1H, -CHHCH2-); 6.54 (dd, 3J=7.8,
4J=1.8, 1H, PC-arom-H); 6.60 (d, 4J=1.8, 1H, PC-arom-
H); 6.70 (m, 2H); 6.83 (dd, 3J=7.8, 4J=1.8, 1H, PC-arom-
3
H); 6.88 (br d, J=7.8, 1H); 7.06 (m, 1H, arom-H); 7.31
(m, 2H, arom-H); 7.46 (dd, 3J=7.5, 4J=1.6, 1H, arom-H).
MS (EI, 70 eV), m/z: 372 (38, M+), 341 (12, M+−OCH3),
340 (31), 211 (16), 210 (82), 209 (100), 208 (16), 196 (26),
195 (84), 194 (29), 181 (16), 180 (15), 179 (67), 178 (61),
177 (24), 176 (12), 167 (19), 166 (20), 165 (45), 152 (31),
132 (11), 131 (23), 119 (15), 104 (16).
11. Very recently the first examples of aryl-ferrocenyl ligands
being planar chiral and potentially axially chiral have been
synthesized: Bringmann, G.; Hinrichs, J.; Peters, K.;
Peters, E.-M. J. Org. Chem. 2001, 66, 629.
12. Rozenberg, V.; Danilova, T.; Sergeeva, E.; Vorontsov, E.;
Starikova, Z.; Korlyukov, A.; Hopf, H. Eur. J. Org. Chem.
2002, 468.
13. Antonov, D. Yu.; Sergeeva, E. V.; Vorontsov, E. V.;
Rozenberg, V. I. Russ. Chem. Bull. 1997, 46, 1897–1900.
14. Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org.
Chem. 1997, 62, 6462.
15. Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505.
16. See: Rozenberg, V. I.; Dubrovina, N. V.; Sergeeva, E. V.;
Antonov, D. Yu.; Belokon’, Yu. N. Tetrahedron: Asymme-
try 1998, 9, 653 and references cited therein.
8. Hopf, H.; Barret, D. G. Liebigs. Ann. 1995, 449.
9. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9550.
10. General experimental conditions for the cross-coupling
reactions of paracyclophanyl halides and arylboronic
acids: A mixture of 0.71 mmol of 5 or 18 (or 0.35 mmol
of 14), 1.065 mmol of anisylboronic acid 10, 0.015 mmol
of PdCl2 (dppf) and 1.42 mmol of K3PO4 in 5 ml of toluene
under argon was stirred at 100–110°C (temperature in the
oil bath) for 6 h for 5 (or 30 h for 20 or 16). The reaction
mixture was cooled, diluted with 10 ml of toluene and
hydrolyzed with 10 ml of 1 M NaOH. The resulting mixture