An improved synthesis of chiral 1-[α-(1-azacycloalkyl)benzyl]-2- naphthols

Article abstract of DOI:10.1016/j.tetasy.2003.12.025

An improved synthesis of homochiral 1-[α-(1-azacycloalkyl)benzyl]-2- naphthols and 1-[α-(2-arylpiperidyl)benzyl]-2-naphthols has been achieved by employing diastereomerically pure α-benzotriazolyl 1-azacycloalka[2,1- b][1,3]oxazines as homochiral precurso

Full text of DOI:10.1016/j.tetasy.2003.12.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 475–479
An improved synthesis of chiral 1-[a-(1-azacycloalkyl)benzyl]-
2-naphthols
Xuenong Xu, Jun Lu, Yanmei Dong, Rui Li, Zongming Ge and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing, 100084, PR China
Received 21 October 2003;revised 11 December 2003;accepted 12 December 2003
Abstract—An improved synthesis of homochiral 1-[a-(1-azacycloalkyl)benzyl]-2-naphthols and 1-[a-(2-arylpiperidyl)benzyl]-2-
naphthols has been achieved by employing diastereomerically pure a-benzotriazolyl 1-azacycloalka[2,1-b][1,3]oxazines as homo-
chiral precursors, which were obtained by condensation between nonracemic Betti base and dialdehydes in the presence of benzo-
triazole.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
NRR1
OH
NH2
OH
Metal ion catalyzed asymmetric reactions are amongst
the more recognized methods in current asymmetric
chemistry, where homochiral ligands play an important
role in the reactivity and stereoselectivity. Recently,
many unnatural homochiral amino-phenol compounds
have been reported as excellent ligands for this pur-
pose.1;2 Among them, the derivatives of chiral N,N-
dialkylated Betti base 1 (Chart 1) are gaining increasing
importance.2
(S)-Betti Base (S)-2
(S)-N,N-Dialkylated Betti Base 1
Ar
N
( )
n
N
OH
OH
Previously,2 homochiral N,N-dialkylated Betti base 1
was prepared either by the resolution of the corre-
sponding racemic isomers or by the Mannich reaction of
chiral amines rather than by the alkylation of nonrace-
mic Betti base (S)-2 or (R)-2. However, we have recently
achieved the synthesis of enantiopure 1-[a-(1-aza-
cycloalkyl)benzyl]-2-naphthols 3a–c from (S)-Betti bases
(S)-2.3 Compounds 3a–c showed excellent chiral induc-
tions in the asymmetric addition of Et2Zn to arylalde-
hydes. However, their preparation suffered from using
large amounts of solvent and as a result, application to
bulk synthesis was limited. Herein, we report an
improved procedure, in which 3a–c and 4a–e, a group of
analogues of 3b with increased steric hindrance, were
prepared conveniently without the drawbacks that
occurred in the previous procedures.
3a-c n = 1-3
4a-e
Chart 1.
2. Results and discussions
Recently, Katritzky has reported an elegant method to
construct the a-benzotriazolyl 1-azacycloalka[2,1-b]-
[1,3]oxazoles 5a–b by the condensation between (R)-(+)-
2-phenylglycinol and dialdehydes in the presence of BtH
(benzotriazole) (Scheme 1).4 The flexible behavior of Bt–
as a leaving group in 5a and b, allowing reduction and
substitution under very convenient conditions, attracted
our interest for the synthesis of 3a–c and 4a–e.
Following the KatritzkyÕs procedure,4b a mixture of (S)-
2, pentane-1,5-dialdehyde and BtH in CH2Cl2 was
stirred at room temperature for 2 h, with the desired
product pyrido[2,1-b][1,3]oxazine 6b being separated
* Corresponding author. Tel.: +86-10-62795380;fax: +86 10-62771149;
e-mail: yfh@mail.tsinghua.edu.cn
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.025

476
X. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 475–479
the reaction time was prolonged (5 h), the enantiomeric
Ph
excess of 3b decreased. However, we found that both C–
Bt and C–O bonds in 6a–c can be cut clearly by LiAlH4
at )5 ꢁC within 1 h to afford chiral ligands 3a–c in high
yields (89–94%) without any loss of enantiomeric excess
(Scheme 2).
Ph
OHC(CH2)nCHO, BtH
m = 2,3
O
N
Bt
HO
NH2
( )
n
1-Azacycloalka[2,1-b][1,3]oxazole
5a-b n = 1-2
(R)-(+)-2-phenylglycinol
As 3b showed the best chiral induction among 3a–c and
the Bt– group was readily substituted by Grignard
reagents, a group of novel chiral ligands with high steric
hindrance 4a–e were designed and synthesized. As
shown in Scheme 3, the intermediate 6b was treated with
PhMgBr 7a at )5 ꢁC for 2.5 h to yield 8a as a single
diastereoisomer in 91% yield. When compared with the
arylation of 5b, the current procedure can be performed
under very mild conditions rather than at )78 ꢁC for
12 h.4b Under similar conditions, the arylations of 6b
with other ArMgBr 7b–e gave the corresponding 8b–e in
high yields and diastereoselectivity. The arylated car-
bons in 8a–e were assigned (R)-configurations, deduced
from the single crystal X-ray diffraction analysis of 8e
(Fig. 2).6 Finally, the reduction of 8a–e with LiAlH4
yielded the target products 4a–e in 84–92% yields. It is
interesting to note that the most hindered compounds,
8e and 4e, gave the best yields.
Scheme 1.
tediously from the mixture with 32% yield. However,
when the reaction was performed at 0 ꢁC for 5 h, 6b was
obtained as the unique product in 91% yield (Scheme 2).
The diastereopurity of 6b was proven by its benzyl
proton appearing as a singlet peak at d ¼ 5:28 ppm in
the 1H NMR. (R)-Configurations for both newly formed
stereogenic carbons were deduced from single crystal
X-ray diffraction analysis (Fig. 1).5 Similarly, replace-
ment of pentane-1,5-dialdehyde by butane-1,4-dialde-
hyde and hexane-1,6-dialdehyde, the five- and seven-
membered azacyclic analogues 6a and 6c, were obtained,
respectively, in high yields (93% and 91%) and diaste-
reopurity.
Although NaBH4 is frequently used to cleave C–Bt or
C–O bonds in oxazoles at room temperature, it failed
with our oxazines. For example, oxazine 6b was treated
with NaBH4 at room temperature for 2 h to give a
mixture, containing the partially reduced product. When
3. Conclusion
Nonracemic Betti base when condensed with dialde-
hydes in the presence of BtH (benzotriazole) produced a
O
OCH(CH2)mCHO
BtH, -5 0 oC, 4h
HO
HO
NH2
OH
OH
OH
Ar
m = 2,3,4
91-93%
R
ArMgBr 7, ether
LiAlH4, ether
0 oC, 0.5 h
O
N
R
S
-5-0 oC, 2-3 h
6b
4a-e
(S)-2.L-(+)-Tartaric Acid
O
84-92%
82-93%
Bt
10
( )n
8 a-e
N
11
7a
LiAlH4, ether, -5 oC, 1 h
89-94%
12
1
O
6a
6
7
3a-c
2
3
6a-c, n
=1-3
Scheme 2.
Scheme 3.
Figure 1. The structure of compound 6b.
Figure 2. The structure of compound 8e.

X. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 475–479
477
group of diastereopure chiral precursors a-benzotriaz-
olyl 1-azacycloalka[2,1-b][1,3]oxazines 6a–c in high
yields. Reduction of 6a–c with LiAlH4 yielded chiral
ligands 1-[a-(1-azacycloalkyl)benzyl]-2-naphthols 3a–c
conveniently. Moreover, 6b can be arylated with
ArMgBr, followed by reduction with LiAlH4 to give a
group of chiral potential ligands 1-[a-(2-arylpiperi-
dyl)benzyl]-2-naphthols 4a–e.
aqueous solution), 6b was obtained as white crystals in
91% yield;mp 196–197 ꢁC (EtOH), ½aŠ ¼ +152.6 (c 1.6,
25
D
CHCl3);Found: C, 77.77;H, 5.71;N, 12.91.
C28H24N4O: C, 77.75;H, 5.59;N, 12.95;
mmax (cmÀ1
)
2900, 1620, 1440; dH 6.78–8.18 (m, 15H), 5.89 (m, 1H),
5.86 (s, 1H), 4.72–4.75 (m, 1H), 2.32–2.68 (m, 2H), 2.16–
2.31 (m, 2H), 1.87–1.95 (m, 2H); dC 152.3, 147.2, 141.8,
132.7, 132.4, 130.1, 129.9 (2C), 129.6, 128.9, 128.5 (2C),
127.8, 127.6, 127.2, 124.7, 123.8, 122.8, 120.8, 119.0,
118.5, 112.1, 110.1, 81.8, 56.5, 31.2, 29.7, 18.2; m=z: 432
(Mþ, 0.01%), 313 (26), 231 (100), 202 (20).
4. Experimental
4.2.3.
(7aR,12R,14S)-12-(1-Benzotriazolyl)-14-phenyl-
4.1. General considerations
7a,8,9,10,11,12-hexahydro-14H-naphtho[10,20:5,6][1,3]ox-
azino[2,1-b]azepine 6c. Using hexane-1,6-dialdehyde, 6c
was obtained as white crystals in 91% yield;mp 205–
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 the
internal reference. The J values are given in hertz. MS
spectra were obtained on a VG-ZAB-HS mass spec-
trometer with 70 eV. The elemental analyses were per-
formed on a Perkin–Elmer 240C instrument. Optical
rotations were determined on a Perkin–Elmer 241
polarimeter. PE is petroleum ether (60–90 ꢁC).
25
206 ꢁC (EtOAc), ½aŠ ¼ +146.2 (c 0.9, CHCl3);Found:
D
C, 77.87;H, 5.81;N, 12.71. C 29H26N4O: C, 78.00;H,
5.87;N, 12.55; mmax (cmÀ1) 3057, 2916, 1622, 1468; dH
7.73–7.79 (m, 3H), 7.09–7.36 (m, 12H), 5.52 (s, 1H),
4.62–4.66 (m, 1H), 2.44 (s, 1H), 1.47–1.77 (m, 8H); dC
152.6, 143.6, 143.0, 131.7, 129.2, 129.1, 128.6 (2C),
128.4, 128.2, 127.9 (2C), 127.7, 127.1, 126.5, 125.9,
123.9, 123.1, 122.8, 119.6, 119.4, 119.2, 114.3, 86.7, 82.4,
54.7, 54.1, 35.5, 24.6; m=z: 327 (Mþ)BtH, 2.74%), 232
(45), 231 (100), 202 (19).
4.2. General procedure for the preparation of compounds
6a–c
4.3. General procedure for the preparation of compounds
3a–c
A mixture of (S)-2 [as salt of L-(+)-tartaric acid, 3.99 g,
To a suspension of LiAlH4 (1.4 g, 30 mmol) in dry THF
(20 mL) was added a solution of 6 (10 mmol) in dry THF
(20 mL) at )5 ꢁC under nitrogen. One hour later (mon-
itored by TLC), a saturated aqueous solution of NH4Cl
(10 mL) was added to quench the reaction and the
resulting mixture stirred for another 0.5 h at the same
temperature. After removal of most of the THF in
vacuum, the residue was extracted with CH2Cl2
(2 · 20 mL). The organic layers were washed with H2O
and brine, and dried over MgSO4. After removal of the
solvent, the residue was purified by chromatography
(silica gel, 5% EtOAc in PE) to give the desired products
3a–c.
10 mmol], dialdehyde (aqueous solution, 12 mmol), and
benzotriazole (1.43 g, 12 mmol) in CH2Cl2 (40 mL) was
stirred at 0 ꢁC under nitrogen for 4 h. The resulting
mixture was then washed with an aqueous solution of
NaOH (1.0 M) to remove any excess benzotriazole. The
organic layer was washed with H2O and brine, and dried
over anhydrous Na2SO4. After the removal of the sol-
vent, the residue was purified by recrystallization to give
the desired product 6.
4.2.1. (7aR,10R,12S)-10-(1-Benzotriazolyl)-12-phenyl-7a,
8,9,10-tetrahydro-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]-
oxazine 6a. Using butane-1,4-dialdehyde, 6a was
obtained as white crystals in 93% yield;mp 138–139 ꢁC
4.3.1. (S)-1-(a-Pyrrolidinylbenzyl)-2-naphthol 3a. By
reduction of 6a, 3a was obtained as white crystals in 89%
25
(EtOAc), ½aŠ ¼ +101.6 (c 1.25, CHCl3);Found: C,
D
25
D
77.21;H, 5.46;N, 13.46. C 27H22N4O: C, 77.49;H, 5.30;
N, 13.39; mmax (cmÀ1) 3057, 2930, 1622, 1466; dH 7.10–
8.21 (m, 13H), 6.68–6.70 (m, 2H), 6.21–6.25 (m, 1H),
5.40–5.42 (m, 1H), 5.29 (s, 1H), 2.35–2.92 (m, 4H); dC
152.3, 147.7, 142.1, 132.6, 131.7, 130.1, 129.6 (2C),
129.0, 128.9, 128.7 (2C), 127.8, 127.7, 127.2, 127.0,
124.7, 123.9, 123.2, 120.2, 119.0, 111.9, 110.0, 85.9, 54.8,
30.3, 28.9; m=z: 418 (Mþ, 0.27%), 300 (36), 231 (100),
202 (61).
yield;mp 159–160 ꢁC (EtOAc–PE); ½aŠ ¼ +179.8 (c 1.5,
25
CHCl3) {lit.3b mp 159–161 ꢁC, ½aŠ ¼ +179.1 (c 1.3,
D
CHCl3)}.
4.3.2. (S)-1-(a-Piperidylbenzyl)-2-naphthol 3b. By reduc-
tion of 6b, 3b was obtained as white crystals in
25
D
94% yield;mp 194–195 ꢁC (EtOAc); ½aŠ ¼ +194.3 (c 2.0,
25
CHCl3) {lit.3b mp 194–195 ꢁC; ½aŠ ¼ +193.8 (c 1.2,
D
CHCl3)}.
4.2.2. (7aR,11R,13S)-11-(1-Benzotriazolyl)-13-phenyl-8,
9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b]-
[1,3]oxazine 6b. Using pentane-1,5-dialdehyde (25%
4.3.3. (S)-1-(a-Azepanylbenzyl)-2-naphthol 3c. By reduc-
tion of 6c, 3c was obtained as white crystals in 93% yield;

478
X. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 475–479
25
mp 118–119 ꢁC (EtOAc–PE); ½aŠ ¼ +183.2 (c
[1,3]oxazine 8d. Using 4-PhPhMgBr 7d, 8d was obtained
as white crystals in 82% yield;mp 151–152 ꢁC (PE);
D
25
D
1.0, CHCl3) {lit.3b mp 117–117.5 ꢁC; ½aŠ ¼ +184.4 (c
25
D
0.34, CHCl3)}.
½aŠ ¼ +95.4 (c 0.2, CHCl3);Found: C, 87.12;H, 6.05;
N, 3.15. C34H29NO requires: C, 87.33;H, 6.25;N, 3.00;
mmax (cmÀ1) 2926, 1622, 1600, 1231; dH 6.72–7.70 (m,
20H), 5.18 (s, 1H), 4.04–4.10 (t, 1H), 3.44–3.48 (t, 1H),
2.34–2.38 (m, 2H), 1.57–1.70 (m, 4H); m=z: 467 (Mþ,
0.09%), 231 (100), 202 (37).
4.4. General procedure for the preparation of compounds
8a–e
To a cold solution (ice-water bath) of 6b (0.86 g, 2 mmol)
in dry Et2O (80 mL) was added ArMgBr 7 (4 mmol)
dropwise under nitrogen. The resultant mixture was
stirred for 2–3 h (monitored by TLC), after which a
saturated aqueous solution of NH4Cl (10 mL) was
added to quench the reaction at 0 ꢁC. The separated
organic layer was washed with an aqueous solution of
NaOH (1.0 M, 30 mL), water (30 mL), and dried over
anhydrous Na2SO4. After removal of the solvent, the
residue was purified by chromatography (silica gel, PE)
to give the pure product 8.
4.4.5. (7aR,11R,13S)-11-(1-Naphthyl)-13-phenyl-8,9,10,
11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]-
oxazine 8e. Using 1-naphthylMgBr 7e, 8e was obtained
as white crystals in 93% yield;mp 190–190.5 ꢁC (PE);
25
½aŠ ¼ +290.5 (c 0.3, CHCl3);Found: C, 87.22;H, 6.35;
D
N, 3.26. C32H27NO requires: C, 87.04;H, 6.16;N, 3.17;
mmax (cmÀ1) 3060, 2941, 2863, 1625, 1241; dH 7.62–7.91
(m, 6H), 7.41–7.49 (m, 3H), 6.98–7.19 (m, 7H), 6.78–
6.80 (m, 2H), 5.57 (s, 1H), 5.20–5.25 (m, 1H), 4.20–4.24
(m, 1H), 2.29–2.33 (m, 1H), 1.23–1.98 (m, 5H); dC 150.8,
139.3, 138.3, 134.7, 131.4, 131.3 (3C), 129.6, 129.4 (2C),
128.8, 128.3 (3C), 128.0, 127.9, 126.7 (2C), 126.2, 125.8,
123.2, 122.6, 111.5, 115.2, 83.1, 57.3, 36.2, 32.6, 32.0,
21.8; m=z: 441 (Mþ, 0.36%), 231 (100), 202 (29), 180 (29),
128 (15).
4.4.1. (7aR,11R,13S)-11,13-Diphenyl-8,9,10,11-tetrahy-
dro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazine 8a.
Using PhMgBr 7a, compound 8a was obtained as white
25
crystals in 91% yield;mp 158–159 ꢁC (PE); ½aŠ ¼ +110.1
D
(c 0.21, CHCl3);Found: C, 85.97;H, 6.34;N, 3.63.
C28H25NO requires: C, 85.90;H, 6.44;N, 3.58;
mmax
(cmÀ1) 2943, 2860, 1601, 1452, 1237; dH 7.06–7.67 (m,
16H), 5.47 (s, 1H), 5.14–5.18 (t, 1H), 3.44–3.48 (t, 1H),
2.04–2.30 (m, 2H), 1.70–1.76 (m, 2H), 1.53–1.57 (m,
2H); dC 150.7, 144.3, 138.3, 131.0, 130.6 (2C), 129.3
(2C), 129.2, 128.8, 128.2, 128.0, 127.9 (2C), 127.5 (2C),
127.0, 126.6, 123.2, 122.5, 118.5, 115.3, 82.7, 62.0, 57.3,
38.0, 32.6, 21.5; m=z: 391 (Mþ, 0.14%), 231 (100), 202
(32), 77 (12).
4.5. General procedure for the preparation of compounds
4a–e
To a stirred suspension of LiAlH4 (0.14 g, 3 mmol) in
dry THF (20 mL) was added a solution of 8 (10 mmol) in
THF (30 mL) dropwise at )5 ꢁC under nitrogen. After
stirring at this temperature for 2 h (monitored by TLC),
the mixture was quenched by the addition of a saturated
aqueous solution of NH4Cl (20 mL) with the resulting
mixture stirred for another 30 min. The mixture was
then extracted with CH2Cl2 (2 · 30 mL) and the com-
bined organic layers washed with H2O, brine and dried
over Na2SO4. The solvent was removed to yield a crude
product, which was purified by chromatography (silica
gel, 2% EtOAc in PE) to give 4.
4.4.2. (7aR,11R,13S)-11-(4-Methylphenyl)-13-phenyl-8,
9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b]-
[1,3]oxazine 8b. Using 4-MePhMgBr 7b, 8b was
obtained as white crystals in 84% yield;mp 122–123 ꢁC
25
(PE); ½aŠ ¼ +97.1 (c 0.3, CHCl3);Found: C, 85.72;H,
D
6.55;N, 3.26. C 29H27NO requires: C, 85.89;H, 6.71;N,
3.49; mmax (cmÀ1) 2925, 1622, 1599, 1232; dH 6.94–7.74
(m, 15H), 5.12–5.18 (m, 1H), 3.77 (m, 1H), 3.44–3.50 (m,
1H), 2.34 (s, 3H), 1.59–2.03 (m, 5H), 1.18–1.22 (m, 1H);
m=z: 405 (Mþ, 0.14%), 231 (100), 202 (32), 91 (19).
4.5.1. (S)-1-[a-[(R)-2-Phenylpiperidyl]benzyl]-2-naphthol
4a. By reduction of 8a, 4a was obtained as white crys-
25
D
tals in 86% yield;mp 154–155 ꢁC (EtOAc), ½aŠ ¼ +46.8
(c 0.3, CHCl3);Found: C, 85.31;H, 7.06;N, 3.48.
4.4.3. (7aR,11R,13S)-11-(4-Chlorophenyl)-13-phenyl-8,
9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b]-
[1,3]oxazine 8c. Using 4-ClPhMgBr 7c, 8c was obtained
C28H27NO requires: C, 85.46;H, 6.92;N, 3.56;
mmax
(cmÀ1) 3120, 2960, 2805, 2505, 1620, 1238; dH 15.61 (s,
1H), 6.92–8.14 (m, 16H), 5.57 (s, 1H), 2.90–3.69 (d,
J ¼ 8:9, 1H), 1.20–2.01 (m, 8H); m=z: 393 (Mþ, 0.14%),
231 (100), 202 (32).
as white crystals in 85% yield;mp 138–140 ꢁC (PE);
25
½aŠ ¼ +124 (c 0.1, CHCl3);Found: C, 78.73;H, 5.51;N,
D
3.34. C28H24ClNO requires: C, 78.95;H, 5.68;N, 3.29;
mmax (cmÀ1) 2950, 1623, 1598, 1234; dH 7.06–7.77 (m,
15H), 5.34 (s, 1H), 5.15–5.18 (m, 1H), 3.69–3.74 (m,
1H), 1.78–2.19 (m, 2H), 1.59–2.03 (m, 4H); m=z: 425
(Mþ, 0.54%), 231 (100), 202 (32).
4.5.2. (S)-1-[a-[(R)-2-(4-Methylphenyl)piperidyl]benzyl]-
2-naphthol 4b. By reduction of 8b, 4b was obtained as
white crystals in 87% yield;mp 134–135 ꢁC (EtOAc),
25
½aŠ ¼ +28.9 (c 0.2, CHCl3);Found: C, 85.26;H, 7.21;
mmax (cmÀ1) 3059, 2936, 1623, 1599; dH 12.49 (s, 1H),
D
N, 3.35. C29H29NO requires: C, 85.47;H, 7.17;N, 3.44;
4.4.4. (7aR,11R,13S)-11-(4-Phenylphenyl)-13-phenyl-8,
9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b]-

X. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 475–479
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2002, 124, 14866;(j) Kocovsky, P.;Vyskocil, S.;Smrcina,
M. Chem. Rev. 2003, 103, 3213.
4.5.3. (S)-1-[a-[(R)-2-(4-Chlorophenyl)piperidyl]benzyl]-
2-naphthol 4c. By reduction of 8c, 4c was obtained as
white crystals in 85% yield;mp 109–110 ꢁC (EtOAc),
25
½aŠ ¼ +54.6 (c 0.2, CHCl3);Found: C, 75.42;H, 6.17;
D
N, 3.31. C28H26ClNO requires: C, 75.58;H, 6.12;N,
3.27; mmax (cmÀ1) 3056, 2960, 1623, 1599, 1238; dH 14.90
(s, 1H), 6.97–8.30 (m, 16H), 5.53 (s, 1H), 2.88–3.65 (m,
1H), 1.20–2.01 (m, 8H); m=z: 427 (Mþ, 0.03%), 313 (18),
231 (100), 202 (18).
2. (a) Cardelliccnio, C.;Ciccarella, G.;Naso, F.;Schingaro,
E.;Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667;(b)
Cardelliccnio, C.;Ciccarella, G.;Naso, F.;Perna, F.;
Tortorella, P. Tetrahedron 1999, 55, 14685;(c) Bernardi-
nelli, G.;Fernandez, D.;Gosmini, R.;Meier, P.;Ripa, A.;
Schupfer, P.;Treptow, B.;Kundig, E. P. Chirality 2000,
12, 529;(d) Palmieri, G. Tetrahedron: Asymmetry 2000,
11, 3361;(e) Liu, D.-X.;Zhang, L.-C.;Wang, Q.;Da,
C.-S.;Xin, Z.-Q.;Wang, R.;Choi, M. C. K.;Chan,
A. S. C. Org. Lett. 2001, 3, 2733;(f) Cimarelli, C.;
Mazzaanti, A.;Palmieri, G.;Volpini, E. J. Org. Chem.
4.5.4. (S)-1-[a-[(R)-2-(4-Phenylphenyl)piperidinyl]ben-
zyl]-2-naphthol 4d. By reduction of 8d, 4d was obtained
as white crystals in 84% yield;mp 159–160 ꢁC (EtOAc),
25
½aŠ ¼ +64.6 (c 0.1, CHCl3);Found: C, 86.89;H, 6.71;
D
N, 2.95. C34H31NO requires: C, 86.96;H, 6.65;N, 2.98;
mmax (cmÀ1) 3058, 2964, 1620, 1597, 1235; dH 14.64 (s,
1H), 6.97–8.30 (m, 20H), 5.57 (s, 1H), 2.79–3.04 (m,
1H), 1.20–2.01 (m, 8H); m=z: 469 (Mþ, 0.05%), 231
(100), 202 (18).
2001, 66, 4759;(g) Wang, Y.;Li, X.;Ding, K.
Tetrahe-
dron: Asymmetry 2002, 13, 1291;(h) Cimarelli, C.;
Palmieri, G.;Volpini, E. Tetrahedron: Asymmetry 2002,
13, 2417;(i) Saidi, M. R.;Azizi, N. Tetrahedron: Asym-
metry 2003, 14, 389;(j) Ji, J.;Qiu, L.;Yip, C. W.;Chan, A.
S. C. J. Org. Chem. 2003, 68, 1589.
4.5.5. (S)-1-[a-[(R)-2-(1-Naphthyl)piperidyl]benzyl]-2-
naphthol 4e. By reduction of 8e, 4e was obtained as
3. (a) Lu, J.;Xu, X.;Wang, C.;He, J.;Hu, Y.;Hu, H.
Tetrahedron Lett. 2002, 43, 8367;(b) Lu, J.;Xu, X.;Wang,
S.;Wang, C.;Hu, Y.;Hu, H. J. Chem. Soc., Perkin Trans.
1 2002, 2900.
white crystals in 92% yield;mp 176–177 ꢁC (EtOAc),
25
½aŠ ¼ +194.5 (c 0.3, CHCl3);Found: C, 86.89;H, 6.71;
D
4. (a) Katritzky, A. R. J. Heterocycl. Chem. 1999, 36, 1501;
(b) Kartritzky, A. R.;Qiu, G.;Yang, B.;Steel, P. J. J. Org.
Chem. 1998, 63, 6699;(c) Kartritzky, A. R.;Cui, X.-L.;
Yang, B.;Steel, P. J. J. Org. Chem. 1999, 64, 1979.
5. Crystal data of compound 6b: C28H24N4O, M ¼ 432:51,
N, 2.90. C32H29NO requires: C, 86.65;H, 6.59;N, 3.16;
mmax (cmÀ1) 3060, 2940, 1623, 1599, 1238; dH 14.52 (s,
1H), 6.97–8.30 (m, 18H), 5.48 (s, 1H), 2.78–3.61 (m,
1H), 1.20–2.01 (m, 8H); m=z: 443 (Mþ, 0.03%), 313 (18),
231 (100), 202 (18).
ꢀ
ꢀ
orthorhombic; a ¼ 10:743ð7Þ A, b ¼ 14:435ð3Þ A, c ¼
3
ꢀ
ꢀ
14:537ð4Þ A; V ¼ 2254:3ð17Þ A , T ¼ 295ð2Þ K, space
group P212121, Z ¼ 4;2305 reflections measured, 2305
unique (Rint ¼ 0:0000);absorption coefficient: 0.079 mm À1
;
Acknowledgements
Final R indices [I > 2rðIÞ]: R1 ¼ 0:0566, wR2 ¼ 0:1509; R
indices (all data): R1 ¼ 0:2504, wR2 ¼ 0:2169. Crystallo-
graphic data for the structural analysis have been depos-
ited with the Cambridge Crystallographic Data Centre,
CCDC No. 221120.
We are grateful to the National Natural Science Foun-
dation of China for financial support.
6. Crystal data of compound 8e: C32H27NO, M ¼ 441:55,
ꢀ
ꢀ
orthorhombic; a ¼ 11:460ð2Þ A, b ¼ 11:630ð4Þ A, c ¼
3
ꢀ
ꢀ
17:370ð4Þ A; V ¼ 2315:1ð10Þ A , T ¼ 293ð2Þ K;space
group: P2(1)2(1)2(1); Z ¼ 4;absorption coefficient:
0.075 mmÀ1;2599 reflections measured, 2566 unique
(Rint ¼ 0:1264);Final R indices [I > 2rðIÞ]: R1 ¼ 0:0874,
References and notes
1. For selected recent reports, see: (a) Smrcina, M.;Lorenc,
M.;Hanus, V.;Sedmera, P.;Kocovsky, P. J. Org. Chem.
1992, 57, 1917;(b) Smrcina, M.;Vyskocil, S.;Maca, B.;
Polasek, M.;Claxton, T. A.;Abbott, A. P.;Kocovsky, P.
J. Org. Chem. 1994, 59, 2156;(c) Carreira, E. M.;Lee, W.;
wR2 ¼ 0:2276;
R
indices (all data): R1 ¼ 0:2841,
wR2 ¼ 0:3368. Crystallographic data for the structural
analysis have been deposited with the Cambridge Crys-
tallographic Data Centre, CCDC No. 221121.