Novel preparation of non-racemic 1-[α-(1-azacycloalkyl)benzyl]-2naphthols from Betti base and their application as ehiral ligands in the asymmetric addition of diethylzinc to aryl aldehydes

Article abstract of DOI:10.1039/b204534f

A novel route for the preparation of non-racemic 1-[α-(1-azacycloalkyl)benzyl]-2-naphthols was developed, which involves regioselective N-cycloalkylation of the Betti base with dials in the presence of NaBH₃CN to give 1-azacycloalka[2,1-b]oxazine followed by the selective cleavage of a C-O bond with LiAlH₄. As a new family of chiral ligands, their application in the enantioselective addition of diethylzinc to aryl aldehydes was tested. The ligands incorporating pyrrolidine and piperidine led to highly efficient asymmetric induction to give products in up to 96% yield and 99% ee.

Full text of DOI:10.1039/b204534f

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Novel preparation of non-racemic 1-[ꢀ-(1-azacycloalkyl)benzyl]-2-
naphthols from Betti base and their application as chiral ligands in
the asymmetric addition of diethylzinc to aryl aldehydes
1
Jun Lu,a Xuenong Xu,a Shaozhong Wang,a Cunde Wang,a Yuefei Hu*†a,b and Hongwen Hua
a Department of Chemistry, Nanjing University, Nanjing 210093, People’s Republic of China
b Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
Received (in Cambridge, UK) 10th May 2002, Accepted 1st October 2002
First published as an Advance Article on the web 12th November 2002
A novel route for the preparation of non-racemic 1-[α-(1-azacycloalkyl)benzyl]-2-naphthols was developed,
which involves regioselective N-cycloalkylation of the Betti base with dials in the presence of NaBH3CN to give
1-azacycloalka[2,1-b]oxazine followed by the selective cleavage of a C–O bond with LiAlH4. As a new family of
chiral ligands, their application in the enantioselective addition of diethylzinc to aryl aldehydes was tested. The
ligands incorporating pyrrolidine and piperidine led to highly efficient asymmetric induction to give products in
up to 96% yield and 99% ee.
or (R)-1. This result strongly implies that there is no suitable
Introduction
method for the regioselective N,N-dialkylation of the Betti base
so far and that the uses of the non-racemic Betti base, (S)-1 or
(R)-1, as a new chiral resource are seriously limited.
Herein, we would like to report a novel synthetic route by
which to prepare a new family of chiral cyclic amino-phenol
ligands 4a–f by direct N-cycloalkylation of (S)-1 and (R)-1. In
the enantioselective addition of diethylzinc to aryl aldehydes,
these ligands gave highly efficient asymmetric induction to give
products in up to 96% yield and 99% ee.
Chiral ligands with 1,2- and 1,3-amino-hydroxy structures have
been employed widely in a variety of asymmetric syntheses
catalyzed by metallic ions and most of them were derived
from a few readily available natural products.1 To increase the
understanding of asymmetric reactions, the design and syn-
thesis of chiral ligands from non-natural resources are essen-
tial.2 Therefore, chiral amino-phenol compounds have recently
been gaining in importance.3
1-(α-Aminobenzyl)-2-naphthol (1, Betti base) has the desired
1,3-amino-hydroxy structure and its racemic compound is
available in bulk.4 Although its enantiomers, (S)-1 and (R)-1,
were reported early last century (Chart 1),5 they were never
Results and discussion
Very recently, several attractive procedures were reported
for the regioselective N-cycloalkylation of amino-hydroxy
compounds. For example, 1,2-aliphatic amino-alcohols can be
N-cycloalkylated using dihalides and a variety of bases,6 and
N-cycloalkylation of 1,3-aromatic amino-phenol has been
achieved by reductive amination with dial in the presence of
NaBH4 and H2SO4.3a Unfortunately, all of our initial attempts
at regioselective N-cycloalkylation of (S)-1 using these pro-
cedures failed. Thus, a mixture of O-alkylated products was
obtained when (S)-1 was treated with 1,5-dibromopentane and
bases, and pentane-1,5-diol was produced almost quantitatively
in the reductive amination of (S)-1 with pentane-1,5-dial and
NaBH4–H2SO4. These results may explain why the Betti base is
a 1,3-aliphatic amino-phenol compound and that the reactions
lack selectivity due to the relatively low reactivity of the
aliphatic amine and the higher reactivity of the phenol.
However, the reaction of 1,2-amino-alcohols with pentane-
1,5-dial to yield 1-azacycloalka[2,1-b]oxazoles has attracted
our interest. The reactions usually proceed in the presence
of a nucleophilic reagent, such as benzotriazole7 or CNϪ 8 to
yield substituted 1-azacycloalka[2,1-b]oxazole derivatives (2)
(Scheme 1). The mechanism suggests that an unsubstituted
1-azacycloalka[2,1-b]oxazine (3b) could be obtained by
replacement of 1,2-amino-alcohols with the Betti base and by
using HϪ as a nucleophilic species.
Chart 1
employed as chiral ligands in asymmetric synthesis until the
work of Cardellicchio et al. in 1998,3b,c in which the resolution
procedure was modified and the N,N-dimethyl derivative of
(S)-1 induced the asymmetric addition of diethylzinc to aryl
aldehydes in up to 99% ee. Since then, several other non-
racemic N,N-dialkylated derivatives of the chiral Betti base
have been reported to give excellent asymmetric inductions.3e–g
Non-racemic amine derivatives of the Betti base showed very
similar behavior to other reported amino-hydroxy ligands. Its
tertiary amines gave better results than primary and secondary
amines in most cases.3c,f However the non-racemic N,N-dialkyl-
ated derivatives of the Betti base that have been reported in the
literature were usually prepared by resolution of the corre-
sponding racemic isomers3b,c,5 or by condensation with chiral
amines3e–g rather than directly from N,N-dialkylation of (S)-1
As expected, when (S)-1 was treated with pentane-1,5-dial
in the presence of NaBH3CN in an aqueous buffer solu-
tion9 (Na2HPO4–KH2PO4), unsubstituted tetrahydropyrido-
[2,1-b]oxazine 3b was obtained in 76% yield over 12 days
(monitored by TLC) (Scheme 2). Fortunately, the reaction time
† Present address: Department of Chemistry, Tsinghua University,
Beijing 100084, People’s Republic of China
2900
J. Chem. Soc., Perkin Trans. 1, 2002, 2900–2903
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b204534f

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Scheme 1
Scheme 2
can be shortened considerably by increasing the ratio of EtOH
in the reaction solvent. In practice, the salt of (S)-1 with -(ϩ)-
tartaric acid, which is a precursor of (S)-1 in its optical reso-
lution, was used directly as the starting material and 3b was
obtained in 61% yield within 30 min in 50% aqueous EtOH
(Scheme 3). The 1H NMR signal due to the proton of the newly
Fig. 1 X-Ray single crystal structure of compound 3b.
Chart 2
To determine the optical purities of 4a–f by 1H NMR, several
chiral shift reagents were scanned to monitor the benzyl
protons of 4a–f and Eu(tfc) showed the best results. It was
observed that the difference in the chemical shift between
R- and S-benzyl protons increases with the size of the aza-
cycloalkane, thus 0.0122 ppm (3.66 Hz) for pyrrolidine, 0.0493
ppm (14.79 Hz) for piperidine and 0.1033 ppm (30.98 Hz)
for azepane. It was also observed that the chemical shifts
of the hydroxy protons in 4a–f are located at a very low-field,
around δ 14.30–13.88 ppm, due to the presence of strong
intramolecular hydrogen bonds between the hydroxy and amine
groups (Fig. 2).
Scheme 3
formed chiral carbon was readily assigned to the formation of
an oxazine ring. As shown in Fig. 1, the structure of 3b was
confirmed and the relative stereochemistry of the newly
formed chiral carbon was established as the R-configuration by
single crystal X-ray diffraction analysis.10 Similarly, 3a (59%)
and 3c (51%) were prepared respectively by the replacement
of pentane-1,5-dial with butane-1,4-dial and hexane-1,6-dial
under the same conditions.
Normally, the selective cleavage of the C–O bond in oxazolo-
[3,2-a]pyridines (2) can be effected by NaBH4 at room temper-
ature over several hours.3b–d,7b This procedure also works well
for the selective cleavage of the C–O bond in the tetrahydro-
pyrido[2,1-b]oxazine ring (3b) in satisfactory yield, but the
optical purity of the product is reduced. Therefore, compound
3b was treated with LiAlH4 at Ϫ10 ЊC for 1.5 h and the desired
amino-phenol 4b was obtained in 94% yield without any loss of
enantiomeric excess. Similarly, reductions of 3a and 3c gave 4a
and 4c, respectively, in excellent yields (Scheme 3).
As shown in the X-ray single crystal structure of compound
4b (Fig. 2),10 its chiral carbon is attached to three rings to build
a wonderful chiral molecular cave and a four-atom plane
is defined by C1 and C2 on the naphthalene as well as the
attached carbon and oxygen. Therefore, it is reasonable to
expect that 4a–f, as chiral ligands, could form conformationally
rigid six-membered rings with metallic ions and that substrates
could approach the center ions only from the side of the benzyl
hydrogen.
The asymmetric addition of ZnEt2 to benzaldehyde was
tested initially in toluene with 5 mol% of 4b to give 1-phenyl-
propanol as the product in 94% yield and 96% ee in 12 hours
(Scheme 4). But using 10 mol% of 4b produced better results
(95% yield and 97% ee) in a shorter reaction time (8 h). It is
By exactly the same route as followed in the preparation of
3a–c and 4a–c, their R-counterparts 3d–f and 4d–f were pre-
pared using the salt of (R)-1 and -(Ϫ)-tartaric acid as the
starting material (Chart 2).
J. Chem. Soc., Perkin Trans. 1, 2002, 2900–2903
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Table 1 Effect of temperature on the addition of ZnEt2 to benzalde-
hydes with 10 mol% ligand 4b
pared by selective N-cyclizations of (S)-(ϩ)- and (R)-(Ϫ)-Betti
bases with dials in the presence of NaBH3CN to give 1-azacyclo-
alka[2,1-b]oxazines followed by selective cleavage of C–O
bonds with LiAlH4. The ligands with pyrrolidine and piperidine
lead to highly efficient asymmetric induction in the addition of
diethylzinc to aryl aldehydes with up to 96% yield and 99% ee.
Entry
T /ЊC
t/h
Yield (%)a
Ee (%)b
1
2
3
4
5
Ϫ10
0
10
30
50
48
16
8
6
3
96
96
95
94
93
98
98
97
95
94
Experimental
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. IR spectra were recorded on a
Nicolet FT-IR 5DX spectrometer as KBr pellets. The 1H NMR
spectra were recorded on a Bruker ACF-300 spectrometer in
CDCl3 with TMS as internal reference. The J values are given in
Hz. MS spectra were obtained on a VG-ZAB-HS mass spec-
trometer at 70 eV. The elemental analyses were performed on a
Perkin-Elmer 240C instrument. Optical rotations were deter-
mined on a Perkin-Elmer 241 polarimeter and are given in units
a Isolated yields. b Determined by chiral GC (10% permethylated
β-CD).
Table
2
Enantioselective addition of ZnEt2 to aryl aldehydes
catalyzed by ligands 4a–f
Entry
Ar
Ligands
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
9
C6H5-
C6H5-
C6H5-
C6H5-
4-CH3C6H4-
4-CH3OC6H4-
2-ClC6H4-
4-FC6H4-
4-CF3OC6H4-
C6H5-
4a
4d
4b
4e
4b
4b
4b
4b
4b
4c
4f
93
91
95
91
95
96
95
96
94
93
92
99 (R)
98 (S)
98 (R)
98 (S)
98 (R)
95 (R)
91 (R)
98 (R)
95 (R)
73 (R)
75 (S)
of 10Ϫ1 deg cm2
g
Ϫ1. The salts of (S)-1ؒ-(ϩ)-tartaric acid
(>99% ee) and (R)-1ؒ-(Ϫ)-tartaric acid (>99% ee) were pre-
pared according to ref. 3b. PE is petroleum ether (60–90 ЊC).
General procedure for the preparation of 1-azacycloalka[2,1-b]-
oxazines 3a–f
To a solution of (S)-1 or (R)-1 (as salts of tartaric acid, 6.4 g,
16 mmol) in 50% aqueous EtOH (600 mL) and buffer solution
(1 : 1 Na2HPO4–KH2PO4, 1.0 M, 40 mL) was added NaBH3CN
(1.3 g, 17 mmol) in one-portion and dial (25 mmol) dropwise at
0 ЊC. The mixture quickly became cloudy. After 30 min, the
crude product, a white solid, was filtered off and was dissolved
in EtOAc. The solution was washed with H2O and brine,
and dried over Na2SO4. The solvent was removed to yield the
desired products.
10
11
C6H5-
a Isolated yields. b Determined by chiral GC (10% permethylated
β-CD).
(7aR,12S )-12-Phenyl-7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]-
pyrrolo[2,1-b][1,3]oxazine (3a)
Using (S)-1ؒ-(ϩ)-tartaric acid and butane-1,4-dial,7d com-
pound 3a was obtained as white crystals in 59% yield; mp
97–98 ЊC (EtOAc–PE), [α]2D5 = ϩ156.8 (CHCl3, c 1.20) (Found:
C, 83.67%; H, 6.60%; N, 4.75%. C21H19NO requires: C, 83.69%;
H, 6.35%; N, 4.65%); νmax/cmϪ1 3060, 2940, 2830, 1618, 1598;
δH 7.80–7.73 (m, 2H), 7.43–7.40 (m, 8H), 7.33–7.27 (m, 1H),
5.48 (s, 1H), 5.12 (t, J 3.0, 1H), 3.40–3.33 (m, 1H), 2.95 (dd,
J 8.4, 16.2, 1H), 2.14–1.97 (m, 4H); m/z 301 (Mϩ, 1.1%), 231
(100), 202 (31).
(7aR,13S )-13-Phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho-
[1,2-e]pyrido[2,1-b][1,3]oxazine (3b)
Fig. 2 X-Ray single crystal structure of compound 4b.
Using (S)-1ؒ-(ϩ)-tartaric acid and pentane-1,5-dial (25%
aqueous solution), compound 3b was obtained as white crystals
in 61% yield; mp 179.5–181.5 ЊC (EtOAc–PE), [α]2D5 = ϩ109
(CHCl3, c 1.33) (Found: C, 83.61%; H, 6.52%; N, 4.50%.
C22H21NO requires: C, 83.78%; H, 6.71%; N, 4.44%); νmax/cmϪ1
3090, 2901, 2850, 1618, 1595; δH 7.75–7.72 (m, 2H), 7.45–7.16
(m, 9H), 5.21 (s, 1H), 4.94 (s, 1H), 2.92–2.88 (m, 2H), 2.03–1.98
(m, 1H), 1.85–1.71 (m, 3H), 1.67–1.59 (m, 2H); δC 152.7, 143.4,
133.2, 129.8 (2C), 129.5, 129.4, 129.0, 128.6 (2C), 127.6, 126.9,
123.4, 123.3, 119.2, 111.6, 81.8, 63.3, 48.8, 30.0, 25.9, 18.8;
m/z 315 (Mϩ, 4.3%), 231 (100), 202 (23).
Scheme 4
interesting to note that the enantioselectivity of the reaction is
not very dependent on temperature (Table 1).
As illustrated in Table 2, the size of the azacycloalkane in
ligands 4a–f plays an important role in their induced asym-
metric additions. Both pyrrolidine (4a and 4d) and piperidine
(4b and 4e) gave products in excellent yields and enantiomeric
excess (Entries 1–9), whilst azepane (4c and 4f ) gave products in
moderate optical yields (Entries 10 and 11). It is worth mention-
ing that ligands 4a–f can be recovered in 70–95% yields con-
veniently by filtration after the reaction and used repeatedly
without any loss of reactivity.
(7aR,14S )-14-Phenyl-7a,8,9,10,11,12-hexahydro-14H-naphtho-
[1Ј,2Ј:5,6][1,3]oxazino[2,1-b]azepine (3c)
Using (S)-1ؒ-(ϩ)-tartaric acid and hexane-1,6-dial,11 com-
pound 3c was obtained as white crystals in 51% yield; mp
99–101 ЊC (CHCl3–PE), [α]2D5 = ϩ95.3 (CHCl3, c 0.68) (Found:
C, 83.70%; H, 7.32%; N, 4.00%. C23H23NO requires: C, 83.85%;
H, 7.04%; N, 4.25%); νmax/cmϪ1 3080, 3040, 2940, 2850, 1620,
1600; δH 7.81–7.74 (m, 2H), 7.38–7.28 (m, 8H), 7.10 (d, J 9.6,
1H), 5.30 (s, 1H), 4.89 (t, J 7.2, 1H), 3.27 (dd, J 9.5, 12.9, 1H),
In summary, a new family of chiral ligands (S)- and (R)-1-
[α-(1-azacycloalkyl)benzyl]-2-naphthols (4a–f ) have been pre-
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J. Chem. Soc., Perkin Trans. 1, 2002, 2900–2903

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2.73 (d, J 14.7, 1H), 2.24 (m, 1H), 1.92–1.72 (m, 5H), 1.53–1.28
(m, 2H); m/z 329 (Mϩ, 4.5%), 231 (100), 202 (30).
respectively. Compounds 4d–f had identical IR, 1H NMR, MS
and optical rotations (opposite direction) as their correspond-
ing counterparts 4a–c.
(7aS,12R)-12-Phenyl-7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]-
pyrrolo[2,1-b][1,3]oxazine (3d), (7aS,13R)-13-phenyl-8,9,10,
11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxa-
zine (3e) and (7aS,14R)-14-phenyl-7a,8,9,10,11,12-hexahydro-
14H-naphtho[1Ј,2Ј:5,6][1,3]oxazino[2,1-b]azepine (3f)
General procedure for the addition of ZnEt2 to aldehydes
To a stirred solution of 4 (0.5 mmol) and aldehyde (5 mmol) in
dry toluene (10 mL) was added a solution of Et2Zn in toluene
(1.0 M, 11 mL, 11 mmol) by syringe at 0 ЊC under Ar. Eight
hours later, a residue was obtained by regular work-up
procedure. Then Et2O (5 mL) was added and ligand 4 was pre-
cipitated in 70–95% yield as white crystals which were filtered
off. The filtrate was concentrated and purified by chromato-
graphy to yield 1-phenylpropanols as shown in Scheme 4 and
Table 2.
By using (R)-1ؒ-(Ϫ)-tartaric acid with butane-1,4-dial,
pentane-1,5-dial or hexane-1,6-dial, 3d–f were produced
respectively. Compounds 3d–f had identical IR, 1H NMR, MS
and optical rotations (opposite direction) as their correspond-
ing counterparts 3a–c.
A general procedure for the preparation of 1-[ꢀ-(1-azacycloalkyl)-
benzyl]-2-naphthols 4a–f
Acknowledgements
To a stirred solution of LiAlH4 (570 mg, 15 mmol) in dry THF
(20 mL) was added a solution of 3 (10 mmol) in THF (30 mL)
dropwise at Ϫ10 ЊC. After stirring at this temperature for 1.5 h
(monitored by TLC), it was quenched by the addition of a
saturated aqueous solution of NH4Cl (20 mL) and stirred for
another 30 min. Then the mixture was extracted with CH2Cl2
(40 mL), and the organic layer was washed with brine and
water, and dried over Na2SO4. The solvent was removed to give
the desired products.
We are grateful to the National Natural Science Foundation of
China for financial support.
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(S )-1-(ꢀ-Pyrrolidinylbenzyl)-2-naphthol (4a)
By reduction of 3a, compound 4a was obtained as white
crystals in 93% yield; mp 159–161 ЊC (EtOAc), [α]2D5 = ϩ179.1
(CHCl3, c 1.30) (Found: C, 83.16%; H, 7.05%; N, 4.62%.
C21H21NO requires: C, 83.13%; H, 6.98%; N, 4.62%); νmax/cmϪ1
3120, 3080, 2970, 2840, 1452, 1200; δH 13.88 (s, 1H), 7.91
(d, J 8.6, 1H), 7.72–7.55 (m, 4H), 7.44–7.03 (m, 6H), 5.16
(s, 1H), 3.27 (br s, 1H), 2.44 (br s, 3H), 1.89 (br s, 4H); m/z 303
(Mϩ, 0.04%), 231 (100), 202 (30), 70 (13).
(S )-1-(ꢀ-Piperidylbenzyl)-2-naphthol (4b)
By reduction of 3b, compound 4b was obtained as white
crystals in 94% yield; mp 194–196 ЊC (EtOAc–PE), [α]2D5
=
ϩ193.8 (CHCl3, c 1.20) (Found: C, 83.16%; H, 7.25%; N,
4.36%. C22H23NO requires: C, 83.24%; H, 7.30%; N, 4.41%);
νmax/cmϪ1 3120, 1238; δH 14.01 (s, 1H), 7.86 (d, J 8.7, 1H), 7.72–
7.57 (m, 4H), 7.38–7.16 (m, 6H), 5.10 (s, 1H), 3.35 (br s, 1H),
2.68 (br s, 1H), 2.15–1.70 (m, 8H); m/z 317 (Mϩ, 0.9%), 232
(48), 231 (100), 202 (23), 85 (11), 84 (43).
(S )-1-(ꢀ-Azepanylbenzyl)-2-naphthol (4c)
By reduction of 3c, compound 4c was obtained as white
crystals in 95% yield; mp 117–117.5 ЊC (EtOAc–PE), [α]2D5
=
ϩ184.4 (CHCl3, c 0.34) (Found: C, 83.41%; H, 7.56%; N,
4.18%. C23H25NO requires: C, 83.34%; H, 7.60%; N, 4.23%);
νmax/cmϪ1 3070, 2940, 2855, 1440, 1240; δH 14.30 (s, 1H), 7.90
(d, J 9.0, 1H), 7.71–7.62 (m, 4H), 7.39–7.36 (m, 1H), 7.29–7.14
(m, 5H), 5.32 (s, 1H), 2.73 (br m, 4H), 1.85–1.60 (m, 10H); m/z
331 (Mϩ, 0.2%), 231 (100), 203 (14), 202 (45), 201 (10), 200 (10),
99 (14).
8 H.-P. Husson and J. Royer, Chem. Soc. Rev., 1999, 28, 383.
9 G. W. Gribble, J. Org. Chem., 1972, 37, 1833.
10 CCDC reference numbers 183966 (for compound 3b) and 183965
(for compound 4b). See http://www.rsc.org/suppdata/p1/b2/
b204534f/ for crystallographic files in .cif or other electronic format.
11 M. Daumas, Y. Vo-Quang, L. Vo-Quang and F. Le Goffic, Synthesis,
1989, 64.
(R)-1-(ꢀ-Pyrrolidinylbenzyl)-2-naphthol(4d), (R)-1-(ꢀ-piperidyl-
benzyl)-2-naphthol (4e) and (R)-1-(ꢀ-azepanylbenzyl)-2-
naphthol (4f)
By the reduction of 3d–f, compounds 4d–f were produced
J. Chem. Soc., Perkin Trans. 1, 2002, 2900–2903
2903

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