Asymmetric synthesis of β-dialkylamino alcohols by transfer hydrogenation of α-dialkylamino ketones

Article abstract of DOI:10.1016/j.tetasy.2009.03.014

Transfer hydrogenation of representative aryl and heteroaryl dialkylaminomethyl ketones with formic acid-triethylamine, catalyzed by RuCl[(R,R)-TsDPEN](η-p-cymene), produces the corresponding β-dialkylamino alcohols, 97-99% ee, in 50-73% yields. Asymmetric synthesis of (R)-macromerine, 98% ee, the cactus Coryphantha macromeris alkaloid, is also described.

Full text of DOI:10.1016/j.tetasy.2009.03.014

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Tetrahedron: Asymmetry 20 (2009) 1138–1143
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of b-dialkylamino alcohols by transfer hydrogenation
of a-dialkylamino ketones
*
Tomasz Kosmalski, Andrzej Wojtczak, Marek Zaidlewicz
Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin St., Torun, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Transfer hydrogenation of representative aryl and heteroaryl dialkylaminomethyl ketones with formic
acid–triethylamine, catalyzed by RuCl[(R,R)-TsDPEN]( -p-cymene), produces the corresponding b-dial-
kylamino alcohols, 97–99% ee, in 50–73% yields. Asymmetric synthesis of (R)-macromerine, 98% ee,
Received 13 February 2009
Accepted 18 March 2009
Available online 22 April 2009
g
the cactus Coryphantha macromeris alkaloid, is also described.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
into the corresponding epoxides,14 and b-alkyl(benzyl)amino alco-
hols are intermediates in the industrial synthesis of b-alkylamino
Chiral b-amino alcohols are widely used as auxiliaries and
ligands,1–4 components of oxazaborolidines,5,6 and are also impor-
tant physiologically active compounds.7,8 Various syntheses of pure
enantiomers, by aminohydroxylation of olefins,9 catalytic hydroge-
alcohols.19 Certain b-dialkylamino alcohols are physiologically ac-
tive.29–32
2. Results and discussion
nation of a
-functionalized ketones,10 their reduction with hydrides,11–13
borane/oxazaborolidines,5,6 and by other approaches,14–18 have been
Aryl and heteroaryl dialkylaminomethyl ketones 1–8, 10, and
11 were prepared from the corresponding methyl ketones by bro-
developed. Resolutionof racemicb-aminoalcohols, enzymaticreductions,
and catalytic enantioselective hydrogenation of a-amino ketones have
mination followed by treatment of the product
a-bromo ketones
been applied onanindustrial scale.19 An attractive alternative to the afore-
mentioned reductive methods is the asymmetric transfer hydrogenation
with secondary amines. 2-Benzofuryl and 2-furyl amino ketones
6–8 are not stable for prolonged periods, and should be freshly pre-
pared. The reduction reactions were carried out with formic acid–
of a-functionalized ketones, due to its simplicity and avoiding the use of
dihydrogen under pressure, and employing phosphine-free
triethylamine 5:2 in the presence of RuCl[(R,R)-TsDPEN](g-p-cym-
catalysts.1,2,10,20–23
ene) catalyst in ethyl acetate at room temperature. The substrate/
catalyst ratio was 400. The product b-amino alcohols were isolated
by column chromatography, crystallization or distillation. The re-
sults are presented in Table 1.
In our earlier asymmetric syntheses of b-amino alcohols, the
reduction of
a-halo ketones with chlorodiisopinocampheylborane
or by transfer hydrogenation with formic acid–triethylamine, cat-
alyzed by RhCl[(R,R)-TsDPEN](C5Me5) was used.24,25 The product
b-halohydrins were transformed into the corresponding b-amino
alcohols by treatment with amines or via the intermediate epox-
ides. However, these reactions are not always highly regioselective,
and mixtures of isomeric b-amino alcohols are often pro-
The pyrrolidino- and piperidino-substituted ketones 3 and 4 re-
act faster when compared to other amino ketones as shown in Ta-
ble 1. On the other hand, the presence of the sterically demanding
dibenzylamino group prevents the reduction of 10. Yields of the
product b-amino alcohols (50–73%) indicate that the catalyst is
not deactivated by the amino ketones or the reaction products.
Aryl and heteroaryl aminomethyl ketones 1–8 are reduced with
high enantioselectivity (>95% ee), however, the simplest alkyl
diethylaminomethyl ketone 9 is reduced with much lower enanti-
oselectivity producing 9a, 60% ee. The same configurations of the
product amino alcohols 1a–5a indicate similar orientations of the
corresponding amino ketones approaching the catalyst. The (S)-
configurations of 6a–8a reflect the nomenclature priority of ben-
zofuryl and furyl groups over the aminomethyl moiety, opposite
to the aryl groups of 1a–5a. The configuration assignments for
1a–4a are based on comparison of the signs of the specific rotation
with the literature data. The assignments for naphthyl and
duced.11,20,26,27 Consequently, transfer hydrogenation of
ketones, leading directly to b-amino alcohols, is highly desirable.
a-amino
Very recently, it was employed for the highly enantioselective
reduction of a
-imidazole-substituted acetophenone.1,28
In this study we focused on the transfer hydrogenation of rep-
resentative dialkylaminomethyl ketones with formic acid–triethyl-
amine 5:2, catalyzed by RuCl[(R,R)-TsDPEN](g-p-cymene). The
product amino alcohols are useful synthetic intermediates, for
example, b-dimethylamino alcohols can be readily transformed
* Corresponding author. Fax: +48 56 6542477.
E-mail address: zaidlevi@chem.uni.torun.pl (M. Zaidlewicz).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.014

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T. Kosmalski et al. / Tetrahedron: Asymmetry 20 (2009) 1138–1143
1139
Table 1
Asymmetric transfer hydrogenation of amino ketones 1–11, catalyzed with RuCl[(R,R)-TsDPEN)]
g
-p-cymene in ethyl acetate at room temperature
O
R2
OH
R2
HCOOH – Et N (5:2)
0.25 % mol {RuCl[R,R)-TsDPEN)]η-p-cymene}
AcOEt, r.t.
3
N
N
R1
R1
R3
R3
1–9,11
1a–9a, 11a
No.
Amino ketone
R2
Time, days
Amino alcohol
Yielda (%)
R1
R3
ee (%)
Conf.
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Me
Et
(CH2)4
(CH2)5
Me
Me
Et
5
6
3
3
6
5
7
5
7
7
7
1a
2a
3a
4a
5a
6a
7a
8a
9a
n.r.
11a
58
73
57
63
60
69
62
61
50
97b
98b
99b
99b
98c
98c
97c
98c
60b
(R)d
(R)d
(R)d
(R)d
(R)e
(S)e
(S)e
(S)f
2-Naphthyl
2-Benzofuryl
2-Benzofuryl
2-Furyl
Me
Me
Me
Me
(CH2)2O(CH2)2
Me
Et
Bn
Me
Me
Et
Bn
Me
(R)d
10
11
Ph
3,4-(MeO)2C6H3
55
98c
(R)d
a
b
c
d
e
f
Isolated.
Determined by GC on a chiral column, Supelco Beta-DEX 325, 30 m ꢁ 0.25 mm. Racemates were also analyzed.
m. Racemates were also analyzed.
Assigned by comparison of the sign of rotation with the literature data (see Section 4).
Assigned by X-ray analysis.
Determined by HPLC on a chiral column, Daicel Chiralcel OD-H, 250 ꢁ 4.6 mm, 5
l
Assignment is based on the close structural similarity to 6a and 7a, and the same sign of rotation.
benzofuryl amino alcohols 5a–7a follow from X-ray analyses of
their crystals (Figs. 1–3). The (S)-configuration of 2-furyl amino
alcohol 8a is based on the same sign of rotation and close struc-
tural similarity to 6a and 7a.
Figure 2. The X-ray structure of 6a.
Figure 1. The X-ray structure of 5a.
Figure 3. The X-ray structure of 7a.
High enantioselectivity of the reduction of dialkylaminomethyl
ketones described above, prompted us to apply the method to the
synthesis of (R)-(ꢀ)-macromerine 11a, which occurs in cactus
Coryphantha macromeris, exhibits a hallucinogenic activity,33 and
is structurally related to (R)-(ꢀ)-adrenaline. The synthesis started
from 3,4-dimethoxyacetophenone, which was brominated with
pyridinium perbromide, followed by treatment with dimethyl-
amine, and transfer hydrogenation of 1-(3,4-dimethoxyphenyl)-
2-(dimethylamino)ethanone 11 producing 11a, 98% ee, in an
overall 39% yield (Scheme 1).
3. Conclusion
Asymmetric transfer hydrogenation of dialkylaminomethyl aryl
and heteroaryl ketones with high enantioselectivity has been
achieved using formic acid–triethylamine and RuCl[(R,R)-TsD-
PEN](g-p-cymene) catalyst. The method provides direct access to
the corresponding b-amino alcohols, avoiding the formation of reg-
ioisomeric amino alcohols observed in the reaction of b-halohyd-
rins with secondary amines. It was applied to the synthesis of
(R)-(ꢀ)-macromerine, 98% ee, the cactus C. macromeris alkaloid.

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1140
T. Kosmalski et al. / Tetrahedron: Asymmetry 20 (2009) 1138–1143
O
O
O
Br
NMe2
MeO
MeO
MeO
MeO
Me2NH
MeO
MeO
C5H6NBr3
AcOH, rt, 4 h
Me
Et2O, rt, 3.5 h
11
89%
80%
Me2
OH
HCOOH – Et3N 5:2
0.25 mol% RuCl[(R,R)-TsDPEN](η-p-cymene)
NMe2
MeO
MeO
AcOEt, rt, 7 days
55%
11a
Scheme 1.
1.08 (t, J = 7.2 Hz, 6H, CH3), 2.71 (q, J = 7.2 Hz, 4H, CH2), 3.92 (s,
2H, CH2N), 7.58–7.42 (m, 3H, CH), 8.00 (dm, J = 7.5 Hz, 2H, CH).
13C NMR (75 MHz, CDCl3) d 11.75 (2CH3), 47.69 (2NCH2), 59.61
(NCH2), 128.06 (CH), 128.33 (CH), 132.90 (CH), 136.18 (C), 198.13
(CO).
4. Experimental
4.1. General
Experiments with air and moisture sensitive materials were
carried under an argon atmosphere. Glassware was oven dried
for several hours, assembled hot, and cooled in a steam of argon.
1H and 13C NMR spectra were recorded on a Varian Gemini 200
multinuclear instrument and on a Bruker AMX 300 MHz instru-
ment. MS spectra were recorded on an AMD 604 spectrometer.
Optical rotations were measured on an Optical Activity PolAAr
3000 automatic polarimeter. GC analyses were performed on a Per-
kin–Elmer Auto System XL chromatograph, and HPLC analyses on a
Shimadzu LC-10AT chromatograph. X-ray analyses were per-
formed on an Oxford Sapphire CCD diffractometer, using Mo K
radiation k = 0.71073 Å, by
determined in open glass capillaries and are uncorrected. Elemen-
tal analyses were performed by the Microanalysis Laboratory,
Institute of Organic Chemistry, Polish Academy of Sciences,
Warsaw.
4.5. 1-Phenyl-2-(pyrrolidin-1-yl)ethanone 3
Prepared from 1-phenyl-2-bromoethanone and pyrrolidine in
benzene/diethyl ether, 45 °C, 6 h, 41% yield, bp 100–102 °C/
0.5 mmHg. Lit.36 bp 88–89/0.1 mmHg 1H NMR (300 MHz, CDCl3)
d 1.84 (m, 4H, CH2), 2.68 (m, 4H, CH2), 3.99 (s, 2H, CH2N), 7.45
(tm, J = 7.5 Hz, 2H, CH), 7.55 (tt, J = 7.5, 1.5 Hz, 1H, CH), 7.99 (dm,
J = 7.2 Hz, 2H, CH). 13C NMR (75 MHz, CDCl3) d 23.66 (2CH2),
54.34 (2CH2N), 62.34 (CH2N), 127.96 (2CH), 128.51 (2CH), 133.06
(CH), 136.00 (C), 196.75 (CO).
a
x
ꢀ 2h method. Melting points were
4.6. 1-Phenyl-2-(piperidin-1-yl)ethanone 4
Prepared from 1-phenyl-2-bromoethanone and piperidine in
benzene/diethyl ether, 45 °C, 9 h, 79% yield, bp 110–112 °C/
0.3 mmHg. Lit.35 bp 134–136 °C/1 mmHg. 1H NMR (300 MHz,
4.2. Materials
CDCl3)
d 1.45 (quintet, J = 5.4 Hz, 2H, CH2), 1.64 (quintet,
J = 5.4 Hz, 4H, CH2), 2.53 (t, J = 5.4 Hz, 4H, CH2), 3.77 (s, 2H,
CH2N), 7.44 (tdd, J = 7.5, 2.1, 1.5 Hz, 2H, CH), 7.56 (tt, J = 7.5,
1.5 Hz, 1H, CH), 8.02 (ddd, J = 7.2, 2.1, 1.5 Hz, 2H, CH). 13C NMR
(75 MHz, CDCl3) d 23.96 (CH2), 25.77 (2CH2), 54.83 (2CH2N),
65.32 (CH2N), 128.14 (2CH), 128.44 (2CH), 133.05 (CH), 136.23
(C), 196.85 (CO).
Silica Gel 60, Merck 230–400 mesh was used for preparative
column chromatography. Macherey-Nagel Polygram Sil G/UV254
0.2 mm plates were used for analytical TLC. Tetrahydrofuran was
freshly distilled from sodium benzophenone ketyl. RuCl[(R,R)-TsD-
PEN](g-p-cymene) was prepared from [RuCl2(g-p-cymene)]2 and
(1R,2R)-N-p-tolylsulfonyl-1,2-diphenylethylenediamine (TsDPEN)
according to the literature.34
4.7. 2-(Dimethylamino)-1-(2-naphthyl)ethanone 5
4.3. 2-(Dimethylamino)-1-phenylethanone 1
Prepared from 1-(2-naphthyl)-2-bromomethanone and dimeth-
ylamine in diethyl ether, ꢀ10 °C, 30 min, room temperature, 4 h,
86% yield, hydrochloride mp 215–217 °C. Lit.37 mp 216–217 °C.
1H NMR (300 MHz, CDCl3) d 2.44 (s, 6H, CH3), 3.91 (s, 2H, CH2N),
7.54 (td, J = 7.5, 1.5 Hz, 1H, CH), 7.60 (td, J = 7.5, 1.5 Hz, 1H, CH),
7.82–7.92 (m, 2H, CH), 7.96 (dm, J = 8.7 Hz, 1H, CH), 8.04 (dd,
J = 8.7, 1.8 Hz, 1H, CH), 8.54 (d, J = 1.5 Hz, 1H, CH). 13C NMR
(75 MHz, CDCl3) d 45.73 (2CH3), 65.53 (CH2N), 123.76 (CH),
126.62 (CH), 127.64 (CH), 128.25 (CH), 128.35 (CH), 129.48 (CH),
129.62 (CH), 132.34 (C), 133.22 (C), 135.52 (C), 196.66 (CO).
Prepared from 1-phenyl-2-bromoethanone and dimethylamine
in benzene/diethyl ether, 12 h, room temperature, 60% yield, bp
76–78 °C/0.5 mmHg. Lit.35 130–132 °C/20 mmHg. 1H NMR
(300 MHz, CDCl3) d 2.38 (s, 6H, CH3), 3.76 (s, 2H, CH2), 7.45 (tm,
J = 7.2 Hz, 2H, CH), 7.56 (tt, J = 7.2, 1.5 Hz, 1H, CH), 7.99 (ddd,
J = 7.2, 2.1, 1.5 Hz, 2H, CH). 13C NMR (75 MHz, CDCl3) d 45.83
(2 NCH3), 65.61 (CH2N), 128.09 (2CH), 128.53 (2CH), 133.16 (CH),
135.99 (C), 196.84 (CO).
4.4. 2-(Diethylamino)-1-phenylethanone 2
4.8. 1-(2-Benzofuryl)-2-(dimethylamino)ethanone 6
Prepared from 1-phenyl-2-bromoethanone and diethylamine in
benzene/diethyl ether, 45 °C, 30 h, 67% yield, bp 88–90 °C/
0.5 mmHg. Lit.35 bp 85 °C/0.2 mmHg. 1H NMR (300 MHz, CDCl3) d
Prepared from 1-(2-benzofuranyl)-2-bromoethanone and
dimethylamine in diethyl ether, ꢀ10 °C, 15 min, 10 °C, 20 min,

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T. Kosmalski et al. / Tetrahedron: Asymmetry 20 (2009) 1138–1143
1141
80% yield, 100–105 °C/0.05 mmHg. 1H NMR (300 MHz, CDCl3) d
2.41 (s, 6H, CH3), 3.75 (s, 2H, CH2), 7.31 (ddd, J = 7.8, 7.2, 1.2 Hz,
1H, CH), 7.47 (ddd, J = 7.2, 1.2, 7.0 Hz, 1H, CH), 7.57 (ddd, J = 7.4,
1.8, 0.9 Hz, 1H, CH), 7.66 (d, J = 0.9 Hz, 1H, CH), 7.70 (ddd, J = 7.4,
1.2, 0.9 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3) d 45.88 (2CH3),
65.50 (CH2), 112.40 (CH), 113.44 (CH), 123.33 (CH), 123.90 (CH),
126.90 (C), 128.31 (CH), 151.67 (C), 155.44 (C), 188.18 (CO). HRMS
(ESI) [M+H]+, found 204.1011, C12H13NO2, requires 204.1019.
4.14. (R)-(–)-2-(Dimethylamino)-1-(phenyl)ethanol 1a: typical
procedure
To a solution of 1 (1.63 g, 10 mmol) in ethyl acetate (5 mL),
RuCl[(R,R)-TsDPEN]( -p-cymene) (20 mg, 0.02 mmol), triethyl-
g
amine (0.1 mL), and an azeotrope mixture of formic acid–triethyl-
amine 5:2 (2.5 mL) were added under argon at room temperature.
The brown-red mixture was stirred for 5 days. The solvent was re-
moved under reduced pressure, 2 M sodium hydroxide (10 mL)
was added, and the mixture was extracted with diethyl ether
(2 ꢁ 40 mL). The extract was washed with water (10 mL), saturated
brine (5 mL), and dried with anhydrous magnesium sulfate. The
product was isolated by distillation 0.95 g, 58% yield, bp 66–
68 °C/1 mmHg. An analytical sample was purified by preparative
4.9. 1-(2-Benzofuryl)-2-(morpholin-4-yl)ethanone 7
Prepared from 1-(2-benzofuryl)-2-bromoethanone and mor-
pholine in diethyl ether, room temperature, 4 h, 59% yield, mp
101–103 °C (from diethyl ether). Lit.38 mp 101.5 °C. 1H NMR
(300 MHz, CDCl3) d 2.65 (dd, J = 3.6, 1.8 Hz, 4H, CH2), 3.80 (dd,
J = 4.8, 1.8 Hz, 4H, CH2), 3.81 (s, 2H, CH2N), 7.32 (ddd, J = 7.8, 6.9,
1.5 Hz, 1H, CH), 7.49 (ddd, J = 7.8, 7.4, 1.5 Hz, 1H, CH), 7.58 (ddd,
J = 7.8, 1.8, 1.2 Hz, 1H, CH), 7.69 (d, J = 0.9 Hz, 1H, CH), 7.72 (ddd,
J = 7.8, 1.8, 0.9 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3) d 53.84
(2CH2N), 64.55 (CH2N), 66.75 (2CH2O), 112.39 (CH), 113.54 (CH),
123.35 (CH), 123.96 (CH), 126.82 (C), 128.43 (CH), 151.59 (C),
155.44 (C), 187.41 (CO).
gas chromatography, ½a D28
ꢂ
¼ ꢀ72:3 (c 1.536, MeOH). Lit.41 (S)-iso-
mer, ½a 2D1
¼ þ74:8 (c 0.95, MeOH). GC analysis on a chiral column
ꢂ
Supelco Beta-DEX 325, 30 m, 0.25 mm, isotherm 105 °C, 97% ee, tR
44.5 R, 45.9 S. The racemate was also analyzed. 1H NMR (300 MHz,
CDCl3) d 2.35 (s, 6H, CH3), 2.37 (dd, J = 12.2, 3.8 Hz, 1H, CH2N), 2.49
(dd, J = 12.2, 10.2 Hz, 1H, CH2N), 3.95 (br s, 1H, OH), 4.69 (dd,
J = 10.2, 3.8 Hz, 1H, OCH), 7.20–7.40 (m, 5H, CH). 13C NMR
(75 MHz, CDCl3)
d 45.21 (CH3), 67.54 (NCH2), 69.48 (OCH),
125.75 (2CH), 127.27 (CH), 128.16 (2CH), 142.28 (C).
4.10. 1-(2-Furyl)-2-(dimethylamino)ethanone 8
4.15. (R)-(ꢀ)-2-(Diethylamino)-1-(phenyl)ethanol 2a
Prepared from 1-(2-furyl)-2-bromoethanone and dimethyl-
amine in diethyl ether, 0 °C, 10 min, room temperature, 30 min,
46% yield, bp 58–59 °C/0.20 mmHg. 1H NMR (300 MHz, CDCl3)
d 2.37 (s, 6H, CH3), 3.62 (s, 2H, CH2), 6.52 (dd, J = 1.8, 3.6 Hz,
1H, CH), 7.30 (dd, J = 0.9, 3.6 Hz, 1H, CH), 7.57 (dd, J = 0.9,
1.8 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3) d 45.69 (CH3), 64.72
(CH2), 112.00 (HCAr), 117.49 (HCAr), 146.21 (HCAr), 151.70 (C),
185.97 (CO). MS (EI, 70 eV) m/z: 153 (M+, 2), 112 (16), 95 (30),
58 (100). HRMS (EI): [M+], found 153.0783, C8H11NO2 requires
153.0790.
Yield 73%, bp 76–78 °C/1 mmHg, ½a D25
¼ ꢀ79:0 (c 1.28, MeOH),
ꢂ
Lit.41 (S)-isomer, ½a 2D5
¼ þ81:0 (c 1.03 MeOH) >99% ee. GC analysis
ꢂ
on a chiral column Supelco Beta-DEX 325, 30 m, 0.25 mm, iso-
therm 110 °C, 98% ee. tR 79.5 S, 81.1 R. Racemate was also analyzed.
1H NMR (300 MHz, CDCl3) d 1.07 (t, J = 7.2 Hz, 6H, CH3), 2.44 (dd,
J = 12.6, 10.5 Hz, 1H, CH2N), 2.59 (dq, J = 13.2, 7.2 Hz, 2H, 2CH2),
2.63 (dd, J = 12.6, 3.6 Hz, 1H, CH2N), 2.73 (dq, J = 13.2, 7.2 Hz, 2H,
2CH2), 4.31 (br s, 1H, OH), 4.63 (dd, J = 10.5, 3.6 Hz, 1H, OCH),
7.24–7.39 (m, 5H, CH). 13C NMR (75 MHz, CDCl3) d 11.93 (2CH3),
46.79 (2CH2), 61.76 (CH2N), 69.14 (OCH), 125.71 (2CH), 127.20
(CH), 128.17 (2CH), 142.62 (C).
4.11. 1-N,N-Diethylamino-2-propanone 9
Prepared from chloroacetone and diethylamine in diethyl ether,
reflux 24 h, 65% yield, bp 155–157 °C/760 mmHg. Lit.39 bp 154–
158 °C/760 mmHg. 1H NMR (200 MHz, CDCl3) d 1.01 (t, J = 7.2 Hz,
6H, CH3), 2.15 (t, J = 0.4 Hz, 3H, CH3), 2.53 (q, J = 7.2 Hz, 4H, CH2),
3.80 (s, 2H, CH2N). 13C NMR (50 MHz, CDCl3) d 11.88 (2CH3),
27.36 (CH3), 48.04 (2NCH2), 63.89 (CH2N), 209.13 (CO).
4.16. (R)-(ꢀ)-1-Phenyl-2-(pyrrolidin-1-yl)ethanol 3a
Yield 57%, mp 72–73 °C (from n-hexane). ½a D27
¼ ꢀ41:0 (c 1.80,
ꢂ
EtOH). Lit.41 (S)-isomer, mp 75 °C, ½a 2D7
¼ þ43:8 (c 0.96, MeOH),
ꢂ
99% ee. Lit.14 (R)-isomer, mp 69.5–70.5 °C, ½a 2D0
¼ ꢀ40:3 (c 1.88,
ꢂ
EtOH), 95% ee. GC analysis on a chiral column Supelco Beta-DEX
325, 30 m, 0.25 mm, isotherm 130 °C, 97% ee, tR 67.3 R, 69.2 S. 1H
NMR (300 MHz, CDCl3) d 1.81 (m, 4H, 2CH2), 2.48 (dd, J = 12.3,
3.3 Hz, 1H, CH2), 2.50–2.60 (m, 2H, CH2), 2.77 (m, 2H, CH2), 2.79
(dd, J = 12.3, 10.5 Hz, 1H, CH2), 4.07 (br s, 1H, OH), 4.71 (dd,
J = 10.5, 3.3 Hz, 1H, OCH), 7.25–7.45 (m, 5H, CH). 13C NMR
(75 MHz, CDCl3) d 23.63 (2CH2), 53.79 (2CH2), 64.06 (CH2), 70.64
(OCH), 125.83 (2CH), 127.37 (CH), 128.25 (2CH), 142.42 (C).
4.12. 2-(Dibenzylamino)-1-phenylethanone 10
Prepared from 1-phenyl-2-bromoethanone and dibenzylamine
in benzene, reflux 24 h, 41% yield, mp 78–79 °C (from n-hexane).
Lit.40 mp 79–81 °C. 1H NMR (300 MHz, CDCl3) d 3.78 (s, 4H CH2),
3.85 (s, 2H, CH2), 7.22–7.56 (m, 13H, CH), 7.83 (d, J = 7.2 Hz, 2H,
CH). 13C NMR (75 MHz, CDCl3) d 58.319 (CH2N), 59.23 (2CH2),
127.16 (CH), 128.26 (CH), 128.30 (CH), 128.70 (CH), 129.12 (CH),
133.01 (CH), 136.10 (C), 138.79 (C), 198.93 (CO).
4.17. (R)-(ꢀ)-1-Phenyl-2-(piperidin-1-yl)ethanol 4a
Yield 63%, mp 83–84 °C (from n-hexane), ½a D29
ꢂ
¼ ꢀ80:5 (c 1.05,
ꢂ ¼ þ81:4 (c 1.0,
4.13. 1-(3,4-Dimethoxyphenyl)-2-(dimethylamino)ethanone 11
CHCl3). Lit.41 mp 84–84.5 °C. Lit.42 (S)-isomer, ½a 2D5
CHCl3). GC analysis on a chiral column Supelco Beta-DEX 325,
30 m, 0.25 mm, isotherm 140 °C, 99% ee, tR 63.0 R, 64.7 S, 99% ee.
Racemate was also analyzed. 1H NMR (200 MHz, CDCl3) d 1.50
(quintet, J = 5.6 Hz, 2H, CH2), 1.60–1.75 (m, 4H, 2CH2), 2.39 (dd,
J = 12.6, 10.2 Hz), 1H, CH2N), 2.30–2.50 (m, 2H, CH2), 2.50 (dd,
J = 12.6, 4.0 Hz, 1H, CHN), 2.60–2.80 (m, 2H, CH2), 3.95 (br s, 1H,
OH), 4.72 (dd, J = 10.2, 4.0 Hz, 1H, OCH), 7.20–7.40 (m, 5H, CH).
13C NMR (50 MHz, CDCl3) d 24.26 (CH2), 26.11 (2CH2), 54.45
(CH2N), 66.90 (CH2N), 68.65 (OCH), 125.83 (2CH), 127.32 (CH),
128.26 (2CH), 142.49 (C).
Prepared from 1-(3,4-dimethoxyphenyl)-2-bromoethanone and
dimethylamine in diethyl ether, 3.5 h, room temperature, 55%
yield, hydrochloride hydrate, mp 98–100 °C. Lit.33 mp 100 °C. 1H
NMR (200 MHz, CDCl3) d 2.37 (s, 6H, CH3), 3.72 (s, 2H, CH2),
3.924 (d, J = 0.2 Hz, 3H, OCH3), 3.930 (d, J = 0.2 Hz, 3H, OCH3),
6.86 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.2,
2.2 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3) d 45.72 (NCH3), 55.97
(OCH3), 56.03 (OCH3), 65.30 (CH2), 110.09 (CH), 110.53 (CH),
122.80 (CH), 129.38 (C), 149.10 (C), 153.44 (C), 195.40 (CO).