Highly regioselective N-alkylation of nonracemic Betti base: A novel one-pot synthesis of chiral N-methyl-N-alkyl Betti bases

Article abstract of DOI:10.1016/j.tetasy.2004.04.006

A novel one-pot preparation of chiral N-methyl-N-alkyl Betti bases has been developed involving a highly regioselective N-alkylation of (S)-(+)-Betti base. The strategy involved formation-cleavage of the oxazine ring and N-methylation with BtCH₂

Full text of DOI:10.1016/j.tetasy.2004.04.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1667–1672
Highly regioselective N-alkylation of nonracemic Betti base: a novel
one-pot synthesis of chiral N-methyl-N-alkyl Betti bases
Yanmei Dong, Jianwei Sun, Xinyan Wang, Xuenong Xu, Liya Cao and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, PR China
Received 26 March 2004; accepted 5 April 2004
Available online 27 April 2004
Abstract—A novel one-pot preparation of chiral N-methyl-N-alkyl Betti bases has been developed involving a highly regioselective
N-alkylation of (S)-(þ)-Betti base. The strategy involved formation-cleavage of the oxazine ring and N-methylation with BtCH2OH
under neutral conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
alkyl group did not bring any additional satisfactory re-
sults, but made the synthetic procedure more difficult.2g;h
Many unnatural homochiral amino-phenol compounds
have been reported as excellent ligands in metal ion cat-
alyzed asymmetric reactions in current asymmetric syn-
thesis.1 The ligands, which have the structure of N,N-
dialkyl Betti base 1 (Chart 1) are gaining increasing
importance.2 Among them, the derivatives of chiral N-
methyl-N-alkyl Betti base 2 have induced satisfactory
reactivities and stereoselectivities in their catalyzed
asymmetric reactions. The replacement of the N-methyl
group in N-methyl-N-alkyl Betti base 2 by a large-sized N-
Because the aliphatic amine moiety of Betti base 3 has a
relatively lower nucleophilic reactivity when compared
to its phenoxyl group moiety, the N-alkylation of Betti
base 3 seriously lacks for regioselectivity by using rou-
tine methods.1f;2a;3 Therefore, no derivatives of chiral
N,N-dialkyl Betti base 1 in the literature were prepared
from nonracemic Betti base 3. The chiral N-methyl-N-
alkyl Betti base 2 was prepared mainly by the Mannich
condensation of a chiral amine with benzaldehyde and
2-naphthol to yield a N-alkyl Betti base 4 followed by a
N-methylation.2e;g;h;j Since few of the N-alkyl Betti bases
42h;g;i prepared by the Mannich condensation had satis-
factory diastereopurity, the diversity of the N-alkyl
group in the N-methyl-N-alkyl Betti base 2 is quite
limited. Herein, we report a highly regioselective N-
alkylation of (S)-(þ)-Betti base (S)-3, by which a series
of enantiopure N-methyl-N-alkyl Betti base 2 was pre-
pared in a convenient one-pot synthesis.
R1
N
Me
N
R
R
OH
OH
N,N-Dialkyl Betti Base 1
N-Methyl-N-Alkyl Betti Base 2
H
NH2
OH
N
R
2. Results and discussions
OH
Recently, we achieved the synthesis of enantiopure 1-[a-
(1-azacycloalkyl)benzyl]-2-naphthols by direct N-alkyl-
ation of the (S)-Betti bases (S)-3, in which a strategy
that involved the formation-cleavage of an oxazine ring,
was employed.3;4 Following this strategy, N-methyl-N-
alkyl Betti base 2 could be prepared by condensation of
(S)-(þ)-Betti base (S)-3 with aldehyde 5 to yield 2-(R)-4-
phenyl-naphtho[1,2-e][1,3]oxazine 6 as an intermediate
(S)-(+)-Betti Base (S)-3
N-Alkyl Betti Base 4
Chart 1.
* Corresponding author. Tel.: +86-10-62795380; fax: +86-10-627711-
49; e-mail: yfh@mail.tsinghua.edu.cn
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.006

1668
Y. Dong et al. / Tetrahedron: Asymmetry 15 (2004) 1667–1672
methylations were made at the scale of 10–50 mmol, 2–
H
N
5% enantiomeric loss was detected. As shown in Scheme
2, two pathways were hypothesized for the conversion of
compound 6 to compound 2, in which the iminiums are
essential intermediates. Thus, the loss of enantiomeric
excess must arise from the acid-catalyzed double bond
shifts of those iminium intermediates.
R
5a-b, MeOH, r.t., 30 min
(S)-3
O
6a R = (CH2)2CH3, 99%
6b R = H, 99%
NaBH4, (CH2O)n, TFA, 0o C, 2 h, or
NaBH4, (CH2O)n, AcOH, r.t., 24 h
BtCH2OH (1-hydroxymethylbenzotriazole), a novel N-
methylation reagent used under neutral conditions
developed by Katritzky et al.5 was then employed for
the N-methylation of 6. To our surprise, when the
mixture of BtCH2OH and 6a was stirred in MeOH
at room temperature for 30 min, the desired product
N-(benzotriazol-1-ylmethyl)-2-propyl-4-phenyl-naphtho-
[1,2-e][1,3]oxazine 7a could be isolated with 98% yield.
Under similar conditions, 6b also converted smoothly
into 2b in 98% (Scheme 3). Although NaBH4 was used
frequently to cleave the C–Bt bond or C–O bond in
oxazoles at room temperature,6 it failed to reduce oxa-
zines 7a and b possibly due to their heavy steric hin-
drance. Finally, reduction was achieved by refluxing the
mixture of 7a and b and LiAlH4 in THF for 30 min.
Since the acidic conditions were obviated, the desired
products 2a and b were obtained in 90–95% yields
without any loss of enantiomeric excess (Scheme 3).
2
67-86% yields, 95-98%ee
2a R = (CH2)2CH3
2b R = H
Scheme 1.
followed by simultaneous N-methylation and cleavage
of the oxazine ring under reductive N-methylation
conditions (Scheme 1).
The condensation of (S)-3 with n-butanal 5a has been
reported to yield 2-propyl-4-phenyl-naphtho[1,2-e][1,3]-
oxazine 6a in 68% yield in 95% EtOH at room temper-
ature for 24 h.2b When we tried this reaction in MeOH,
6a was obtained unexpectedly in quantitative yield in
just 30 min. Under similar conditions, formaldehyde 5b
(37% aq solution) also gave quantitatively the corre-
sponding 4-phenyl-naphtho[1,2-e][1,3]oxazine 6b. Com-
pound 6a proved to be a pure single diastereoisomer by
its NMR spectra [a single peak (5.45 ppm) for its benzyl
proton in 1H NMR and one group peaks in 13C NMR].
However, no special effort was made to identify the
absolute conformation of the newly formed stereogenic
carbon, since its configuration would disappear in the
next step.
Realizing that both products 6 and 7 can be readily
prepared in quantitative yields in MeOH, the prepara-
tion of 2a and b from (S)-3 can be accomplished by a
one-pot procedure. Thus, a mixture of (S)-3 and n-
butanal 5a or formaldehyde 5b was stirred in MeOH at
room temperature for 30 min (monitored by TLC).
BtCH2OH was then added and stirring continued for
another 30 min (monitored by TLC). After removal of
MeOH, a solution of LiAlH4 in THF was added and the
resultant mixture refluxed for 30 min to give 2a and b in
high yields (Scheme 4).
The reductive N-methylations of 6a and b were then
tested by using NaBH4–TFA2e;g;j or NaBH4–AcOH,2h
respectively. As expected, N-methylation and cleavage
of the oxazine ring occurred smoothly to give the desired
compounds 2a and b in 67–86% yields. Unfortunately,
the enantiomeric excess of product 2 was found to
decrease with a scale-up of the reaction. When the N-
To determine the scope of this one-pot procedure,
aldehydes 5c–l were employed in the same reaction. As
Bt
N
R
BtCH OH, MeOH
2
r.t., 1h
99%
6a-b
O
N+
R
N+
R
CH2O
Route 1
6
O
O
7a R = (CH ) CH
2 2
3
7b R = H
LiAlH , THF, Reflux, 0.5 h
90-95% yields, > 99%ee
4
H-
H-
2a-b
H-
Route 2
(S)-2
(+)-2
Scheme 3.
H-
H-
N+
R
OH
N+
R
OH
1. RCHO 5a-l, MeOH, r.t., 0.5-1.0 h
CH2O
2. BtCH2OH, MeOH, r.t., 1.0-12 h
4
(S)-3 3. LiAlH , THF, Reflux, 0.5 h
2a-l
4
90-95%
Scheme 2.
Scheme 4.

Y. Dong et al. / Tetrahedron: Asymmetry 15 (2004) 1667–1672
Table 1. The N-methyl-N-alkyl Betti bases 2a–l prepared
1669
4. Experimental
4.1. General considerations
5,2
R
T (h)a
Yield of 2 (%)b;c
a
b
c
d
e
f
CH3(CH2)2–
H–
CH3–
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
2.0
2.0
12
90
94
95
94
92
90
91
92
91
91
92
90
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 spectrometer with
70 eV. The elemental analyses were performed on a
Perkin–Elmer 240C instrument. Optical rotations were
determined on a Perkin–Elmer 343 polarimeter. PE is
petroleum ether (60–90 °C).
CH3CH2–
CH3(CH2)5–
CH3(CH2)8–
Me2CHCH2–
Et2CH–
g
h
i
C6H5CH2–
Cyclohexyl
C6H5–
j
k
l
3,4-(EtO)2C6H3–
12
a Time for the N-alkylation with BtCH2OH.
b The isolated yields.
c Enantiopurity was detected by chiral HPLC [Hypersil Pirkle(S)
Napht, product of Thermo Electron Cooperation].
4.2. General procedure for the preparation of 2-(R)-4-
phenyl-naphtho[1,2-e][1,3]oxazine 6a–b
To a stirred solution of (S)-3 (2.5 g, 10 mmol) in meth-
anol (50 mL) was added aldehyde 5 (11 mmol) in one
portion at room temperature. Thirty minutes later, the
solvent was removed in vacuum and the residue purified
by recrystallization to give desired product 6.
Bt
LiAlH4, THF
Reflux, 0.5 h
BtCH2OH, MeOH
(S)-3 r.t., 1.5 h
N
2b
O
95%
7b
4.2.1. 2-Propyl-4-phenyl-naphtho[1,2-e][1,3]oxazine 6a.
Using n-butanal 5a, compound 6a was obtained as
Scheme 5.
white crystals in 99% yield; mp 96–98 °C (methanol)
25
(Lit.2b mp 97–98 °C); ½aꢀ ¼ ꢁ19:8 (c 0.50, CHCl3)
D
[Lit.2b ¼ ꢁ15:2 (c 1.5, CH2Cl2)]; (Found: C, 83.26%; H,
6.99%; N, 4.57%, C21H21NO requires: C, 83.13%; H,
6.98%; N, 4.62%); mmax/cmꢁ1 3323, 2888, 1623, 1466; dH
7.08–7.90 (m, 11H), 5.45 (s, 1H), 4.60–4.66 (m, 1H), 2.39
(d, J ¼ 9:6 Hz, 1H), 1.68 (m, 2H), 1.49 (m, 2H), 0.88 (t,
J ¼ 7:1 Hz, 3H); dC 152.6, 143.0, 132.0, 129.2 (2C),
129.0, 128.6 (2C), 128.4, 128.1, 127.1, 126.4, 123.0,
122.8, 119.2, 114.0, 82.0, 53.7, 37.3, 17.7, 13.9; m=z: 303
(Mþ, 0.14%), 231 (100).
shown in Table 1, the corresponding enantiopure
derivatives of N-methyl-N-alkyl Betti bases 2c–l were
produced in excellent yields. For all of aliphatic alde-
hydes 5a–j, the step for the N-alkylation with BtCH2OH
was accomplished within 0.5–2 h. However a longer
reaction time (12 h) was required for aryl aldehydes 5k–l
possibly due to the steric hindrance of the benzene rings.
It is interesting to note that keeping the addition
sequence of aldehyde 5a–l and BtCH2OH is critical
otherwise, a mixture containing 2b would be obtained
because of the competing N,N-dialkylation that leads to
N-benzotriazolylmethyl-4-phenyl-naphtho[1,2-e][1,3]ox-
azine 7b (Scheme 5).
4.2.2. 4-Phenyl-naphtho[1,2-e][1,3]oxazine 6b. Using
formaldehyde 5b, compound 6b was obtained as white
crystals in 99% yield; mp 98–102 °C (methanol);
25
½aꢀ ¼ ꢁ36:3 (c 0.50, CHCl3); (Found: C, 82.78%; H,
D
5.81%; N, 5.26 %, C18H15NO requires: C, 82.73%; H,
5.79%; N, 5.36%); mmax/cmꢁ1 3344, 2890, 1623, 1468; dH
7.08–7.80 (m, 11H), 5.51 (s, 1H), 4.85 (s, 2H), 2.86 (br s,
1H); dC 152.1, 142.5, 131.6, 129.4 (2C), 129.1, 128.8
(2C), 128.5, 128.4, 127.4, 126.5, 123.2, 122.8, 119.1,
114.8, 73.6, 53.3; m=z: 261 (Mþ, 1.69%), 231 (100).
3. Conclusion
In summary, a novel preparation of chiral N-methyl-N-
alkyl Betti base 2 has been developed by highly regiose-
lective N-alkylation of (S)-(þ)-Betti base (S)-3. 2-(R)-4-
phenyl-naphtho[1,2-e][1,3]oxazine 6, obtained by con-
densation of (S)-(þ)-Betti base (S)-3 and aldehyde 5, was
N-methylated with BtCH2OH under essentially neutral
conditions to yield 2-(R)-N-benzotriazolylmethyl-4-phen-
yl-naphtho[1,2-e][1,3]oxazine 7. Chiral N-methyl-N-al-
kyl Betti base 2 was then obtained by simultaneously
cleaving the C–Bt bond and C–O bond in the structure of
7 via LiAlH4. Since every step can be operated in the
same solvent and almost in quantitative yields, in prac-
tice, they were performed in a one-pot procedure.
4.3. General procedure for the preparation of N-benzo-
triazolylmethyl-2-(R)-4-phenyl-naphtho[1,2-e][1,3]oxazine
7a–b
A mixture of 6 (10 mmol) and BtCH2OH (2.2 g,
15 mmol) in methanol (50 mL) was stirred at room
temperature for 0.5 h. The solvent was then removed in
vacuum and the residue purified by recrystallization to
give pure product 7.

1670
Y. Dong et al. / Tetrahedron: Asymmetry 15 (2004) 1667–1672
4.3.1. N-Benzotriazolylmethyl-4-phenylnaphtho[1,2-e]-
[1,3]oxazine 7a. Using compound 6a, product 7a was
4.4.2. (S)-1-[a-(N,N-Dimethylamino)benzyl]-2-naphthol
2b. Using aldehyde 5b, compound 2b was obtained as
obtained as white crystals in 98% yield; mp 162–164 °C
white crystals; mp 136–138 °C (acetone) (Lit.2a 158 °C);
20
20
(acetone); ½aꢀ ¼ þ65:0 (c 0.3, CHCl3); (Found: C,
½aꢀ ¼ þ228:0 (c 0.5, EtOH) [Lit.2a þ238 (c 0.5, EtOH)];
D
D
77.35%; H, 6.33%; N, 12.94%, C28H26N4O requires: C,
77.39%; H, 6.03%; N, 12.89%); mmax/cmꢁ1 3062, 2946,
1623, 1449; dH 6.87–8.07 (m, 15H), 5.50–5.89 (dd,
J ¼ 13:6 Hz, 2H), 5.62 (s, 1H), 4.86 (t, J ¼ 6:4 Hz, 1H),
2.06 (m, 2H), 1.44 (m, 2H), 0.85 (m, 3H); dC 152.9,
146.3, 141.5, 133.0, 132.8, 129.5, 129.2 (2C), 128.5, 128.1
(2C), 127.4, 126.8, 126.6, 126.3, 124.0, 123.6, 122.9,
120.2, 118.4, 111.3, 110.0, 84.6, 60.0, 60.1, 34.0, 18.5,
13.5; m=z: 434 (Mþ, 1.69%), 231 (100).
(C, 82.17%; H, 6.87%; N, 5.13%. C19H19NO requires: C,
82.28%; H, 6.90%; N, 5.05%); mmax/cmꢁ1 3062, 2983,
1621, 1600, 1477; dH 13.74 (s, 1H), 7.14–7.86 (m, 1H),
4.97 (s, 1H), 2.34 (br s, 6H); dC 155.4, 140.3, 132.2, 129.5
(2C), 128.8, 128.7 (2C), 128.0, 126.3 (2C), 122.4, 121.0,
120.0 (2C), 116.2, 73.0, 44.3 (2C); m=z: 278 (Mþ þ1,
0.33%), 277 (Mþ, 1.50), 231 (100).
4.4.3. (S)-1-[a-(N-Methyl-N-ethylamino)benzyl]-2-naph-
thol 2c. Using aldehyde 5c, compound 2c was obtained
as yellowish crystals; mp 107–109 °C (PE);
20
4.3.2. N-Benzotriazolylmethyl-4-phenyl-naphtho[1,2-e]-
[1,3]oxazine 7b. Using compound 6b, product 7b was
½aꢀ ¼ þ187:9 (c 2.0, CHCl3); (Found: C, 82.19%; H,
D
7.36%; N, 4.88%. C20H21NO requires: C, 82.44%; H,
7.26%; N, 4.81%); mmax/cmꢁ1 3060, 2978, 1622, 1601; dH
13.68 (s, 1H), 7.15–7.87 (m, 11H), 5.15 (s, 1H), 2.50–2.78
(br d, 5H), 1.15 (t, J ¼ 7:0 Hz, 3H); dC 155.7, 140.2,
132.3, 129.4, 129.0 (2C), 128.9 (2C), 128.8, 128.7, 127.9,
126.3, 122.3, 121.0, 120.1, 116.4, 71.4, 49.4, 39.1, 11.9;
m=z: 291 (Mþ, 0.94%), 231 (100).
obtained as white crystals; mp 179–180 °C (acetone);
20
½aꢀ ¼ þ70:2 (c 0.35, CHCl3); (Found: C, 76.57%; H,
D
5.31%; N, 14.26%. C25H20N4O requires: C, 76.51%; H,
5.14%; N,14.28%); mmax/cmꢁ1 3062, 2892, 1622, 1451; dH
6.88–8.10 (m, 15H), 5.78 (S, 2H), 5.51 (S, 1H), 4.93 (s,
2H); dC 151.6, 146.4, 141.3, 133.0, 132.4, 129.6, 129.2
(2C), 129.1, 128.6, 128.3 (2C), 127.6, 126.9, 124.2, 123.7,
122.7, 120.1, 118.4, 111.2, 110.2, 76.2, 65.9, 57.7; m=z:
392 (Mþ, 3.33%), 231 (100).
4.4.4.
naphthol 2d. Using aldehyde 5d, compound 2d was ob-
(S)-1-[a-(N-Methyl-N-propylamino)benzyl]-2-
20
D
tained as a yellowish gum; ½aꢀ ¼ þ206:5 (c 0.3, CHCl3);
4.4. General one-pot procedure for the preparation of (S)-
1-[-(N-methyl-N-alkylamino)benzyl]-2-naphthol 2a–l
(Found: C, 82.46%; H, 7.68%; N, 4.62%. C21H23NO
requires: C, 82.58%; H, 7.59%; N, 4.59%); mmax/cmꢁ1
3061, 2966, 2932, 1621, 1601, 1473; dH 13.94 (s, 1H),
7.13–7.87 (m, 11H), 5.12 (s, 1H), 2.29 (br d, 5H), 1.60
(m, 2H), 0.84 (t, J ¼ 7:4 Hz, 3H); dC 155.6, 140.2, 132.2,
129.4 (2C), 128.9 (2C), 128.8, 128.7, 128.6, 127.9, 126.3,
122.3, 121.0, 120.0, 116.5, 72.0, 57.4, 39.9, 19.9, 11.6;
m=z: 306 (Mþþ1, 0.28%), 305 (Mþ, 1.84), 232 (100), 231
(100), 202 (100), 44 (100).
To a stirred solution of (S)-3 (2.5 g, 10 mmol) in meth-
anol (50 mL) was added aldehyde 5 (11 mmol). After the
(S)-3 was exhausted (0.5–1.0 h, monitored by TLC), a
solution of BtCH2OH (2.2 g, 15 mmol) in methanol
(20 mL) was added to the system at room temperature.
The resultant mixture was stirred until intermediate 6
disappeared completely (0.5–12 h, monitored by TLC).
The solvent was then removed in vacuum and a solution
of LiAlH4 in THF (1.0 M, 50 mL, 50 mmol) added by
syringe. After refluxing for 30 min (monitored by TLC),
the reaction was cooled to 0 °C and quenched by the
addition of a saturated aqueous solution of NH4Cl. The
mixture was extracted with CH2Cl2 and the organic
layer washed with water, brine and dried over Na2SO4.
The solvent was evaporated under reduced pressure to
yield the crude product, which was purified by chro-
matography to give the pure compound 2 (Table 1).
4.4.5. (S)-1-[a-(N-Methyl-N-hexylamino)benzyl]-2-naph-
thol 2e. Using aldehyde 5e, compound 2e was obtained
20
D
as a yellowish gum; ½aꢀ ¼ þ167:9 (c 0.36, CHCl3);
(Found: C, 83.11%; H, 8.51%; N, 3.75%. C25H31NO
requires: 83.06%; H, 8.64%; N, 3.87%); mmax/cmꢁ1 3061,
2955, 2928, 2855, 1621, 1600, 1454; dH 13.93 (s, 1H),
7.13–7.87 (m, 11H), 5.11 (s, 1H), 2.29–2.38 (br d, 5H),
1.56 (s, 2H), 1.21 (s, 8H), 0.85 (t, J ¼ 5:6 Hz, 3H); dC
155.6, 140.2, 132.3, 129.4 (2C), 130.0, 128.9 (2C), 128.7,
128.6, 127.9, 126.3, 122.3, 121.0, 120.0, 116.5, 72.0, 55.6,
40.0, 31.6, 29.0, 27.1, 26.7, 22.6, 14.0; m=z: 361 (Mþ,
0.68%), 232 (100), 231 (100), 44 (100).
4.4.1. (S)-1-[a-(N-Methyl-N-butylamino)benzyl]-2-naph-
thol 2a. Using aldehyde 5a, compound 2a was obtained
20
D
as a yellowish gum; ½aꢀ ¼ þ198:4 (c 0.31, CHCl3);
4.4.6. (S)-1-[a-(N-Methyl-N-nonylamino)benzyl]-2-naph-
thol 2f. Using aldehyde 5f, compound 2f was obtained as
(Found: C, 82.66%; H, 8.02%; N, 4.32%. C22H25NO re-
quires: 82.72%; H, 7.89%; N, 4.38%); mmax/cmꢁ1 3061,
2959, 1621, 1600, 1473, 1454; dH 13.94 (s, 1H), 7.13–7.87
(m, 11H), 5.11 (s, 1H), 2.29–2.40 (br d, 5H), 1.56 (m, 2H),
1.26 (m, 2H), 0.84 (t, J ¼ 7:2 Hz, 3H); dC 155.57, 140.2,
132.2, 129.4 (2C), 130.0, 128.9 (2C), 128.7, 128.6, 127.9,
126.3, 122.3, 121.0, 120.0, 116.5, 72.0, 55.3, 40.0, 28.9,
20.3, 13.8; m=z: 319 (Mþ, 1.35%), 231 (100).
20
D
a yellowish gum; ½aꢀ ¼ þ142:6 (c 0.3, CHCl3); (Found:
C, 83.36%; H, 9.26%; N, 3.31%. C28H37NO requires: C,
83.33%; H, 9.24%; N, 3.47%); mmax/cmꢁ1 3061, 2958,
2925, 1621, 1601, 1455; dH 13.94 (s, 1H), 7.13–7.87 (m,
11H), 5.10 (s, 1H), 2.27–2.38 (br d, 5H), 1.56 (s, 2H),
1.21 (s, 14H), 0.87 (t, J ¼ 6:1 Hz, 3H); dC 155.6, 140.2,
132.3, 129.4 (2C), 129.0, 128.8, 128.7, 128.0, 127.8,

Y. Dong et al. / Tetrahedron: Asymmetry 15 (2004) 1667–1672
1671
126.3, 122.3, 121.0 (2C), 120.0, 116.5, 72.0, 55.5, 40.0,
31.8, 29.5, 29.4, 29.3, 29.2, 27.1, 26.7, 22.6, 14.1; m=z:
404 (Mþþ1, 0.38%), 403 (Mþ, 1.56), 232 (100), 231
(100), 202 (100), 127 (100), 44 (100).
4.4.11.
naphthol 2k. Using aldehyde 5k, compound 2k was ob-
tained as
(S)-1-[a-(N-Methyl-N-phenylamino)benzyl]-2-
a
white solid; mp 54–56 °C (PE);
20
½aꢀ ¼ þ149:8 (c 0.30, CHCl3); (Found: C, 84.95%; H,
D
6.63%; N, 3.96%. C25H23NO requires: C, 84.95%; H,
6.56%; N, 3.96%); mmax/cmꢁ1 3061, 2963, 1621, 1600,
1520, 1453; dH 13.73 (s, 1H), 7.19–7.92 (m, 16H), 5.24 (s,
1H), 3.60 (br s, 2H), 2.19 (s, 3H); dC 155.2, 140.2, 137.0,
132.3, 129.6, 129.4 (2C), 128.9 (2C), 128.8, 128.6, 128.1,
127.6, 126.5, 122.3 (2C), 121.0 (2C), 120.0 (2C), 116.5,
71.8, 60.4, 40.3; m=z: 353 (Mþ, 0.20%), 231 (100).
4.4.7. (S)-1-[a-(N-Methyl-N-(3-methylbutyl)amino)benz-
yl]-2-naphthol 2g. Using aldehyde 5g, compound 2g was
obtained as a yellowish solid; mp 76–80 °C (PE);
20
½aꢀ ¼ þ167:9 (c 0.36, CHCl3); (Found: C, 82.86%; H,
D
7.97%; N, 4.27%. C23H27NO requires: C, 82.84%; H,
8.16%; N, 4.20%); mmax/cmꢁ1 3061, 2960, 1621, 1600,
1474, 1453; dH 13.96 (s, 1H), 7.13–7.87 (m, 11H), 5.11 (s,
1H), 2.27–2.43 (br d, 5H), 1.43–1.54 (m, 3H), 0.76–0.82
(m, 6H); dC 155.6, 140.1, 132.2, 129.4 (2C), 129.0, 128.8
(2C), 128.7 (2C), 127.9, 126.3, 122.3, 121.0, 120.0, 116.4,
72.0, 53.6, 40.1, 35.7, 26.1, 22.8, 22.2; m=z: 333 (Mþ,
1.15%), 231 (100), 44 (100).
4.4.12. (S)-1-[a-(N-Methyl-N-(3,4-diethoxyphenyl)-
amino)-benzyl]-2-naphthol 2l. Using aldehyde 5l, com-
pound 2l was obtained as a yellowish solid; mp 51–52 °C
20
(PE); ½aꢀ ¼ þ217:2 (c 0.30, CHCl3); (Found: C,
D
78.64%; H, 7.13%; N, 3.16%. C29H31NO3 requires: C,
78.88%; H, 7.08%; N, 3.17%); mmax/cmꢁ1 3439, 2977,
1621, 1600, 1514, 1473; dH 155.5, 149.3, 148.7, 140.3,
132.4, 129.6 (2C), 129.1, 129.0, 128.9 (2C), 128.0, 126.4,
122.4 (2C), 122.3, 122.2, 121.1, 120.1, 116.4, 115.7,
114.3, 71.5, 65.0, 64.9, 60.2, 40.1, 14.9, 14.8; m=z: 441
(Mþ, 0.23%), 232 (100), 231 (100), 202 (100).
4.4.8. (S)-1-[a-(N-Methyl-N-(2-ethylbutyl)amino)benzyl]-
2-naphthol 2h. Using aldehyde 5h, compound 2h was
obtained as a yellowish solid; mp 76–80 °C (PE);
20
½aꢀ ¼ þ148:6 (c 0.36, CHCl3); (Found: C, 82.90%; H,
D
8.56%; N, 4.13%. C24H29NO requires: C, 82.95%; H,
8.41%; N, 4.03%); mmax/cmꢁ1 3062, 2962, 1621, 1600,
1519, 1454; dH 13.59 (s, 1H), 6.98-7.88 (m, 11H), 4.56 (s,
1H), 2.13-2.36 (m, 5H), 1.25-1.53 (m, 5H), 0.81 (t,
J ¼ 7:2 Hz, 3H), 0.72 (t, J ¼ 7:2 Hz, 3H); dC 155.5,
140.3, 132.4, 129.5, 129.2, 128.9, 128.7, 127.9, 126.3,
122.3 (2C), 121.1 (2C), 120.0, 116.8, 73.2, 59.2, 41.4,
38.4, 24.0, 23.5, 11.0, 9.8; m=z: 347 (Mþ, 0.85%), 232
(100), 231 (100), 202 (100), 44 (100).
Acknowledgements
We are grateful to the National Natural Science Foun-
dation of China for financial support.
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.;
Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649; (d)
Carriera, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc.
1995, 117, 12360; (e) Kim, Y.; Singer, R. A.; Carreira,
E. M. Angew. Chem., Int. Ed. 1998, 37, 1261; (f) Vyskocil, S.;
Jaraz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.;
Kocovsky, P. J. Org. Chem. 1998, 63, 7727; (g) Belokon, Y.
N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Larionov, O. V.; North, M.; Kagen, H. B. Angew. Chem.,
Int. Ed. 2001, 40, 1948; (h) Yuan, Y.; Long, J.; Sun, J.;
Ding, K. Chem. Eur. J. 2002, 8, 5033; (i) Yuan, Y.; Long, J.;
Sun, J.; Ding, K. J. Am. Chem. Soc. 2002, 124, 14866; (j)
Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev. 2003,
103, 3213.
4.4.9.
naphthol 2i. Using aldehyde 5i, compound 2i was ob-
tained as
(S)-1-[a-(N-Methyl-N-benzylamino)benzyl]-2-
a
yellowish solid; mp 44–46 °C (PE);
20
½aꢀ ¼ þ143:4 (c 0.3, CHCl3); (Found: C, 84.29%; H,
D
6.75%; N, 4.01%. C26H25NO requires: C, 84.98%; H,
6.86%; N, 3.81%); mmax/cmꢁ1 3060, 2968, 1621, 1600,
1469, 1453; dH 13.96 (s, 1H), 7.02–7.95 (m, 16H), 5.18 (s,
1H), 2.76–2.86 (br d, 4H), 2.40 (s, 3H); dC 155.3, 140.1,
139.1, 132.2, 129.4 (2C), 129.0, 128.8 (2C), 128.7, 128.6,
128.4, 127.9 (2C), 126.3, 126.2, 122.3 (2C), 121.0 (2C),
120.0 (2C), 116.4, 72.0, 53.6, 40.1, 35.7, 26.1, 22.8, 22.2;
m=z: 367 (Mþ, 0.15%), 232 (100), 231 (100), 44 (100).
4.4.10. (S)-1-[a-(N-Methyl-N-cyclohexylamino)benzyl]-2-
naphthol 2j. Using aldehyde 5j, compound 2j was
obtained as a white solid; mp 134–135 °C (PE);
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. 2001, 66, 4759; (g)
Wang, Y.; Li, X.; Ding, K. Tetrahedron: Asymmetry 2002,
20
½aꢀ ¼ þ152:0 (c 0.35, CHCl3); (Found: C, 83.49%; H,
D
8.22%; N, 3.98%. C25H29NO requires: C, 83.52%; H,
8.13%; N, 3.90%); mmax/cmꢁ1 3025, 2960, 1621, 1600,
1474, 1453; dH 13.94 (s, 1H), 7.13–7.87 (m, 11H), 5.07 (s,
1H), 2.23–2.34 (br d, 4H), 1.66 (m, 7H), 1.14 (m, 3H),
0.78 (m, 2H); dC 155.2, 140.2, 132.2, 129.4 (2C), 128.8
(2C), 128.7, 128.6, 127.9, 126.3, 122.3 (2C), 121.0 (2C),
120.0, 116.5, 72.8, 62.1, 40.9, 35.3, 31.4, 31.2, 26.4, 26.0,
25.9; m=z: 360 (Mþþ1, 1.18%), 359 (Mþ, 4.69), 232
(100), 231 (100), 202 (100), 44 (100).

1672
Y. Dong et al. / Tetrahedron: Asymmetry 15 (2004) 1667–1672
13, 1291; (h) Cimarelli, C.; Palmieri, G.; Volpini, E.
4. (a) Xu, X.; Lu, J.; Li, R.; Ge, Z.; Dong, Y.; Hu, Y. Synlett
2004, 122; (b) Xu, X.; Lu, J.; Dong, Y.; Li, R.; Ge, Z.; Hu,
Y. Tetrahedron: Asymmetry 2004, 15, 475.
5. Kartrizky, A. R.; He, H.-Y.; Jiang, R.; Long, Q. Tetra-
hedron: Asymmetry 2001, 12, 2427.
Tetrahedron: Asymmetry 2002, 13, 2417; (i) Saidi, M. R.;
Azizi, N. Tetrahedron: Asymmetry 2003, 14, 389; (j) Ji, J.;
Qiu, L.; Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68,
1589.
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.
6. (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.