6,6'-Dibromo-3,3'-dimethoxy-2,2'-dihydroxy-1,1'-biphenyl: Preparation and resolution

Article abstract of DOI:10.1016/S0957-4166(00)00121-X

A pratical route to prepare the title biphenyl 1 starting from 3,3',2,2'-tetramethoxy-1,1'-biphenyl 2 is described. Resolution of 1 was achieved by its conversion into the corresponding diastereomeric menthyldicarbonate. The absolute configuration of (P)-(+)-1 was confirmed by X-ray analysis of the related diastereomer. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00121-X

Tetrahedron: Asymmetry 11 (2000) 1827±1833
6,60-Dibromo-3,30-dimethoxy-2,20-dihydroxy-1,10-biphenyl:
preparation and resolution
Giovanna Delogu,a,* Davide Fabbri,a Maria Antonietta Dettori,a Gianluigi Casaloneb,y
and Alessandra Fornib,y
aIstitutoCNRApplicazionedelleTecnicheChimicheAvanzateaiProblemiAgrobiologici, ViaVienna2, I-07100Sassari, Italy
b
Á
Centro del CNR per lo Studio delle Relazioni tra Struttura e Reattivita Chimica, Via Golgi 19, I-20133 Milano, Italy
Received 3 March 2000; accepted 27 March 2000
Abstract
A pratical route to prepare the title biphenyl 1 starting from 3,30,2,20-tetramethoxy-1,10-biphenyl 2 is
described. Resolution of 1 was achieved by its conversion into the corresponding diastereomeric menthyl-
dicarbonate. The absolute con®guration of (P)-(+)-1 was con®rmed by X-ray analysis of the related dia-
stereomer. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The geometrical possibilities o€ered by the chemical transformation of the biphenyl skeleton
make it a versatile building block in drug synthesis1 and in catalysis.2 The growing number of
hydroxylated biphenyls isolated from natural sources3 establishes the biphenol unit as the back-
bone for the preparation of biologically active compounds. We have recently developed4
inexpensive synthetic and resolution procedures for the preparation of enantiopure hydroxylated
biphenyls with a C2 symmetry axis, e.g. 3 and 4.
* Corresponding author. E-mail: g.delogu@iatcapa.ss.cnr.it
y
Authors to whom inquiries concerning the X-ray structure analysis should be directed. E-mail: g.casalone@csrsrc.mi.cnr.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00121-X

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G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
Hydroxylated biphenyls containing bromo substituents assume an important role in therapy as
antibacterials as well as anti-HIV-1 agents.5 The presence of bromo or chloro functionality in
hydroxylated biaryls makes them e€ective chiral ligands or chiral activators (e.g. 5) in asymmetric
catalytic processes.6 In fact, the halide improves the Lewis acidity and provides small but sig-
ni®cant changes in the biphenol conformation. Slight variations in structural and electronic
properties of the chiral ligand often induce important changes in the eciency of asymmetric
catalysis,6,7 as well as in therapy, the relative position of bromine in hydroxylated biphenyls
being of primary importance on the biological activity.8 Our starting point was to design a new
dibromobiphenol in enantiopure form. Bromo substitution at the 6,60-positions may have a
more decisive in¯uence on the torsional angle and therefore on the reactivity and stereoselectivity
of 1. Furthermore, dimethoxy functionality at the 3,30-positions should improve chemical and
biological activity of dibromobiphenol 1.
2. Results and discussion
In order to develop a synthetically useful method we have used 2,20,3,30-tetramethoxy-1,10-
biphenyl 2 as the starting biphenyl. Compound 2 was prepared in two steps in 80% overall yield,
by known procedures,9 starting from commercially available 1,2-dimethoxybenzene. Regio-
selective reduction of biphenyl 2 to diol 6 and successive treatment with 2.2 equiv. of (^)-menthyl-
chloroformate gave dicarbonates 7 in high yield. Bromination of 7 under the usual conditions
.
failed, whereas in the presence of [BTEA Br3] using ZnCl2, we were able to obtain the two dia-
stereomers 8 in 79% yield10 (Scheme 1). Complete regioselectivity as well as conformational
stability of dibromo derivative 8 were achieved in only one reaction step. All compounds prepared
were solids, air stable, and easily separated and puri®ed by ¯ash chromatography using appropriate
solvent mixtures.
ꢀ
.
Scheme 1. (a) BBr3, CH2Cl2, ^70 C, 90% yield; (b) (S)-(^)-Cl2P(S)NHCH(CH3)Ph 10, py, 80% yield; (c) [BTEA Br3],
CH2Cl2, CH3OH, 50ꢀC, 80% yield; (d) (1R,2S,5R)-(^)-menthyl chloroformate, Et3N, benzene or toluene, rt, 88%
yield; (e) [BTEA Br3], ZnCl2, CH3COOH, 60 C, 79% yield; (f) separation of diastereomers; (g) LiAlH4, THF, rt, 90%
yield
ꢀ
.

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
1829
Each diastereomer 8 was readily separated by ¯ash chromatography with 99 and 95% de,
respectively.11 Reduction of the carbonate group was performed with LiAlH4, in 90% yield at rt,
to give diol (P)-1 and (M)-1 in 99 and 95% ee, respectively. In order to apply an alternative and
cheaper resolution procedure of 1, we prepared the phosphorothioamidate 9, treating 6 with (S)-
(^)-Cl2P(S)NHCH(CH3)Ph 10 in the presence of pyridine.12 In this case we chose a cheaper chiral
source, (S)-(±)-a-methylbenzylamine, which was used in equimolar ratio and which we expected
to recover, under reduction condition, without loss of enantiomeric purity. Unfortunately, under
the usual bromination conditions10 and using a mixture of MeOH and CH2Cl2 as solvent, phos-
phorothioamidate 9 gave phosphorothioate 11 as the main product. All attempts to carry out
bromination of 9 at the 6,60-positions, failed.
One diastereomer 8 was further puri®ed by two recrystallizations from CH2Cl2±EtOH and its
structure was de®ned unequivocally by X-ray analysis. The asymmetric unit of the crystal
structure of diastereomer 8 comprises two molecules identical in conformation at the biphenyl
structure. The plot of one molecule, as reported in Fig. 1, shows the P con®guration for this
diastereomer. The conformational stability of 8 is con®rmed by the large value of the dihedral
angle between the least-squares planes of the two aromatic rings. For the two molecules of
the asymmetric unit the dihedral angles measure 86.1(2)ꢀ and 87.6(3)ꢀ, which compare well to the
values measured for conformationally stable biphenyls.13 Further indication of the stability of
this diastereomer comes from an analysis of the intramolecular distances between the ortho
...
substituents. The shortest Br Br and Br O separations are 4.024(1) A and 3.936(4) A, respectively,
...
Figure 1. ORTEP plot of diastereomer 8. Displacement ellipsoids are drawn at the 20% probability level

1830
G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
which are signi®cantly greater than the corresponding sums of the van der Waals radii of 3.7 A
and 3.4 A, as given by Bondi.14
Crystals of diastereomer 8, under mild reduction conditions, gave (P)-(+)-6,60-dibromo-3,30-
dimethoxy-2,20-dihydroxy-1,10-biphenyl 1 which have quite a high atropisomerization barrier in
solution in most solvents. Interconversion of the biphenyl structure was monitored by NMR
spectroscopy. Enantiopure biphenyl 1 does not racemize in organic solution even when heated to
150ꢀC for 20 h. Bromobiphenol 1 is thermally and chemically very stable.
In conclusion, both enantiomers of 1 were readily prepared from commercially available
starting materials by using a straightforward method. Our strategy takes advantage of two key
steps: (1) the regioselective reduction of 2; and (2) regioselective bromination of 7 and formation of
conformationally stable biphenyl 8. The stereochemical features of biphenol 1, governed both by the
size and shape of the substituents at the 3,30- and 6,60-positions and by the high value of torsional
angle, are a promising approach to the development of an ecient chiral Lewis acid catalyst.
We are currently exploring the scope of the 6,60-dibromo-3,30-dimethoxy-2,20-dihydroxy-1,10-
biphenyl 1 in asymmetric catalysis as well as in the agro- and biological ®eld.
3. Experimental
3.1. General procedures
1
Melting points were determined on a Buchi 530 apparatus and are uncorrected. All H NMR,
13C NMR and 31P NMR spectra were recorded in CDCl3 solution with a Varian VXR 5000
spectrometer at 299.94, 75.42 and 121.42 MHz, respectively. 31P NMR chemical shifts are relative
to H3PO4 (external standard) in CDCl3. Chemical shifts are given in ppm (ꢀ); multiplicities are
indicated by s (singlet), d (doublet), t (triplet), m (multiplet). Elemental analyses were performed
using an elemental analyzer Perkin±Elmer model 240 C. Optical rotations were measured with a
Perkin±Elmer 343 spectropolarimeter. Tetrahydrofuran (THF), benzene and toluene were freshly
distilled from sodium benzophenone ketyl. Pyridine (py) and triethylamine (Et3N) were dried over
KOH and distilled before use. All reagents were of commercial quality and used as purchased. Flash
chromatography was carried out with silica gel 60 (230±400 mesh, Kiesgel, EM Reagents) eluting
with appropriate solution in the stated v:v proportions. Analytical thin-layer chromatography
(TLC) was performed with 0.25 mm thick silica gel plates (Polygram1 Sil G/UV254, Macherey±
1
Nagel). The purity of all new compounds was judged to be >98% by H NMR and 13C NMR
spectral determination.
3.2. 3,30-Dimethoxy-2,20-dihydroxy-1,10-biphenyl 6
To a stirred solution of 2 (2 g, 7.3 mmol) in CH2Cl2 (30 mL) at ^70ꢀC under N2, BBr3 (0.45 mL,
4.8 mmol) was added. The cooling bath was removed and the mixture was stirred at rt for 24 h.
The crude reaction was poured into ice-water, stirred for 30 min, saturated with salt and
extracted with CH2Cl2. The organic extract was dried (Na2SO4) and concentred to a€ord a
brown solid. The crude material was puri®ed by ¯ash chromatography using a 1:5 mixture of
ꢀ
ꢀ
1
CH2Cl2:petroleum as eluent to give 6 (1.62 g, 90%): mp 139.0 C [lit.15 mp 142.5±143 C]. H
NMR ꢀ 3.92 (s, 6H), 6.15 (bs, 2H), 6.89±7.00 (series of m, Ar, 6H); 13C NMR ꢀ 56.00, 110.12,
121.14, 125.31, 127.82, 142.34, 149.98.

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
1831
3.3. [1,10-Biphenyl]-2,20-diyl-O,O0-bis[5-methyl-2-(1-methylethyl)cyclohexyl]carbonic ester 7
A solution of 6 (2.10 g, 8.50 mmol) and Et3N (2 mL) in benzene (15 mL) was added, dropwise,
to a solution of (^)-(1R,2S,5R)-menthyl chloroformate (4.10 g, 18.76 mmol) in benzene (15 mL)
at rt under N2. The solution was stirred at rt for 1 h, washed with 10% HCl and water and the
organic phase extracted with CH2Cl2. The crude, dried over Na2SO4, gave a colourless solid that
was puri®ed by ¯ash chromatography using a 1:1 mixture of CH2Cl2:petroleum as eluent to give 7
(4.57 g, 88%): mp 202±204ꢀC. H NMR ꢀ 0.66 (d, J=6.9 Hz, 6H), 0.78 (d, J=6.9 Hz, 6H), 0.84
1
(d, J=6.9 Hz, 6H), 0.80±1.95 (series of m, 18H), 3.79 (s, 6H), 4.44 (m, 2H), 6.84 (d, J=7.8 Hz,
Ar, 2H), 6.90 (d, J=7.8 Hz, Ar, 2H), 7.20 (t, J=7.8 Hz, Ar, 2H); 13C NMR ꢀ 16.15, 20.70, 21.95,
23.20, 25.76, 31.31, 34.00, 40.37, 46.87, 55.93, 70.04, 111.76, 122.32, 125.94, 137.83, 151.62,
152.64. Anal. calcd for C36H50O8: C, 70.79; H, 8.25; found: C, 70.83; H, 8.10.
3.4. 6,60 -Bis(bromo)[1,10 -biphenyl]-2,20 -diyl-O,O0 -bis[5-methyl-2-(1-methylethyl)cyclohexyl]-
carbonic ester 8
.
To a solution of 7 (5 g, 8.2 mmol) in acetic acid (40 mL) BTEA Br3 (7.78 g, 18.0 mmol) and
ZnCl2 (2.78 g, 20.5 mmol) were added in one pot. The reaction mixture was stirred at 60ꢀC for 5 h
until the initial orange colour faded. Aqueous Na2S2O5 was added to the mixture and the organic
phase was then extracted with CH2Cl2. The organic layer was dried over Na2SO4 to obtain a 1:1
mixture of the two diastereomers (P,1R,10R,2S,20S,5R,50R)-8 and (M,1R,10R,2S,20S,5R,50R)-8 as
an orange solid that was separated by ¯ash chromatography using a 1:1 mixture of CH2Cl2:
petroleum as eluent (4.98 g, 79%). (P,1R,10R,2S,20S,5R,50R)-8: ®rst diastereomer eluted with
Rf=0.4 (2.0 g, 40%), 99% de, mp 175ꢀC. 1H NMR ꢀ 0.70 (d, J=6.6 Hz, 6H), 0.77 (d, J=6.6 Hz,
6H), 0.86 (d, J=6.6 Hz, 6H), 0.85±2.10 (series of m, 18H), 3.81 (s, 6H), 4.45 (m, 2H), 6.87 (d,
J=8.7 Hz, Ar, 2H), 7.40 (d, J=8.7 Hz, Ar, 2H); 13C NMR ꢀ 16.37, 20.66, 21.99, 23.37, 25.85,
31.49, 34.06, 40.28, 46.99, 56.08, 79.34, 113.49, 114.59, 129.95, 131.28, 139.15, 151.04, 151.67.
20
Anal. calcd for C36H48Br2O8: C, 56.26; H, 6.29; found: C, 56.82; H, 6.20; ‰ꢁŠ ^95.3 (c 1, CHCl3).
D
(M,1R,10R,2S,20S,5R,50R)-8: second diastereomer eluted with Rf=0.3 (2.2 g, 44%), 95% de, mp
113±115ꢀC. 1H NMR ꢀ 0.72 (d, J=6.6 Hz, 6H), 0.81 (d, J=6.6 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H),
0.85±2.10 (series of m, 18H), 3.81 (s, 6H), 4.45 (m, 2H), 6.87 (d, J=8.7 Hz, Ar, 2H), 7.42 (d,
J=8.7 Hz, Ar, 2H); 13C NMR ꢀ 16.14, 20.64, 21.95, 23.21, 25.82, 31.25, 34.00, 40.14, 46.77,
56.96, 79.30, 113.37, 114.39, 129.88, 131.14, 150.89, 151.29, 151.97. Anal. calcd for C36H48Br2O8:
20
C, 56.26; H, 6.29; found: C, 56.87; H, 6.19; ‰ꢁŠ +27.1 (c 1, CHCl3).
D
3.5. (P)-(+)-6,60-Dibromo-3,30-dimethoxy-2,20-dihydroxy-1,10-biphenyl 1
A solution of (P)-8 (99% de) (0.5 g, 0.65 mmol) in dry THF (30 mL) was cooled at 0ꢀC under
N2. LiAlH4 (0.23 g, 6 mmol) was added in portions with vigorous magnetic stirring. After 12 h at
rt, water and 10% HCl were cautiously added. The organic phase was extracted with ether, dried
over Na2SO4 and evaporated to a€ord a colourless solid. After puri®cation by ¯ash chromatography
using CH2Cl2 as eluent, enantiomerically pure (P)-1 (0.24 g, 90%) and enantiomerically pure
(^)-menthol (0.80 g, 85%) were obtained. (P)-1: mp 143±145ꢀC. 1H NMR ꢀ 3.90 (s, 6H), 5.75 (bs,
2H), 6.81 (d, J=8.4 Hz, Ar, 2H), 7.19 (d, J=8.4 Hz, Ar, 2H); 13C NMR ꢀ 56.05, 111.51, 115.66,
123.03, 144.23, 144.99, 145.87. Anal. calcd for C14H12Br2O4: C, 41.62; H, 2.99; found: C, 41.58;
20
D
20
D
H, 3.03. ‰aŠ +6.44 (c 0.7, CHCl3), ‰ꢁŠ +26.3 (c 0.5, THF).

1832
G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
3.6. (M)-6,60-Dibromo-3,30-dimethoxy-2,20-dihydroxy-1,10-biphenyl 1
20
D
Using the above procedure, diastereomer (M)-8 (95% de) gave (M)-1 (0.24 g, 90%); ‰ꢁŠ ^6.24
20
D
(c 0.8, CHCl3), ‰ꢁŠ ^25.5 (c 0.8, THF). Enantiomerically pure (±)-menthol (0.85 g, 87%) was
recovered.
3.7. 4,40-Dimethoxy-6-N-(ꢁ-methylbenzyl)aminedibenzo-(d,f)(1,3,2)dioxaphosphepin-6-oxide 9
N-((S)-a-Methylbenzyl)dichlorothiophosphoroamidate 10 (0.52 g, 2.0 mmol) was added drop-
wise to a solution of 6 (0.42 g, 1.70 mmol) in py (50 mL) at rt under N2. After 12 h under re¯ux,
the reaction mixture was cooled and acidi®ed with 10% H2SO4. Water was added and the
organic phase was extracted with CH2Cl2, dried over Na2SO4 and evaporated to dryness to
obtain a colourless solid. The crude was puri®ed by ¯ash chromatography using a 1:1 mixture of
CH2Cl2:petroleum as eluent to give 9 (0.58 g, 80%): mp 165ꢀC. H NMR ꢀ 1.41 (d, J=6.6 Hz,
1
3H), 3.63 (s, 3H), 3.65 (s, 3H), 4.20 (bs, 1H), 4.60 (m, 1H), 6.60±7.70 (series of m, Ar, 11H); 31P
NMR ꢀ 80.27. Anal. calcd for C21H22O4NPS: C, 60.71; H, 5.34; found: C, 60.65; H, 5.40.
3.8. 4,40-Dimethoxy-2-bromo-6-methoxydibenzo-(d,f)(1,3,2)dioxaphosphepin-6-oxide 11
.
To a solution of 9 (0.36 g, 0.85 mmol) in CH2Cl2 (20 mL) and CH3OH (5 mL) BTEA Br3 (1.1
g, 2.52 mmol) was added. The reaction mixture was stirred at 50ꢀC under N2 for 5 h until the
initial orange colour faded. Aqueous Na2S2O5 was added to the mixture, then the organic phase
was extracted with CH2Cl2. The organic layer was dried over Na2SO4 to obtain an orange solid
that was puri®ed by ¯ash chromatography using a 1:1 mixture of CH2Cl2:petroleum as eluent to
give 11 (0.25 g, 80%): mp 180±182ꢀC. H NMR ꢀ 3.90 (s, 3H), 3.92 (s, 3H), 3.40 (d, J=11.7 Hz,
1
3H), 7.00 (d, J=7.8 Hz, Ar, 1H), 7.08 (d, J=7.8 Hz, Ar, 1H), 7.12 (d, J=2.1 Hz, Ar, 1H), 7.20
(d, J=2.1 Hz, Ar, 1H), 7.25 (t, J=7.8 Hz, Ar, 1H); 31P NMR ꢀ 3.71. Anal. calcd for
C15H14BrO6P: C, 44.91; H, 3.52; found: C, 44.93; H, 3.40.
3.9. X-Ray structure determination of 8
Di€racted intensities were collected with a Bruker P4 di€ractometer, using graphite mono-
chromated Mo-Ka radiation=0.71073 A. Crystal description: colourless prism 0.46Â0.43Â0.35
mm. Mr=1537.13, monoclinic, space group P21, a=13.813(1) A, b=18.078(2) A, c=15.846(2) A,
ꢂ=102.386(8)ꢀ, V=3864.8(7) A, Z=2, T=293(2) K, ꢃ=2.143 mm, !/2ꢄ scans, 3.6ꢀ<2ꢄ<50ꢀ,
empirical absorption correction via -scans. The structure was solved by SIR92 and re®ned on F2
by full matrix least-squares using SHELX97. Heavy atoms were anisotropic, H atoms isotropic.
Flack parameter16 for determination of the absolute con®guration=^0.010(8). Final R=0.058 and
wR=0.13 for data with I>2ꢅ(I); 13422 re¯ections, 1055 parameters, 688 restraints. Restraints
were applied for the re®nement of the menthyl groups of one molecule and of the isopropyl
groups of the other molecule of the asymmetric unit, which are a€ected by a high disorder.
Acknowledgements
This work was supported by CNR, Rome, partially by Sardinia Autonomous Region.

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 1827±1833
1833
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