1,1′-Binaphthylazepine-based ligands for asymmetric catalysis. Part 1: Preparation and characterization of some new aminoalcohols and diamines

Article abstract of DOI:10.1016/S0957-4166(01)00199-9

Starting from (S)-1,1′-binaphthol, a series of ten novel enantiopure 1,1′-binaphthylazepine-based aminoalcohols and diamines 1a-1j were efficiently prepared and fully characterized. These derivatives, having either only an atropisomeric bridged-binaphthyl backbone or an additional stereogenic carbon center, can be interesting ligands for asymmetric catalysis.

Full text of DOI:10.1016/S0957-4166(01)00199-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1225–1233
1,1%-Binaphthylazepine-based ligands for asymmetric catalysis.
Part 1: Preparation and characterization of some new
aminoalcohols and diamines
Tommaso Mecca, Stefano Superchi, Egidio Giorgio and Carlo Rosini*
Dipartimento di Chimica, Universita` della Basilicata, Via Nazario Sauro 85, 85100 Potenza, Italy
Received 6 April 2001; accepted 2 May 2001
Abstract—Starting from (S)-1,1%-binaphthol, a series of ten novel enantiopure 1,1%-binaphthylazepine-based aminoalcohols and
diamines 1a–1j were efficiently prepared and fully characterized. These derivatives, having either only an atropisomeric
bridged-binaphthyl backbone or an additional stereogenic carbon center, can be interesting ligands for asymmetric catalysis.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Oxaziridinium6 and N-oxoammonium7 salts of such
binaphthylazepines were used, respectively, in the enan-
tioselective epoxidation of alkenes and in the oxidation
of secondary alcohols. Aminophosphines having such
chiral scaffolds gave high enantioselectivities in allylic
alkylation8 and amination reactions,8c but gave only
moderate results in cross-coupling reactions8b and
hydrogenations.8b Finally, the aminoalcohol with R=
CH2CH2OH was used by Noyori9 in the catalytic enan-
tioselective addition of ZnEt2 to benzaldehyde, the
secondary alcohol being obtained with moderate e.e.
Very recently, higher e.e.s have been obtained in the
same reaction employing binaphthylazepine-based N-
benzyl and N-methylferrocenyl aminoalcohols possess-
ing both axial and planar chirality.10
Optically active 2,2%-disubstituted-1,1%-binaphthyls con-
stitute the chiral backbone of a large number of auxil-
iaries and ligands for asymmetric synthesis.1 However,
among them, chiral 1,1%-binaphthylazepine ligands (Fig.
1) have received only limited attention, despite the fact
that in some cases they showed promising levels of
enantiodiscrimination.
From this literature re´sume´ it is evident that, although
1,1%-binaphthylazepine-based ligands have been known
since the early 1980s, and have been tested in several
asymmetric processes, they have been employed quite
randomly and their use has never been approached in a
systematic way. Moreover, a detailed study aimed at
defining the structural features which are responsible
for their efficiency as chiral inducers is still lacking.
These considerations prompted us to carry out a sys-
tematic study on a larger group of chiral ligands
belonging to this class, with the aim of improving their
performance and widening their use as ligands in asym-
metric catalysis. Taking into account the high efficiency
displayed by aminoalcohols and diamines in asymmet-
ric synthesis,11 we decided to undertake an investigation
aimed at evaluating the scope and limitations of the
Figure 1.
The diamine with R=CH2CH2N(CH3)2, reported by
Cram et al.2 in 1981 for the stoichiometric enantioselec-
tive addition of RLi to aldehydes, has been more
recently employed in the enantioselective dihydroxyla-
tion of olefins.3 The simple amine with R=H was
employed in the asymmetric Michael addition to croto-
nates,4 while the alkyl-substituted amine having R=
(S)-CH(Ph)CH3 was used5 as
a
ligand in the
asymmetric reduction of ketones with borane.
* Corresponding author. Tel.: +39-0971-202241; fax: +39-0971-
202223; e-mail: rosini@unibas.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00199-9

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T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
binaphthylazepines (S)-1h and (S)-1j, having an addi-
tional aromatic or heteroaromatic moiety, were also
prepared taking into account the promising enantiose-
lectivity afforded by chiral aminopyridine13 and
aminophenol11,14 ligands.
aminoalcohols and diamines 1a–1j possessing the
binaphthylazepine skeleton (Fig. 2) as chiral catalysts.
Thus, we herein report the preparation and characteri-
zation of the ligands 1a–1j.
The dibromide (S)-2, common precursor for 1a–1j, was
prepared in enantiopure form by modifying a recent
literature method (Scheme 1).12 The ditriflate (S)-3 was
prepared from (S)-1,1%-binaphthol according to the lit-
erature.15 A cross-coupling reaction16 of (S)-3 with
MeMgBr in THF, in the presence of a nickel catalyst (5
mol%), provided the 2,2%-dimethyl derivative (S)-4.
Instead of NiCl2(dppp), as reported in the literature,16
we tested both NiCl2(dppe) and NiCl2(PPh3)2 as cata-
lysts in this reaction. The former afforded the coupled
2. Results and discussion
Compounds 1a–1j can be easily obtained (vide infra)
from
homochiral
(S)-2,2%-bis(bromomethyl)-1,1%-
binaphthalene (S)-2, which is readily synthesized from
enantiopure (S)-1,1%-binaphthol.12 Compounds (S)-1a–
1g have the interesting feature that, by changing the
substituents at C(O), ligands where the chirality is
either due only to atropisomerism or also due to the
presence of a stereogenic center can be prepared. The
Figure 2.
Scheme 1.

T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
1227
Scheme 2.
product (S)-4 in 92% yield from a reaction of 48 h
duration, while the latter gave rise, unexpectedly, to a
rapid exothermic reaction (1 h) and afforded (S)-4 in
90% yield. Subsequent benzylic bromination of (S)-4
with NBS in refluxing CCl4 (with light irradiation)
afforded the desired (S)-2 in 80% yield. HPLC analy-
sis on a chiral column (Chiralcel OJ chiral stationary
phase) showed that both (S)-4 and (S)-2 were enan-
tiomerically pure. Therefore, the sequence from (S)-
1,1%-binaphthol to (S)-2 is completely stereospecific.
Enantiopure (S)-2 was then used to synthesize the
binaphthylazepines 1a–1j.
ride with 6 equiv. of PhMgBr in THF).17 Reaction of
(S)-2 with the commercially available 1-aminomethyl-
cyclohexanol hydrochloride 5b afforded the cyclohexyl
analog (S)-1d in 91% yield. The monophenyl analog
(aS,R)-1e was prepared in 55% yield by reaction
between (S)-2 and enantiomerically pure (R)-2-amino-
1-phenylethanol18 (R)-5c and, similarly, reaction of
(S)-2 with (S)-2-amino-1-phenylethanol (S)-5c and
(S)-2-amino-1-cyclohexylethanol (S)-5d afforded the
aminoalcohols (aS,S)-1f (84% yield) and (aS,S)-1g
(92% yield), respectively.
(S)-5c was prepared starting from (S)-mandelic acid
according to the procedure reported in Scheme 4. (S)-
Mandelic acid was treated with 2,2-dimethoxypropane
(S)-2 was reacted with glycine ethyl ester hydrochlo-
ride, in the presence of excess of Et3N in refluxing
THF, affording (S)-1k in 50% yield (Scheme 2). The
latter was then converted to the aminoalcohol (S)-1a
(67% yield) by reaction with 2.2 equiv. of MeMgBr in
THF and to compound (S)-1b (30% yield) by reac-
tion with 2 equiv. of tert-BuLi in THF.
,
in CHCl3 in the presence of 4 A molecular sieves to
obtain the cyclic dioxolanone (S)-6c in 85% yield.19
The latter was then reacted with NH3 in EtOH to
afford the (S)-mandelamide (S)-7c in 78% yield,
which was subjected to LiAlH4 reduction in THF to
afford (S)-5c in 30% yield. Accordingly, (S)-5d was
prepared from (S)-hexahydromandelic acid.
The synthesis of compounds 1c–1g was performed
following the same approach. The dibromide (S)-2
was reacted with the aminoalcohol precursors 5a–5d
by heating under reflux in THF with excess Et3N
(Scheme 3). Thus, the diphenyl analog (S)-1c was
prepared in 93% yield by reaction of (S)-2 with 1,1-
diphenyl-2-aminoethanol 5a (previously obtained in
52% yield by reacting glycine ethyl ester hydrochlo-
The aminopyridine (S)-1h was prepared in 90% yield
by reacting (S)-2 with 6.0 equiv. of 2-
(aminomethyl)pyridine (Scheme 5). Reaction of (S)-2
with 3 equiv. of N-acetylethylenediamine gave the
compound (S)-1l in 97% yield, which was further
reduced with LiAlH4 in THF to obtain the diamine
(S)-1i in 50% yield (Scheme 5). Finally, reaction of
(S)-2 with 2 equiv. of 2-methoxybenzylamine in THF
containing 3 equiv. of Et3N afforded (S)-1m in 69%
yield. The latter was then demethylated with BBr3 in
CH2Cl2 at rt to provide the aminophenol (S)-1j in
96% yield (Scheme 6).
3. Conclusions
We have prepared and characterized a series of new
1,1%-binaphthylazepines 1a–1j in enantiopure form.
The synthetic methods developed for preparing 1a–1j
are very straightforward and efficient and 1a–1j, dis-
Scheme 3.
Scheme 4.

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T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
Scheme 5.
Scheme 6.
playing either only atropisomeric chirality or additional
stereogenic centers, constitute promising and interesting
chiral ligands to be tested in the multitude of
asymmetric tranformations catalyzed by aminoalcohols
and diamines.11 The availability of a large number of
compounds with the same chiral backbone but with
different structural features will allow the determination
of the features which affect the performance of such
compounds in asymmetric catalysis. This type of
information will certainly be useful to both
experimental and theoretical researchers in clarifying
the correlation between structure and catalytic activity.
The efficiency of compounds 1a–1g as chiral ligands has
been tested in the enantioselective addition of Et2Zn to
aromatic aldehydes, taken as a benchmark reaction.20
Work is now in progress to study the efficiency of
compounds 1a–1j in other asymmetric transformations.
CH2Cl2 were distilled, respectively, from CaH2 and
,
P2O5 and stored over activated 4 A molecular sieves.
Triethylamine was distilled over CaH2 and stored under
nitrogen on KOH. Methylmagnesium bromide
(Aldrich) was used as a 3.0 M solution in diethyl ether,
phenylmagnesium bromide (Aldrich) was used as a 1.0
M solution in THF, and tert-butyl lithium (Aldrich)
was used as a 1.7 M solution in pentane. The additions
of organometallic reagents were performed using the
syringe-septum cap technique under a nitrogen atmo-
sphere. Enantiopure (R)-2-amino-1-phenylethanol (R)-
5c18 and (S)-1,1%-binaphthol21 were prepared according
to literature procedures. (S)-1,1%-Bi-2-naphthol-bis(tri-
fluoromethanesulfonate) (S)-3 was prepared from (S)-
1,1%-binaphthol according to literature procedures.15
Glycine ethyl ester hydrochloride, 1-aminomethylcyclo-
hexanol hydrochloride, 2-aminomethylpyridine, N-
acetylethylendiamine, and 2-methoxybenzylamine were
used as purchased (Aldrich). Analytical and preparative
TLC were performed, respectively, on 0.2 and 2.0 mm
silica gel plates Merck 60 F-254 and column chro-
matography was carried out with silica gel Merck 60
(80–230 mesh) or neutral aluminum oxide activity grade
1 Riedel deHaen (70–290 mesh).
4. Experimental
4.1. General procedures
Melting points were determined with a Kofler hot-stage
1
apparatus and are uncorrected. H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded in
CDCl3 on a Bruker Aspect 300 spectrometer. Optical
rotations were measured with a JASCO DIP-370 digital
polarimeter. Enantiomeric purities of compounds (S)-2
and (S)-4 were checked by HPLC analyses on a Daicel
Chiralcel OJ chiral stationary phase using a 95:5 hex-
ane/iso-propanol mixture as eluent. THF was freshly
distilled prior to use from sodium benzophenone ketyl
and stored under a nitrogen atmosphere. CCl4 and
4.2. (S)-(+)-2,2%-Dimethyl-1,1%-binaphthalene 4
To a solution of (S)-3 (5.0 g, 9.1 mmol) and
NiCl2(PPh3)2 (417 mg, 0.64 mmol) in anhydrous Et2O
(35 mL) under nitrogen was slowly added MeMgBr (3.0
M, 12.2 mL, 36.4 mmol). During the addition the
mixture spontaneously warmed and the solvent started
to boil vigorously. The reaction was cooled with a

T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
1229
water-ice bath and monitored by TLC. After stirring for
1 h the solution was diluted with Et2O, washed with 5%
aqueous HCl, brine and dried over anhydrous Na2SO4.
The solvent was evaporated and the residue was purified
by column chromatography (SiO2; petroleum ether)
affording (S)-4 as a colorless glass (2.26 g, 88%). E.e.
99%; [h]2D1=+37.7 (c 1.0; CHCl3) {lit.:22 [h]2D0=−35.6 (c
1.0; CHCl3) for (R)-4 in 94% e.e.}; 1H NMR (300 MHz,
CDCl3): l 2.0 (s, 6H), 7.0 (d, 2H, J=8.4 Hz), 7.2 (m, 2H),
7.4 (t, 2H, J=7.4 Hz), 7.5 (d, 2H, J=8.4 Hz), 7.9 (m,
4H).
dropwise MeMgBr (3.0 M, 0.45 mL, 1.35 mmol). The
mixture was stirred at rt for 16 h, then quenched with
a few drops of H2O and the solvent evaporated. The
residue was dissolved in CHCl3 and washed sequentially
with H2O and brine. The organic solution was dried over
anhydrous Na2SO4 and concentrated in vacuo. The
recovered residue was purified by column chromatogra-
phy (SiO2; CHCl3/Et2O, 9:1) affording 1a as a colorless
1
glass (110 mg, 67%). [h]2D1=+226.7 (c 1.0; THF); H
NMR (300 MHz, CDCl3): l 1.24 (s, 3H), 1.26 (s, 3H),
2.21 (d, 1H, J=13.8 Hz), 2.85 (d, 1H, J=13.8 Hz),
3.1–3.6 (br s, 1H), 3.40 (d, 2H, J=12.2 Hz), 3.71 (d, 2H,
J=12.2 Hz), 7.2–7.3 (m, 2H), 7.4–7.5 (m, 4H), 7.54 (d,
2H, J=8.2 Hz), 7.9–8.0 (m, 4H). Anal. calcd for
C26H25NO: C, 84.98; H, 6.86; N, 3.81. Found: C, 84.91;
H, 6.93; N, 3.77%.
4.3. (S)-(−)-2,2%-Dibromomethyl-1,1%-binaphthalene 2
To a solution of (S)-4 (2.16 g, 7.66 mmol) in CCl4 (20
mL) was added N-bromosuccinimide (2.72 g, 15.32
mmol). The solution was stirred under reflux under
visible light for 4 h and cooled to rt. After evaporation
of the solvent, the residue was dissolved in CHCl3. The
resultant organic solution was washed with H2O and
brine, dried over anhydrous Na2SO4 and concentrated in
vacuo. The recovered product was dissolved in petroleum
ether/CH2Cl2 (1:1) and filtered through a short pad of
silica gel and the filtrate evaporated. The evaporation
residue was purified by recrystallization from hexane to
afford (S)-2 as a white solid (2.73 g, 81%). Mp 183.0–
183.7°C, lit.23 mp 183.5–184°C; [h]2D1=−160.0 (c 1.0;
benzene) {lit.:23 [h]D20=−160.3 (c 1.0; benzene) for (S)-2
in 99% e.e.}; 1H NMR (300 MHz, CDCl3): l 4.2 (s, 4H),
7.1 (d, 2H, J=8.4 Hz), 7.2 (m, 2H), 7.3 (m, 2H), 7.5 (m,
2H), 7.7 (d, 2H, J=8.5 Hz), 8.0 (d, 2H, J=8.5 Hz).
4.6. (S)-(+)-2,2%-[2-(2,2-Di-tert-butyl-2-hydroxyethyl)-2-
azapropane-1,3-diyl]-1,1%-binaphthalene 1b
To a solution of tert-BuLi (1.7 M, 1.1 mL, 1.8 mmol)
in dry THF (2 mL) under nitrogen was added at −70°C
a solution of (S)-1k (115 mg, 0.3 mmol) in dry THF (1
mL). The solution was stirred at −70°C for 90 min, then
quenched with water, diluted with Et2O and washed
sequentially with saturated aqueous NH4Cl and brine.
The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. The recovered residue was
purified by column chromatography (SiO2; petroleum
ether/Et2O, 7:3) affording 1b as a slightly yellow glass (40
1
mg, 32%). [h]2D0=+104.5 (c 1.0; THF); H NMR (300
MHz, CDCl3): l 0.91 (s, 9H), 0.92 (s, 9H), 1.4–1.9 (br
s, 1H), 2.21 (d, 1H, J=14.0 Hz), 2.88 (d, 1H, J=14.0 Hz),
3.41 (d, 2H, J=12.1 Hz), 3.69 (d, 2H, J=12.1 Hz),
7.2–7.3 (m, 2H), 7.4–7.5 (m, 4H), 7.54 (d, 2H, J=8.2 Hz),
7.9–8.0 (m, 4H). Anal. calcd for C32H37NO: C, 85.10; H,
8.26; N, 3.10. Found: C, 85.01; H, 8.39; N, 3.02%.
4.4. (S)-(+)-2,2%-[2-(Ethoxycarbonylethyl)-2-azapropane-
1,3-diyl]-1,1%-binaphthalene 1k
To a solution of (S)-2 (200 mg, 0.45 mmol) in anhydrous
THF (15 mL) under an inert atmosphere were added
glycine ethyl ester hydrochloride (100 mg, 0.7 mmol) and
triethylamine (251 mL, 1.8 mmol). The mixture was
stirred under reflux for 48 h and then cooled to rt. The
solution was filtered, the solid residue was washed with
THF and the collected resulting solution was concen-
trated in vacuo. The recovered solid residue was dis-
solved in CHCl3, washed sequentially with H2O and
brine, and the organic layer was dried over anhydrous
Na2SO4. After evaporation of solvent, the recovered
residue was purified by column chromatography (SiO2;
CHCl3/MeOH, 6:1) affording 1k (81 mg, 51%). [h]2D1=
+278 (c 1.1; CHCl3); 1H NMR (300 MHz, CDCl3): l 1.3
(t, 3H, J=7.1 Hz), 3.2 (d, 2H, J=16.2 Hz), 3.3 (d, 2H,
J=12.3 Hz), 3.4 (d, 2H, J=16.2 Hz), 3.8 (d, 2H, J=12.3
Hz), 4.2 (q, 2H, J=7.1 Hz), 7.3 (m, 2H), 7.5 (m, 4H),
7.6 (d, 2H, J=8.2 Hz), 7.9 (d, 4H, J=8.1 Hz); 13C NMR
(75 MHz, CDCl3): l 170.7, 135.1, 133.3, 133.0, 131.4,
128.4, 128.3, 127.8, 127.5, 125.8, 125.5, 60.8, 57.8, 57.0,
55.7, 14.3. Anal. calcd for C26H23NO2: C, 81.86; H, 6.08;
N, 3.67. Found: C, 81.73; H, 5.96; N, 3.59%.
4.7. 2-Amino-1,1-diphenylethanol 5a
Glycine ethyl ester hydrochloride (1.4 g, 10 mmol) was
slowly added (ca. 3 h) to a solution of PhMgBr (1.0 M,
60 mL, 60.0 mmol) in anhydrous THF (100 mL). The
solution was stirred at 40°C for 3 h, then cooled at rt and
quenched with H2O (20 mL). The mixture was diluted
with Et2O (100 mL) and washed with brine. The aqueous
layer was extracted twice with Et2O/THF (3:2). The
combined organic layers were washed with brine and
dried over anhydrous Na2SO4. After evaporation of
solvent, the recovered residue was recrystallized three
times from Et2O and purified by column chromatogra-
phy (SiO2; CHCl3/MeOH, 8:2) affording 5a as a white
1
solid (1.1 g, 52%). Mp 110°C; H NMR (300 MHz,
CDCl3): l 2.8–3.2 (br s, 3H), 3.38 (s, 2H), 7.2–7.5 (m,
10H).
4.8. (S)-(+)-2,2%-[2-(2,2-Diphenyl-2-hydroxyethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1c
4.5. (S)-(+)-2,2%-[2-(2,2-Dimethyl-2-hydroxyethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1a
To a solution of (S)-2 (440 mg, 0.1 mmol) in anhydrous
THF (15 mL) under an inert atmosphere were added 5a
(341 mg, 1.6 mmol) and triethylamine (505 mL, 5.0
mmol). The resulting mixture was stirred under reflux
To a solution of (S)-1k (172 mg, 0.45 mmol) in anhyd-
rous THF (15 mL) under an inert atmosphere was added

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T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
for 18 h then cooled to rt. The solution was filtered and
the solid filtration residue was washed with THF and
the collected resulting solution concentrated in vacuo.
The solid evaporation residue was dissolved in CH2Cl2
and washed sequentially with H2O and brine. The
organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by
chromatography (SiO2; CH2Cl2/Et2O, 96:4) affording
1c as a glassy solid (455 mg, 93%). [h]2D1=+85.0 (c 1.0;
residue triturated with hot Et2O yielding, after evapora-
tion of solvent, pure 7c as a white solid (1.95 g, 77%).
Mp 119–120°C; lit.19 mp 118–120°C; [h]2D0=+54.5 (c
1
1.0; THF), lit.:19 [h]D25=+94.7 (c 2.4; water); H NMR
(300 MHz, CDCl3): l 1.7–2.1 (br s, 1H), 5.08 (s, 1H),
5.5–5.7 (br s, 1H), 5.9–6.1 (br s, 1H), 7.3–7.5 (m, 5H).
4.12. (S)-(+)-2-Amino-1-phenylethanol 5c
1
THF); H NMR (300 MHz, CDCl3): l 1.4–1.8 (br s,
To a stirred solution of (S)-7c (1.74 g, 11.5 mmol) in
dry THF (80 mL) under an inert atmosphere was added
LiAlH4 (4 g, 103.5 mmol). The mixture was heated
under reflux for 3 days, cooled at rt and quenched with
a minimum quantity of ice-water. The organic phase
was diluted with EtOAc and the solid residue was
washed with EtOAc. The collected organic phases were
washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The solid residue was dissolved
in boiling hexane (400 mL), the insoluble remaining 7c
was filtered off, and the solution was left to cool
yielding pure 5c as a white solid (475 mg, 30%). [h]2D0=
+58.0 (c 1.0; THF) {lit.:18 [h]D23=+45.0 (c 1.32;
1H), 3.20 (d, 3H, J=12.5 Hz), 3.28 (d, 2H, J=12.4
Hz), 3.73 (d, 1H, J=12.9 Hz), 7.1–7.5 (m, 14H), 7.53
(d, 2H, J=8.2 Hz), 7.61 (d, 2H, J=8.1 Hz), 7.93 (d,
4H, J=8.2 Hz). Anal. calcd for C36H29NO: C, 87.95;
H, 5.95; N, 2.85. Found: C, 87.86; H, 6.03; N, 2.91%.
4.9. (S)-(+)-2,2%-[2-(1-Hydroxycyclohexylmethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1d
To a solution of (S)-2 (440 mg, 1.0 mmol) in anhydrous
THF (40 mL) under an inert atmosphere were added
1-aminomethylcyclohexanol hydrochloride (330 mg, 2.0
mmol) and triethylamine (665 mL, 5.0 mmol). The
mixture was stirred at reflux for 24 h and then cooled to
rt. The solution was filtered and the solid residue was
washed with THF and the collected resulting solution
was evaporated in vacuo. The resulting solid residue
was dissolved in CHCl3, washed sequentially with H2O
and brine, and the organic layer was dried over anhyd-
rous Na2SO4. After evaporation of solvent, the residue
was purified by column chromatography (neutral
Al2O3; CHCl3) affording 1d as a colorless glass (370
1
CHCl3)}; H NMR (300 MHz, CDCl3): l 1.8–2.2 (br s,
3H), 2.79 (dd, 1H, J=11.5, 19.1 Hz), 2.98 (dd, 1H,
J=6.0, 19.1 Hz), 4.62 (dd, 1H, J=6.0, 11.5 Hz), 7.2–
7.4 (m, 5H).
4.13. (aS,R)-(+)-2,2%-[2-(2-Phenyl-2-hydroxyethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1e
To a solution of (S)-2 (440 mg, 1 mmol) in anhydrous
THF (30 mL) under a nitrogen atmosphere were added
(R)-5c (165 mg, 1.2 mmol) and triethylamine (0.5 mL, 4
mmol). The solution was stirred under reflux for 16 h,
then cooled to rt, diluted with Et2O (60 mL), washed
with saturated NH4Cl and brine. The organic layer was
dried on anhydrous Na2SO4 and concentrated in vacuo.
The product was purified by column chromatography
(neutral Al2O3; CHCl3/ethyl acetate, 3:1) affording 1e
as a colorless glass (230 mg, 55%). [h]2D0=+170 (c 1.0;
1
mg, 91%). [h]2D1=+223.8 (c 1.0; CHCl3); H NMR (300
MHz, CDCl3): l 1.2–1.9 (m, 10H), 2.24 (d, 1H, J=13.2
Hz), 2.5–3.1 8 (br s, 1H), 2.89 (d, 1H, J=13.2 Hz), 3.42
(d, 2H, J=12.2 Hz), 3.73 (d, 2H, J=12.2 Hz), 7.2–7.3
(m, 2H), 7.4–7.5 (m, 4H), 7.55 (d, 2H, J=8.2 Hz),
7.9–8.0 (m, 4H). Anal. calcd for C30H33NO: C, 85.06;
H, 7.85; N, 3.31. Found: C, 84.92; H, 7.77; N, 3.28%.
1
THF); H NMR (300 MHz, CDCl3): l 2.34 (dd, 1H,
J=10.6, 13.0 Hz), 2.5–2.9 (br s, 1H), 2.88 (dd, 1H,
J=3.2, 13.0 Hz), 3.31 (d, 2H, J=12.3 Hz), 3.76 (d, 2H,
J=12.3 Hz), 4.95 (dd, 1H, J=3.2, 10.6 Hz), 7.2–7.3 (m,
4H), 7.3–7.4 (m, 2H), 7.4–7.5 (m, 5H), 7.57 (d, 2H,
J=8.3 Hz), 7.9–8.0 (m, 4H). Anal. calcd for C30H25NO:
C, 86.71; H, 6.06; N, 3.37. Found: C, 86.53; H, 5.98; N,
3.31%.
4.10. (S)-(+)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-one
6c
To a solution of (S)-mandelic acid (3.0 g, 19.7 mmol)
and 2,2-dimethoxypropane (25 mL) in dry CHCl3 (30
,
mL) were added activated 4 A molecular sieves and the
mixture was stirred for 2 days at room temperature.
The mixture was filtered through a short pad of silica
gel using CHCl3 eluent. Evaporation of solvent from
the eluate afforded pure 6c as a white solid (3.05 g,
85%). Mp 72–73°C, lit.19 mp 72–73°C; [h]2D0=+91.0 (c
4.14. (aS,S)-(+)-2,2%-[2-(2-Phenyl-2-hydroxyethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1f
To a solution of (S)-2 (220 mg, 0.5 mmol) in anhydrous
THF (15 mL) under an inert atmosphere were added
(S)-5c (82 mg, 0.6 mmol) and triethylamine (280 mL; 2
mmol). The resulting solution was stirred under reflux
for 12 h, cooled to rt and diluted with Et2O (40 mL).
The solution was washed with saturated NH4Cl and
brine, dried over anhydrous Na2SO4 and concentrated
in vacuo. The product was purified by column chro-
matography (neutral Al2O3; CHCl3/ethyl acetate, 3:1)
affording 1f as a colorless glass (174 mg, 84%). [h]2D0=
1
1.0; THF), lit.:19 [h]D25=+84.0 (c 1.0; CHCl3); H NMR
(300 MHz, CDCl3): l 1.69 (s, 3H), 1.74 (s, 3H), 5.40 (s,
1H), 7.3–7.5 (m, 5H).
4.11. (S)-(+)-Mandelamide 7c
(S)-6c (3 g, 16.66 mmol) was dissolved in a solution of
NH3 (2.0 M in anhydrous EtOH, 33 mL) and the
mixture was stirred under a nitrogen atmosphere for 18
h at rt. The mixture was concentrated in vacuo and the
1
+140.7 (c 1.0; THF). H NMR (300 MHz, CDCl3): l

T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
1231
1.4–2.0 (br s, 1H), 2.64 (dd, 1H, J=3.3, 12.1 Hz), 2.82
(dd, 1H, J=12.1, 10.5 Hz), 3.37 (d, 2H, J=12.2 Hz),
3.77 (d, 2H, J=12.2 Hz), 4.78 (dd, 1H, J=3.3, 10.5
Hz), 7.2–7.4 (m, 7H), 7.4–7.6 (m, 6H), 7.9–8.0 (m, 4H).
Anal. calcd for C30H25NO: C, 86.71; H, 6.06; N, 3.37.
Found: C, 86.59; H, 6.02; N, 3.28%.
(S)-5d (86 mg, 0.6 mmol) and triethylamine (280 mL, 2
mmol) and the solution was stirred under reflux for 12
h. After cooling to rt, the solution was filtered and the
solid residue was washed with THF. The resulting
collected solution was then concentrated in vacuo, and
the recovered residue was dissolved in Et2O, washed
with saturated NH4Cl and brine. The organic layer was
dried on anhydrous Na2SO4 and concentrated in vacuo.
The product was purified by column chromatography
(neutral Al2O3). Elution with petroleum ether/CHCl3
(1:1) allowed recovery of unreacted (S)-2, then elution
with CHCl3/ethyl acetate (3:1) allowed recovery of 1g
as a colorless glass (194 mg, 92%). [h]2D0=+220.5 (c 1.0;
THF). 1H NMR (300 MHz, CDCl3): l 0.8–1.4 (m, 6H),
1.5–1.8 (m, 4H), 1.9–2.0 (m, 1H), 2.53 (dd, 1H, J=3.0,
11.7 Hz), 2.70 (dd, 1H, J=11.7, 10.8 Hz), 3.28 (d, 2H,
J=12.2 Hz), 3.46 (ddd, 1H, J=3.0, 10.8, 6.4 Hz),
3.4–3.8 (br s, 1H), 3.71 (d, 2H, J=12.2 Hz), 7.2–7.3 (m,
2H), 7.4–7.5 (m, 4H), 7.54 (d, 2H, J=8.3 Hz), 7.9–8.0
(m, 4H). Anal. calcd for C30H31NO: C, 85.47; H, 7.41;
N, 3.32. Found: C, 85.41; H, 7.52; N, 3.23%.
4.15. (S)-(−)-2,2-Dimethyl-5-cyclohexyl-1,3-dioxolan-4-
one 6d
To a solution of (S)-hexahydromandelic acid (1.0 g, 6.3
mmol) and 2,2-dimethoxypropane (8 mL, 63 mmol) in
,
dry CHCl3 (10 mL) were added activated 4 A molecular
sieves. The resultant mixture was stirred for 2 days at
rt. The mixture was then filtered through a short pad of
silica gel using CHCl3 eluent. Evaporation of the sol-
vent afforded pure 6d as a white solid (1.25 g, 99%).
1
Mp 35.5–36.0°C; [h]D20=−16.5 (c 1.0; CHCl3). H NMR
(300 MHz, CDCl3): l 1.0–1.3 (m, 6H), 1.53 (s, 3H),
1.59 (s, 3H), 1.6–1.9 (m, 5H), 4.23 (d, 1H, J=3.6 Hz).
Anal. calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.51; H, 9.07%.
4.19. (S)-(+)-2,2%-[2-(Methyl-2-pyridyl)-2-azapropane-
1,3-diyl]-1,1%-binaphthalene 1h
4.16. (S)-(+)-Hexahydromandelamide 7d
(S)-6d (1.25 g, 6.3 mmol) was dissolved in a solution of
NH3 (2.0 M in anhydrous EtOH, 9.5 mL) and the
mixture was stirred under an inert atmosphere for 18 h
at rt. The mixture was then concentrated in vacuo and
the residue was triturated with hot Et2O yielding pure
(S)-7d as a white solid (670 mg, 67%). Mp 157–158°C;
[h]2D0=+13.5 (c 1.0; THF). 1H NMR (300 MHz,
CDCl3): l 1.0–1.4 (m, 6H), 1.5–1.9 (m, 5H), 2.55 (br s,
1H), 3.99 (br s, 1H), 5.5–5.7 (br s, 1H), 6.2–6.4 (br s,
1H). Anal. calcd for C8H15NO2: C, 61.12; H, 9.62; N,
8.91. Found: C, 61.20; H, 9.76; N, 8.79%.
To a solution of (S)-2 (440 mg, 1.0 mmol) in anhydrous
THF (40 mL) under an inert atmosphere was added
2-aminomethylpyridine (620 mL, 6.0 mmol). The solu-
tion was stirred under reflux for 18 h then cooled to rt.
The solution was filtered and the solid residue was
washed with THF. The resulting collected solution was
concentrated in vacuo. The recovered residue was dis-
solved in CHCl3, washed sequentially with H2O and
brine, and the organic layer was dried over anhydrous
Na2SO4. The solid residue recovered after evaporation
of the solvent was then purified by column chromatog-
raphy (neutral Al2O3; CH2Cl2/Et2O, 85:15) affording 1h
as a slightly yellow glass (346 mg, 90%). [h]2D1=+294.9
4.17. (S)-(−)-2-Amino-1-cyclohexylethanol 5d
1
(c 1.0; CHCl3). H NMR (300 MHz, CDCl3): l 3.27 (d,
To a stirred solution of (S)-7d (660 mg, 4.2 mmol) in
dry THF (30 mL) under an inert atmosphere was added
LiAlH4 (1.0 g, 25 mmol). The reaction mixture was
heated under reflux for 2 days, then cooled to room
temperature and quenched with ice-water. The mixture
was diluted with EtOAc and the solid residue filtered
off. The organic solution was then washed with brine,
dried on anhydrous Na2SO4 and concentrated in vacuo.
The recovered solid residue was dissolved in boiling
hexane (300 mL), the resulting solution was filtered and
left cooling, recovering unreacted (S)-7d as white crys-
tals. The remaining mother liquor was concentrated in
vacuo to afford 5d as a white solid (395 mg, 66%). Mp
2H, J=12.2 Hz), 3.67 (d, 2H, J=12.2 Hz), 3.69 (d, 2H,
J=13.6 Hz), 3.85 (d, 2H, J=13.6 Hz), 7.1–7.3 (m, 2H),
7.4–7.7 (m, 8H), 7.9–8.0 (m, 4H), 8.61 (m, 1H). Anal.
calcd for C28H22N2: C, 87.01; H, 5.74; N, 7.25. Found:
C, 86.93; H, 5.73; N, 7.34%.
4.20. (S)-(+)-2,2%-[2-(N-Acetyl-2-aminoethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1l
To a solution of (S)-2 (440 mg, 1.0 mmol) in anhydrous
THF (40 mL) under an inert atmosphere was added
N-acetyl-ethylenediamine (290 mL, 3.0 mmol). The
solution was stirred under reflux for 18 h then cooled to
rt. The solution was filtered and the solid residue was
washed with THF. The resulting solution was evapo-
rated to dryness. The collected residue was dissolved in
CHCl3 and washed sequentially with H2O and brine.
The organic layer was dried on anhydrous Na2SO4 and
concentrated in vacuo. The product was purified by
column chromatography (SiO2; CHCl3/MeOH, 6:1)
affording 372 mg of 1l (98% yield) as a colorless glass.
[h]2D1=+231.7 (c 1.0; CHCl3). 1H NMR (300 MHz,
CDCl3): l 2.03 (s, 3H), 2.5 (m, 1H), 2.8 (m, 1H), 3.20
(d, 2H, J=12.2 Hz), 3.4–3.5 (m, 2H), 3.66 (d, 2H,
1
86.7–87°C; [h]2D0=−44.0 (c 1.0; THF). H NMR (300
MHz, CDCl3): l 0.9–1.4 (m, 6H), 1.6–2.1 (m, 8H), 2.56
(dd, 1H, J=8.9, 12.5 Hz), 2.88 (dd, 1H, J=3.1, 12.5
Hz), 3.24 (ddd, 1H, J=3.1, 6.4, 12.5 Hz). Anal. calcd
for C8H17NO: C, 67.09; H, 11.96; N, 9.78. Found: C,
67.25; H, 12.17; N, 9.59%.
4.18. (aS,S)-(+)-2,2%-[2-(2-Cyclohexyl-2-hydroxyethyl)-
2-azapropane-1,3-diyl]-1,1%-binaphthalene 1g
To a solution of (S)-2 (220 mg, 0.5 mmol) in anhydrous
THF (15 mL) under an inert atmosphere were added

1232
T. Mecca et al. / Tetrahedron: Asymmetry 12 (2001) 1225–1233
1
J=12.2 Hz), 6.4 (br s, 1H), 7.2–7.3 (m, 2H), 7.4–7.6 (m,
6H), 7.9–8.0 (m, 4H). Anal. calcd for C26H24N2O: C,
82.07; H, 6.36; N, 7.36. Found: C, 82.25; H, 6.49; N,
7.26%.
mg, 96%). [h]2D0=+213.8 (c 1.0; THF); H NMR (300
MHz, CDCl3): l 3.26 (br d, 2H, J=12.5 Hz), 3.76 (d,
2H, J=12.5 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.84 (d, 1H,
J=13.2 Hz), 6.8–6.9 (m, 2H), 7.03 (m, 1H), 7.2–7.3 (m,
3H), 7.4–7.6 (m, 6H), 7.9–8.0 (m, 4H). Anal. calcd for
C29H23NO: C, 86.75; H, 5.77; N, 3.49. Found: C, 86.83;
H, 5.83; N, 3.38%.
4.21. (S)-(+)-2,2%-[2-(N-Ethyl-2-aminoethyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1i
To a stirred solution of (S)-1l (180 mg, 0.47 mmol) in
dry THF (6 mL) under an inert atmosphere was added
LiAlH4 (54 mg, 1.41 mmol). The reaction mixture was
heated at reflux for 30 h then cooled at rt and quenched
with ice-water. The mixture was diluted with CHCl3,
washed with brine, dried on anhydrous Na2SO4 and
concentrated in vacuo. The recovered solid residue was
purified by column chromatography (neutral Al2O3;
CHCl3/AcOEt/EtOH, 68:30:2) affording 1i as a color-
Acknowledgements
Financial support from MURST (COFIN 2000) and
Universita` della Basilicata (Potenza) is gratefully
acknowledged.
1
less glass (86 mg, 50%). [h]2D1=+213.2 (c 1.0; THF). H
References
NMR (300 MHz, CDCl3): l 1.16 (t, 3H, J=7.1 Hz),
1.7–2.1 (br m, 1H), 2.5–2.6 (m, 1H), 2.73 (q, 2H, J=7.1
Hz), 2.7–2.9 (m, 3H), 3.20 (d, 2H, J=12.2 Hz), 3.68 (d,
2H, J=12.2 Hz), 7.2–7.3 (m, 2H), 7.4–7.5 (m, 4H), 7.54
(d, 2H, J=8.2 Hz), 7.9–8.0 (m, 4H). Anal. calcd for
C26H26N2: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.29;
H, 7.19; N, 7.52%.
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To a solution of (S)-2 (330 mg, 0.75 mmol) in anhyd-
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added 2-methoxybenzylamine (219 mL, 1.69 mmol) and
triethylamine (420 mL, 3 mmol). The solution was then
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and washed with saturated NH4Cl and brine. The
organic layer was dried on anhydrous Na2SO4 and
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1
69%). [h]2D0=+229 (c 1.0; THF). H NMR (300 MHz,
CDCl3): l=3.28 (d, 2H, J=12.2 Hz), 3.54 (d, 1H,
J=13.5 Hz), 3.73 (d, 2H, J=12.2 Hz), 3.82 (d, 1H,
J=13.5 Hz), 3.86 (s, 3H), 6.8–7.0 (m, 2H), 7.2–7.3 (m,
4H), 7.4–7.5 (m, 4H), 7.59 (d, 2H, J=8.2 Hz), 7.95 (d,
4H, J=8.2 Hz). Anal. calcd for C30H25NO: C, 86.71;
H, 6.06; N, 3.37. Found: C, 86.56; H, 5.98.; N, 3.29%.
10. Arroyo, N.; Haslinger, U.; Mereiter, K.; Widhalm, M.
4.23. (S)-(+)-2,2%-[2-(Methyl-2-hydroxyphenyl)-2-aza-
propane-1,3-diyl]-1,1%-binaphthalene 1j
Tetrahedron: Asymmetry 2000, 11, 4207.
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stirred at rt for 7 h, then quenched with saturated
NaHCO3 until a neutral pH was reached and washed
with brine. The organic layer was dried on anhydrous
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