Syntheses and resolutions of new chiral biphenyl backbones: 2-Amino-2′-hydroxy-6,6′-dimethyl-1,1′-biphenyl and 2-amino-2′-hydroxy-4,4′,6,6′-tetramethyl-1,1′- biphenyl

Article abstract of DOI:10.1016/S0957-4166(03)00217-9

The new chiral backbones (R)-(+)- and S-(-)-2-amino-2′-hydroxy-6,6′-dimethyl-1,1′-biphenyl and (R)-(+)- and (S)-(-)-2-amino-2′-hydroxy-4,4′,6,6′- tetramethyl-1,1′-biphenyl were synthesized from o-methylaniline and 2,4-dimethyl-aniline respectively in seven steps. A new resolution method was developed to provide homochiral enantiomers (from diastereomeric salts) in reasonably high yields. The absolute configuration of the new biphenyls was confirmed by X-ray structural analysis.

Full text of DOI:10.1016/S0957-4166(03)00217-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1267–1273
Syntheses and resolutions of new chiral biphenyl backbones:
-amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl and
-amino-2%-hydroxy-4,4%,6,6%-tetramethyl-1,1%-biphenyl
2
2
Yuxue Liang, Shuang Gao, Huihui Wan, Junwei Wang, Huilin Chen, Zhuo Zheng and
Xinquan Hu*
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian 116023, PR China
Received 23 December 2002; revised 26 February 2003; accepted 26 February 2003
Abstract—The new chiral backbones (R)-(+)- and S-(−)-2-amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl and (R)-(+)- and (S)-(−)-
2-amino-2%-hydroxy-4,4%,6,6%- tetramethyl-1,1%-biphenyl were synthesized from o-methylaniline and 2,4-dimethyl-aniline respec-
tively in seven steps. A new resolution method was developed to provide homochiral enantiomers (from diastereomeric salts) in
reasonably high yields. The absolute configuration of the new biphenyls was confirmed by X-ray structural analysis. © 2003
Elsevier Science Ltd. All rights reserved.
1
. Introduction
2%-hydroxy-4,4%,6,6%-tetramethyl-1,1%-biphenyl
from 2,4-dimethyl-aniline in seven steps.
(S)-1b
Asymmetric catalysis is currently one of the most
attractive research areas in synthetic chemistry. Within
1
asymmetric catalysis, the discovery of new chiral lig-
ands plays a crucial role in developing new efficient
metal-catalyzed asymmetric transformations since the
electronic and steric properties of the ligand are usually
the decisive factors that can influence the reactivity and
2. Results and discussion
The biphenyl framework has certain unique characteris-
tics, which allow one to make subtle alterations to its
geometric, steric, and electronic properties. The sub-
stituents at the 6,6%-positions are deemed necessary to
warrant sufficient thermal stability to thermal racemiza-
tion. In this regard, we have designed the new axially
chiral biphenyl backbones (R)-1a, (S)-1a from 2-methyl-
2
enantioselectivity of asymmetric reactions. It is impor-
tant to explore effective ligands with new chiral back-
bones for broad application in asymmetric catalysis. In
the past decade, 1,1%-binaphthyls with different sub-
7
3
stituents at the 2,2%-positions, such as MOP and
aniline and (R)-1b, (S)-1b from 2,4-dimethyl-aniline
4
NOBIN have gained much attention. A number of
(
Scheme 1).
chiral ligands derived from the above backbones have
been developed for transition metal-catalyzed asymmet-
2
2
-Methyl-6-nitroaniline 3a could be synthesized from
-methylaniline 2a via nitration and separated from the
mixture of 3a and 2-methyl-4-nitroaniline by steam
5
,6
ric reactions. In contrast to the binaphthyl deriva-
tives, non-C2 symmetrical biphenyl analogues are
relatively unexplored. Herein, we report the syntheses
and resolutions of new chiral biphenyl backbones (+)-2-
amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl (R)-1a, (−
8
distillation according to the literature report. However,
steam distillation cannot be easily scaled up in the
laboratory, because 3a is a structure which could form
an intermolecular hydrogen bond, while 2-methyl-4-
nitroaniline is not. We thus developed an effective
separation method of 3a and 2-methyl-4-nitroaniline.
When the concentrated HCl solution of the mixture
hydrochloric salts of 3a and 2-methyl-4-nitroaniline was
diluted with water, 3a was precipitated as a solid in
60% yield after recrystallization, while the hydrochloric
)
-2-amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl (S)-1a
from 2-methylaniline and (+)-2-amino- 2%-hydroxy-
4
,4%,6,6%-tetramethyl-1,1%-biphenyl (R)-1b, (−)-2-amino-
*
Corresponding author. Tel.: 0086+411-4379233; fax: 0086+411-
4
684746; e-mail: xinquan@ms.dicp.ac.cn
0
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00217-9

1
268
Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
salt of 2-methyl-4-nitroaniline stayed in the dilute HCl
solution (Scheme 2).
Compound 5 was prepared from 3 via diazotation/iodi-
10
nation and Ullmann coupling. Dinitro derivative 5
was converted into nitroamine 6 through selective
11
2
,4-Dimethyl-6-nitroaniline 3b was easily obtained by
reduction. Na S was found to be superior to Na S
2 2 2 x
9
nitration from 2,4-dimethylaniline 2b. The yield of the
reaction can be increased to 86% (Ref. 9: 75%) by using
as the reducing agent because it is difficult to remove
the residual sulfur in the latter case, which would
poison the Pd catalyst in the following step. Moreover,
96% instead of 65% nitric acid.
Scheme 1. Reagents and conditions: (a) i. (CH CO) O, HNO , ii. HCl; (b) NaNO , H SO , KI; (c) DMF, Cu powder, reflux; (d)
3
2
3
2
2
4
i. Na S ; ii. HCl; (e) NaNO , H SO , H O; (f) H , Pd/C, EtOH; (g) treatment with (1S)-(+)-10-camphorsulfonic acid to form
2
2
2
2
4
2
2
diastereomeric salts; (h) treatment with saturated aqueous NaHCO solution to obtain (R)-isomer, then treated the residue with
3
ammonia to obtain (S)-isomer.
Scheme 2.

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
1269
the selectivity of the reduction of nitroamine 6 was very
and reaction time. 48 mg of (−)-1a with 39% ee was
obtained when 0.20 g of 1a–CSA was stirred in 11 ml of
1/10 ammonia solution at room temperature for 24 h.
good even if excess Na S was used. The crude product
2
2
was purified by using hot aqueous HCl to remove the
unreacted 5, followed by recrystallization. The yield was
When a less basic saturated aqueous NaHCO solution
3
60% when one equivalent of reducing agent was used. The
was employed, the selectivity was improved. However, the
yield could be significantly improved to 85% by using two
equivalents of the reducing agent and charging with three
portions.
liberation rate in saturated aqueous NaHCO solution
was much slower. Because of the insolubility of
3
diastereomeric salt in diethyl ether, 1a–CSA salt was
stirred in a saturated aqueous NaHCO solution and
3
With diazotation/hydrolysis, nitroamine 6 was trans-
ferred into compound 7. This transformation was com-
plicated by lot of by-products. The crude hydrolysis
product was then dissolved in concentrated NaOH/
MeOH aqueous solution, some insoluble impurities were
filtered off, and other organic impurities were removed
by toluene extraction. The clean aqueous solution was
treated with concentrated HCl solution and extracted
with toluene. The pure compound 7 can be easily obtained
by passing through a short silica-gel column. Compound
diethyl ether at 25°C. The ee of 1a in diethyl ether layer
wasdeterminedbyHPLCanalysis. Theresultsofeeversus
time were summarized in Figure 1. The major isomer
liberated by NaHCO was (+)-1a.
3
7
can be hydrogenated to give racemic 1 in almost
11
quantitative yield. It is of note that the procedures for
a and 1b can be operated in a large scale.
1
After obtaining sufficient racemic 1, we tried a number
of resolution methods which had been successfully
1
2
employed in the resolution of NOBIN. The failure of
1
2c
the molecular crystal method was not expected, because
Toda succeeded in using benzylcinchonidium chloride to
resolve racemic 2,2%-dihydroxy-1,1%-binaphthyl (BINOL)
Figure 1. Ee of (R)-1a versus liberation time in satd aq.
NaHCO solution.
13
3
and 2,2%-dihydroxy-4,4%,6,6%-tetramethyl-1,1%-biphenyl1.
2c
Ding also used this method to resolve NOBIN.
Recently, Kocovsk y´ has successfully used this method to
The actual resolution was carried out in the mixture of
diastereomeric salt and saturated aqueous NaHCO3
solution. Experimental data showed half amount of
diastereomeric salt of 1a liberated in 14 days. The first
liberated 1a was extracted with diethyl ether and after
evaporation of the solvent, the residue was twice recrys-
tallized with benzene to afford (R)-1a (>99% ee) in
48–50% yield. The residual NaHCO3 solution was
extracted with methylene chloride. After removal of
methylene chloride under reduced pressure, and the
residue was treated with concentrated ammonia at 50°C
overnight. After cooling to room temperature, the mix-
turewas extractedwithdiethyl ether, followedbythe same
procedure as described for (R)-1a to afford (S)-1a (>99%
ee) in 48–52% yield (Scheme 3).
1
2d
resolve iso-NOBIN. We believed this molecular crystal
method would help us obtain both enantiomers. Unfor-
tunately, no precipitate was observed under the same
conditions that Toda made 2,2%-dihydroxy-4,4%,6,6%-tetra-
1
3b
methyl-1,1%-biphenyl. Changingthesolventdidnotgive
any promising results.
We then tried (1S)-(+)-10-camphorsulfonic acid (CSA) as
the resolving reagent and toluene/ethanol as the solvent
for resolution, a mixture of diastereomeric salts was
obtained in a high yield. When we used ammonia to
liberate the diastereomeric salt (1a–CSA) to recover
racemic 1a, we found that the precipitate was optically
active, which was confirmed by HPLC analysis. Consid-
ering that two salts may have different reaction rates with
a base, we mixed the diastereomeric salts, ammonia and
diethyl ether together at room temperature, then checked
ether layer by HPLC with a chiral OD-H column. We
found that the liberated 1a in the ether layer had about
The absolute configuration of (−)-1a was confirmed by
the X-ray structural analysis of the crystal of the amide
arising from (−)-1a and (+)-10-camphorsulfonyl chloride.
The resolution procedure for 1b was almost the same. The
liberation time of half amount of diastereomeric salt was
about 12 days for R-1b. The ee’s of enan-
1
0% ee. We then optimized the resolution conditions, by
changing the concentration of ammonia, temperature,
Scheme 3.

1
270
Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
tiomers of R-1b and S-1b were above 99% after two
recrystallizations from benzene.
until no precipitate observed. Compound 3a was liber-
ated as an orange solid and recrystallized from ethanol
to afford 90.5 g (60%) of 3a as needles: mp 95–96°C
1
(
Ref. 8: 94–95°C); H NMR l 2.23 (s, 3H), 6.12 (br,
3. Conclusion
2H), 6.62 (t, J=7.8 Hz, 1H), 7.26 (d, J=6.8 Hz, 1H),
.02 (d, J=8.8 Hz, 1H).
8
We have optimized the process of the preparation of
racemic 1a and 1b on a practical scale, and developed a
novel resolution method of providing the enantiomers,
which makes use of the difference of reaction rates of
diastereomeric salts ((±)-1-CSA) with saturated
4.3. 2,4-Dimethyl-6-nitroaniline 3b
To a 1000 ml jacketed flask, was added 500 ml of acetic
anhydride. Under stirring, 75 g of 2,4-dimethylaniline
2b (0.6 mol) was slowly added and then cooled to
5–7°C. To the mixture, 50 ml of 96% nitric acid (d=
1.5, 1.2 mol) was carefully added in a period of 1 h, the
temperature was strictly controlled below 7°C during
the addition. After the addition was complete, kept
stirring for another 10 min. The mixture was poured
into 2 L of ice-water with stirring. The yellowish solid
was collected by suction, and the wet product was
added into a 1000 ml round flask and added 100 ml of
aqueous NaHCO solution. The new homochiral back-
3
bones
biphenyl R-1a and (S)-(−)-2-amino-2%-hydroxy-6,6%-
dimethyl-1,1%-biphenyl S-1a, (R)-(+)-2-amino-2%-
hydroxy-4,4%,6,6%-tetramethyl-1,1%-biphenyl R-1b and
S)-(−)-2-amino-2%-hydroxy-4,4%,6,6%-tetramethyl-1,1%-
biphenyl S-1b can be obtained in reasonable yields.
(R)-(+)-2-amino-2%-hydroxy-6,6%-dimethyl-1,1%-
(
4. Experimental
3
7% HCl solution and 200 ml of EtOH, then heated to
4
.1. Material and equipment
reflux for 4 h. Distilled 150 ml of aqueous ethanol,
poured the residue into 200 ml of ammonia and 1000
ml of water. The red–brown solid was collected by
suction, washed with water (3×500 ml) and dried to
afford 86.5 g of 3b (86%), which could be directly used
for next step by TLC. Analysis sample was recrystal-
lized from ethanol to obtain a pale yellow crystal: mp:
Melting points (uncorrected) were obtained on a
Yazawa micro apparatus. Optical rotations were mea-
sured on a JASCO 1200 polarimeter. H, C NMR
spectra were recorded on a Bruker DRX 400/Mercury-
3
nal reference. The FAB-HRMS spectra were measured
by Beijing Institute of Chemistry, the Chinese Academy
of Sciences. HPLC analysis of ee’s of chiral backbones
was performed on an Agilent 1100 with a Chiralcel
OD-H column at 254 nm. X-Ray structural analysis
was carried out in Shanghai Institute of Organic Chem-
istry, the Chinese Academy of Sciences. 2,4-Dimethyl-
aniline, (1S)-CSA and (+)-10-camphorsulfonyl chloride
were purchased from Acros. All solvents were treated
with standard methods before using,
1
13
00 using CDCl as the solvent with TMS as an inter-
3
1
69–71°C (Ref. 9: 68–70°C); H NMR l 2.22 (s, 3H),
2.24 (s, 3H), 6.05 (br. 2H), 7.13 (s, 1H), 7.82 (s, 1H).
4.4. 2-Methyl-6-nitro-iodobenzene 4a
To a 1500 ml four-necked flask, were added 90 g of 3a
(0.59 mol) and 600 ml of glacial acetic acid. The
mixture was warmed to form a clear solution, then
cooled to 15°C. A pre-cooled solution of 60 g of
sodium nitrite (0.95 mol) in 330 ml of cold concentrated
sulfuric acid was slowly added in a period of 1 h and
stirred for another hour, then heated to 75°C, stirred
for 2 h and cooled to 25°C. The mixture was poured
into 2500 ml of ice-water with stirring then successively
treated with 60 g of urea, aqueous KI solution (140
g/600 ml). After aqueous KI solution was completely
added, lots of solid was precipitated, then added solid
4.2. 2-Methyl-6-nitroaniline 3a
To a 1500 ml four-necked jacketed flask with a
mechanic stirrer, a reflux condenser, a dropping funnel
and a thermometer, was charged 650 ml of acetic
anhydride. 107g of 2-methylaniline 2a (1.0 mol) was
slowly added through the funnel. After the addition
was complete, the mixture was cooled to 12–13°C and
stirred until the aniline was totally converted to amide.
To the other dropping funnel was added 126 ml of 65%
nitric acid (2.0 mol). After the mixture was cooled to
the desired temperature, nitric acid was added dropwise
to the cold slurry at a rate which the temperature could
be controlled between 10–12°C in 1–2 h. After the
addition was complete, stirring was kept for another
half an hour. The mixture was poured into 3 L of
ice-water with stirring. The resulting cream-colored
solid was collected by suction, washed with ice water
NaHSO until the color of the mixture was obviously
3
changed. The crude product was collected by suction
and washed with water (3×200 ml). Recrystallized the
wet solid from aqueous ethanol to afford 122 g (79%)
1
of 4a: mp 66–68°C (Ref. 10: 66–68°C); H NMR l 2.58
(s, 3H), 7.38 (m, 3H).
4.5. 2,4-Dimethyl-6-nitro-iodobenzene 4b
With the same method of synthesis of 4a, from 86 g of
3b (0.52 mol), obtained 113 g of crude product. Recrys-
tallized from petroleum ether to afford 98.6 g of 4b
(69%) as orange crystals: mp 107–108°C (Ref. 9: 106–
(
3×500 ml). The wet product was charged into a 1000
ml round flask, then added 300 ml of concentrated HCl
solution and heated to reflux until the solid was com-
pletely dissolved, kept the reflux another hour. The
mixture was cooled to rt and added water with stirring
1
107°C); H NMR l 2.34 (s, 3H), 2.52 (s, 3H), 7.25 (s,
2H).

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
1271
4
.6. 2,2%-Dinitro-6,6%-dimethyl-1,1%-biphenyl 5a
g of NaNO (0.24 mol) in 20 ml water, kept the mixture
2
temperature below 0°C in an ice bath. When the addi-
tion was complete, the mixture was stirred for another
hour at 0°C. The resulting dark red diazonium-salt
solution was added dropwise to a boiling mixture of
To a 1000 ml four-necked flask, were charged 150 ml of
dry DMF and 122 g of 4a (0.46 mol). The resulting
solution was heated to 100°C with stirring. About 120 g
of fresh copper powder was added gradually. The mix-
ture was heated to reflux for 6 h. Cool to rt. The
residual copper powder was filtered off and the wet
cake was washed with DMF. DMF was removed under
reduced pressure. 400 ml of water was added to the
residue to obtain an earth yellow solid. Recrystallized
the wet solid from ethanol to afford 59.5 g (95%) of 5a
6
00 ml of 15% of H SO and 250 ml of toluene. When
2 4
gaseous N was no longer given off, the mixture was
2
cooled to rt. Toluene layer was separated, the aqueous
layer was extracted with toluene (3×200 ml). After
evaporation of toluene under reduced pressure, the
residue was treated with 75 ml of 40% NaOH and 25 ml
of MeOH, then filtered off. The filtrate was extracted
with toluene (3×20 ml). The aqueous layer was acidified
with concentrated HCl. The resulting precipitate was
extracted with toluene (5×50 ml). The combined toluene
solutions were dried over anhydrous Na SO and the
as pale yellow needles: mp 108–110°C (Ref. 10: 109–
1
1
1
10°C); H NMR l 1.98 (s, 3H). 7.46 (t, J=8.0 Hz,
H), 7.56 (d, J=7.6 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H).
2
4
4.7. 2,2%-Dinitro-4,4%,6,6%-tetramethyl-1,1%-biphenyl 5b
solvent was removed under reduced pressure. The
residue was purified by a silica gel column (petroleum
ether/EtOAc: 30/1) and recrystallized from methylene
chloride/petroleum ether to afford 26 g of 7a (60%): mp
With the same method of synthesis of 5a, from 98.5 g
of 4b (0.36 mol), obtained 45.1g (84%) of 5b as yellow
crystals: mp 136–138°C (Ref. 11: 136–137°C); H NMR
1
1
l 1.93 (s, 6H), 2.43 (s, 6H), 7.37 (s, 2H), 7.76 (s, 2H).
82–84°C; H NMR l 1.90 (s, 3H), 2.06 (s, 3H), 4.71 (br,
1
H), 6.74 (d, J=8.0 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H),
4
.8. 2-Amino-2%-nitro-6,6%-dimethyl-1,1%-biphenyl 6a
7.16 (t, J=8.0 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.55 (d,
1
3
J=7.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H); C NMR
19.52, 19.73, 113.23, 121.50, 122.55, 128.66, 129.23,
129.78, 134.36, 137.07, 140.44, 150.72, 152.32; FAB-
4
0.8 g of 5a (0.150 mol) was dissolved in 300 ml of
boiling ethanol, then an Na S solution prepared from
2
2
+
7
2.0 g of Na S 9H O (0.30 mol) and 9.6 g of sulfur
2 2
HRMS (m/z): (M+1) calcd for C H NO 244.0968;
14
14
3
(
0.30 mol) in 250 ml of water was added in three
found, 244.0966.
portions at a rate of ca. 1.5 ml per minute via a pump.
The mixture was kept refluxing for 3 h between the
portions. After concentration to about 300 ml and
cooling, the precipitate was extracted with toluene (2×
4
.11. 2-Hydroxy-2%-nitro-4,4%,6,6%-tetramethyl-1,1%-
biphenyl 7b
200 ml). Toluene was removed under reduced pressure,
With the same method as for the synthesis of 7a, from
the residue was boiled with 350 ml of 2 M HCl solu-
tion, filtered off. The water insoluble solid was treated
with 60 ml of 2 M HCl solution and filtered off. The
combined aqueous filtrates were neutralized with
ammonia. The solid was collected by suction and
3
0.0g of 6b (0.11 mol), obtained 18.0 g (60%) of 7b as
1
pale yellow crystals: mp 127–128°C; H NMR l 1.88 (s,
3
2
1
H), 2.02 (s, 3H), 2.29 (s, 3H), 2.43 (s, 3H), 4.44 (br.
H), 6.60 (s, 1H), 6.67 (s, 1H), 7.35 (s, 1H), 7.53 (s,
H); C NMR 19.72, 19.94, 21.19, 21.46, 114.12,
13
recrystallization with aqueous ethanol to afford 31.9 g
1
(
2
6
88%) of 6a: mp: 124–126°C; H NMR l 1.86 (s, 3H),
.09 (s, 3H), 3.25 (br, 2H), 6.64 (d, J=7.96 Hz, 1H),
.70 (d, J=7.4 Hz, 1H), 7.09 (t, J=7.74 Hz, 1H), 7.43
119.72, 121.96, 123.64, 126.77, 129.23, 135.11, 137.07,
139.23, 139.41, 140.58, 152.30, 152.62; FAB-HRMS
+
(m/z): (M+1) calcd for C H NO 272.1281; found,
16
18
3
(
t, J=7.88 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.73 (d,
272.1284.
13
J=8.0 Hz, 1H); C NMR 19.69, 19.46, 113.09, 120.20,
1
1
21.19, 121.31, 128.35, 128.78, 131.20, 134.23, 136.18+,
4
.12. (±)-2-Amino-2%-hydroxy-6,6%-dimethyl-1,1%-biphenyl
40.36, 143.67, 150.72; FAB-HRMS (m/z): (M+1)
(
±)-1a
calcd for C H N O 243.1128; found, 243.1125.
1
4
15
2
2
2
2.0 g of racemic 1a was obtained via catalytic hydro-
genation of 26.0 g (98%, recrystallized with EtOH) of
a (0.21 mol) over 10% Pd/C in ethanol according to
4
.9. 2-Amino-2%-nitro-4,4%,6,6%-tetramethyl-1,1%-biphenyl
6
b
7
11
1
the literature report. Mp 162–164°C; H NMR l 1.94
With the same method as for the synthesis of 6a, from
(
(
s, 3H), 2.01 (s, 3H), 3.46 (br, 2H), 4.93 (br, 1H), 6.64
d, J=7.92 Hz, 1H), 6.73 (d, J=7.52 Hz, 1H), 6.89–
6
5.4 g of 5b (0.218 mol), obtained 51.3 g (87%) of 6b as
orange crystals: mp 122–123°C (Ref. 11: 117–118°C);
1
6.85 (m, 2H), 7.11 (t, J=7.78 Hz, 1H), 7.22 (t, J=7.84
Hz, 1H); C NMR 19.31, 19.65, 112.79, 112.93, 118.60,
1
1
H NMR l 1.82 (s, 3H), 2.05 (s, 3H), 2.25 (s, 3H), 2.43
13
(
1
s, 3H), 3.30 (br, 2H), 6.45 (s, 1H), 6.51 (s, 1H), 7.36 (s,
H), 7.51 (s, 1H).
20.27, 122.25, 122.72, 129.05, 129.36, 138.23, 138.77,
+
45.02, 153.08; FAB-HRMS (m/z): (M+1) calcd for
4.10. 2-Hydroxy-2%-nitro-6,6%-dimethyl-1,1%-biphenyl 7a
C H16NO 214.1226; found, 214.1228. HPLC analysis
condition for (±)-1a: Chiralcel OD-H, 80/20 hexanes/i-
14
To a suspension of 42.0 g of 6a (0.17 mol) and 12 ml of
7% HCl solution and 88 ml of EtOH, was added 16.3
PrOH, 0.7 ml/min, 25°C, retention time: t (S)=8.15
R
3
min; t (R)=11.03 min.
R

1
272
Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
4
.13. (±)-2-Amino-2%-hydroxy-4,4%,6,6%-tetramethyl-1,1%-
solution. The mixture was extracted with diethyl ether
biphenyl (±)-1b
(2×10 ml). The combined organic layers were washed
with brine (10 ml), dried over anhydrous Na SO . The
2
4
With the same procedure, from 3.60 g of 7b (13.3
mmol), obtained 3.07 g (96%) of (RS)-1b as white
solvent was removed under reduced pressure. The
residue was purified by column chromatography on
silica gel to afford 0.38 g of amide (94.7%). The analysis
sample was recrystallized from hexanes. Mp: 102–
1
crystals: mp 178–180°C; H NMR l 1.92 (s, 3H), 1.98
(
s, 3H), 2.23 (s, 3H), 2.32 (s, 3H), 3.43 (br, 2H), 4.78 (s,
12
1
1
1
1
1
H), 6.49 (s, 1H), 6.57 (s, 1H), 6.70 (s, 1H), 6.71 (s,
104°C. [h]D −14.5 (c 0.5, CHCl ). H NMR (CDCl ) l
3 3
1
3
H); C NMR 19.56, 19.90, 21.56, 113.45, 113.84,
15.82, 119.96, 121.60, 123.41, 138.34, 139.01, 139.20,
0.73 (s, 3H), 0.91 (s, 3H), 1.34–1.38 (m, 1H), 1.48–1.53
(m, 1H), 1.85–1.90 (m, 2H), 1.92–1.97 (m, 4H), 2.04 (t,
J=4.4 Hz, 1H), 2.11 (s, 3H), 2.17–2.21 (m, 1H), 2.28–
2.35 (m, 1H), 2.57 (d, J=14.8 Hz, 1H), 3.27 (d, J=14.8
Hz), 4.38 (br, 2H), 6.68–6.78 (m, 2H), 7.07–7.12 (m,
+
39.41, 145.40, 153.29; FAB-HRMS (m/z): (M+1)
calcd for C H NO 242.1539; found, 242.1532. HPLC
1
6
20
condition for (±)-1b: Chiralcel OD-H, 80/20 hexanes/i-
13
PrOH, 0.7 ml/min, 25°C, retention time: t (S)=6.64
1H), 7.26–7.35 (m, 3H); C NMR 19.41, 19.50, 19.90,
R
min; t (R)=8.99 min.
24.75, 26.83, 42.35, 42.65, 47.84, 48.20, 57.59, 113.90,
R
1
1
21.05, 122.12, 128.81, 128.94, 129.01, 130.25, 137.81,
40.03, 142.80, 147.26, 213.67. X-Ray structural analy-
4.14. Diastereomeric salt of 1a–CSA
sis, see Fig. 2.
To a 250 ml of flask, 5.01 g of racemic 1a (23.5 mmol),
.90 g of CSA (25.4 mmol) and 80 ml of toluene were
4
.16. Diastereomeric salt of 1b–CSA
5
added. The mixture was stirred at 90°C, the white
precipitate appeared after half an hour, and stirring was
continued overnight. The mixture was cooled down to
rt, filtered off, the solid washed with toluene (2×20 ml),
and dried to afford 9.90 g (94%) of white solid as the
diastereomeric salt.
To a 250 ml of flask, were added 5.00 g of racemic 1b
20.7 mmol), 5.30 g of CSA (22.8 mmol) and 80 ml of
toluene. The mixture was stirred at 95°C overnight,
cooled down to rt, as the white precipitate collected by
suction, washed with toluene (2×20 ml) and dried to
afford 9.25 g (94%) of white solid as the diastereomeric
salt 1b–CSA.
(
4
.14.1. (R)-(+)-1a. To a 1000 ml flask, 9.90 g of
diastereomeric salt and 500 ml of saturated aqueous
4
.16.1. (R)-(+)-1b. To a 1000 ml flask, were added 9.25
NaHCO solution were added. The solution was stirred
3
g of 1b–CSA and 500 ml of saturated aqueous
for 14 days at 25°C. The mixture was transferred into a
NaHCO solution. The solution was stirred for 12 days
3
1
000 ml separation funnel. The liberated 1a was
at 25°C. The mixture was transferred into a 1000 ml
separation funnel. The liberated 1b was extracted with
diethyl ether (3×100 ml). The combined ether layers
were washed with 50 ml of water, dried over anhydrous
Na SO . The solvent was removed under reduced pres-
extracted with diethyl ether (3×80 ml). The combined
ether layers were washed with 50 ml of water, dried
over anhydrous Na SO . The solvent was removed
2
4
under reduced pressure to afford 2.35 g of reddish solid
61.5% ee by HPLC analysis). Recrystallization twice
from benzene (80 ml) to afford 1.20 g (48%) of white
2
4
(
sure to afford 2.32 g of yellowish solid (61.9% ee).
Recrystallization twice from benzene to afford 1.18 g
2
4
solid as R-(+)-1a, mp: 192–194°C; [h] 73.8 (c 0.5,
24
D
(
5
47%) of white solid as (R)-(+)-1b, mp: 210–212°C; [h]D
CHCl ), >99% ee (t (R)=11.02 min).
3
R
9.5 (c 0.5, CHCl ), >99% ee (t (R)=8.99 min).
3 R
4
.14.2. (S)-(−)-1a. The residual aqueous NaHCO layer
3
was then extracted with methylene chloride (3×80 ml).
Combined methylene chloride layers and evaporated
the solvent, added 80 ml of concentrated ammonia to
the residue. Heated up to 50°C and stirred overnight,
then cooled to rt. The mixture was extracted with
diethyl ether (3×80 ml). The combined ether layers were
washed with 50 ml of water, dried over anhydrous
Na SO . The solvent was removed under reduced pres-
2
4
sure to afford 2.40 g of reddish solid (66.5% ee).
Recrystallization twice from benzene to afford 1.30 g
24
(
−
52%) of white solid as S-(−)-1a, mp: 192–194°C; [h]D
74.7 (c 0.5, CHCl ), >99% ee (t (S)=8.17 min).
3
R
4
.15. (−)-(S)-2-((D)-10-Camphorsulfonyl amido)-2%-
hydroxy-6,6%-dimethyl-1,1%-diphenyl
To a solution of 0.20 g of (−)-1a (0.94 mmol) and 0.282
g of D-(+)-10-camphor sulfonyl chloride (1.12 mmol) in
2
0 ml of methylene chloride, was added 0.5 ml of
triethylamine via syringe. The solution was stirred at
0°C for 3 h, then diluted with 10 ml of 5% HCl
Figure 2. X-Ray structural analysis of 2-(D-(+)-10-camphor-
sulfonyl amido)-2%-hydroxy-6,6%-dimethyl-1,1%-diphenyl (hydro-
gen atoms omitted).
1

Y. Liang et al. / Tetrahedron: Asymmetry 14 (2003) 1267–1273
1273
4
.16.2. (S)-(−)-1b. The residual aqueous NaHCO layer
R. A. J. Am. Chem. Soc. 1994, 116, 3649; (c) Singer, R.
A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360;
(d) For a review on application of MOP, see: Hayashi, T.
Acc. Chem. Res. 2000, 33, 354.
3
was then extracted with methylene chloride (3×80 ml).
After evaporation of the solvent and addition of 250 ml
of concentrated ammonia to the residue, it was heated
to 50°C and stirred overnight, then cooled to rt. The
mixture was extracted with methylene chloride (3×80
ml). The combined organic layers were washed with 50
4. (a) Smrcina, M.; Lorenc, M.; Hanu sˇ , V.; Kocovsk y´ , P.
Synlett 1991, 231; (b) Smrcina, M.; Lorenc, M.; Hanu sˇ ,
V.; Sedmera, P.; Kocovsk y´ , P. J. Org. Chem. 1992, 57,
1917; (c) Smrcina, M.; Pol a´ kov a´ , S.; Vyskocil, S.; Kocov-
sk y´ , P. J. Org. Chem. 1993, 58, 4535; (d) Smrcina, M.;
Vyskocil, S.; Maca, B.; Polacek, M.; Claxton, T. A.;
Abbott, A. P.; Kocovsk y´ , P. J. Org. Chem. 1994, 59,
2156.
ml of water, dried over anhydrous Na SO . Removal of
2
4
the solvent under reduced pressure afforded 2.26 g of
yellowish solid (67.7% ee). Recrystallization twice from
benzene afforded 1.23 g (49%) of white solid as (S)-(−)-
2
4
1
b, mp: 210–212°C; [h] −58.7 (c 0.5, CHCl ), >99% ee
D
3
(
tR(S)=6.60 min).
5. (a) Vsykocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.;
Hanu sˇ , V.; Polasek, M.; Kocovsk y´ , P. J. Org. Chem.
1
998, 63, 7727; (b) Vsykocil, S.; Jaracz, S.; Smrcina, M.;
Acknowledgements
Sticha, M.; Hanu sˇ , V.; Polasek, M.; Kocovsk y´ , P. J. Org.
Chem. 1998, 63, 7738; (c) Hu, X.; Chen, H.; Zhang, X.
Angew. Chem., Int. Ed. Engl. 1999, 38, 3518; (d) Tang,
W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43, 3075.
. (a) Uehara, A.; Bailar, J. C. J. Organomet. Chem. 1982,
This work was supported by the National Natural
Science Foundation of China (29933050), the CAS R.
C. Wang Post-doctoral Research Award Fund, the
CAS Post-doctoral Research Fund and the Young Fac-
ulty Research Fund of DICP.
6
7
2
39, 1; (b) Bennett, M. A.; Bhargava, S. K.; Griffiths, K.
D.; Robertson, G. B. Angew. Chem., Int. Ed. Engl. 1987,
6, 260.
2
. Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.;
Hansen, H. J. Helv. Chim. Acta 1988, 71, 897.
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