Chiral α-alkylation/arylation in 1-phenyl-2-(1-pyrrolidinyl)-1-propanol through Grignard reactions

Article abstract of DOI:10.1016/j.tetasy.2009.11.019

Complete asymmetric induction has been achieved during Grignard alkylations/arylations resulting in (1S,2R)- and (1R,2R)-1-phenyl-1-alkyl/aryl-2-(1-pyrrolidinyl)-1-propanols which are isolated as hydrochlorides.

Full text of DOI:10.1016/j.tetasy.2009.11.019

Tetrahedron: Asymmetry 20 (2009) 2773–2779
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral
a-alkylation/arylation in 1-phenyl-2-(1-pyrrolidinyl)-1-propanol through
Grignard reactions
Borkatte N. Hitesh Kumar a,b, Velayudham Murugesan b, Tangirala Prakasam a, Pathangi S. Srinivasan a,
Devalla V. Ramana a,
*
a Research and Development Centre, Malladi Drugs and Pharmaceuticals Ltd No. 788/1, Irulapalayam, Kuthambakkam 602 107, India
b Department of Chemistry, College of Engineering, Guindy, Anna University, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Complete asymmetric induction has been achieved during Grignard alkylations/arylations resulting in
(1S,2R)- and (1R,2R)-1-phenyl-1-alkyl/aryl-2-(1-pyrrolidinyl)-1-propanols which are isolated as
hydrochlorides.
Received 6 August 2009
Accepted 24 November 2009
Available online 6 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
liberated from the hydrochloride salt (Scheme 2). The specific rota-
tion of the hydrochloride of the ketone was +64.6. The various
Ephedrine, (1R,2S)-(ꢀ)-1-phenyl-2-methylamino-1-propanol,
pseudoephedrine and (1S,2S)-(+)-1-phenyl-2-methylamino-1-pro-
panol are used in the pharmaceutical industry as decongestants,
analgesics, bronchodilators and mydriatics.1 The ketone, (R)-(+)
ephedrone, obtained upon oxidation of (1S,2R)-ephedrine contains
one stereogenic carbon at the b-position. Suter and Weston have
compounds prepared using these Grignard reactions are given in
Table 1.
The physical properties of all the 1-phenyl-1-alkyl/aryl-2-(1-
pyrrolidinyl)-1-propanol hydrochlorides are reported in Table 2.
It can be observed that all the synthesised alkyl/arylpropanol
hydrochlorides are found to be laevo-rotatory except for the
prepared racemic ephedrone hydrochloride and obtained
a
-alkyl-
a-phenylethyl and naphthyl derivatives which are found to be
ephedrines via Grignard reactions of the keto function.2 These
authors observed, on physiological studies of these racemic
dextro-rotatory. During Grignard synthesis with 1-phenyl-2-(1-
pyrrolidinyl)-1-propanone, asymmetry is expected to be induced
at the reaction site due to the presence of a stereogenic carbon at
the b-position with respect to the phenyl ring.
a-alkylephedrines, that the presence of an alkyl group at the
-position of ephedrine lowers the toxicity without significant loss
a
of therapeutic activity. The
these authors are racemic mixtures. Herein we report the prepara-
a
-alkylated ephedrines studied by
Chiral induction during Grignard reactions has been reported
during the synthesis of 1,2-diphenyl-3-methyl-4-dimethylamino-
2-butanol.3,4,5
tion of chiral
a-alkylated/arylated ephedrine derivatives from opti-
cally active
(R)-(+)-1-phenyl-2-(1-pyrrolidinyl)-1-propanone
through Grignard reactions. These newly obtained a-alkylated/ary-
3. Stereochemical aspects
lated ephedrine derivatives are expected to exhibit manifold phar-
maceutical activities with lesser toxicity, as is well established in
the case of active pharmaceutical ingredients.3–5
The expected asymmetric induction at the a-carbon of the Grig-
nard reaction product leads to one of the possible diastereomers.
The absolute configuration of the new stereogenic centre formed
through the Grignard reaction can be predicted with the help of
Cram’s rule7 as applied to the Grignard synthesis of 1-phenyl-1-
ethyl-2-(1-pyrrolidinyl)-1-propanol (Scheme 3) and also by exper-
imental analogy (Scheme 6).
It should be noted that at carbon-1, where asymmetry is in-
duced, the absolute configuration, as inferred by Cram’s rule, is
‘S’ and the product is an erythro isomer. The enantiomeric purity
of this Grignard product is 100% as observed from the HPLC
chromatogram using a chiral column with a retention time of
5.43 (Table 3). The driving force for the exclusive formation of
the erythro isomer appears to be the ability of the magnesium cat-
ion of the Grignard reagent to complex with the electron-rich
2. Results and discussion
(1S,2R)-(+)-1-Phenyl-2-aminopropanol-16 was treated with 1,4-
dibromobutane in the presence of sodium carbonate to obtain
(1S,2R)-(+)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol. The pyrrolidi-
nyl compound was oxidised to the corresponding ketone isolated
as the hydrochloride (Scheme 1). All Grignard reactions have been
performed with the ketone, (R)-(+)-1-phenyl-2-(1-pyrrolidinyl)-1-
propanone. The Grignard reactions were carried out with the base
* Corresponding author. Tel.: +91 44 26812221; fax: +91 44 22330914.
E-mail address: dvramana@malladi.co.in (D.V. Ramana).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.019

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B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
O
H
HO
N
N
C
[O]
.HCl
.HCl
(S)
(R)
CH3
(R)
H
H
CH3
(1S,2R)-(+)-1-Phenyl-2-(1-pyrrolidinyl)-1-
(R)-(+)-1-Phenyl-2-(1-pyrrolidinyl)-1-
propanone hydrochloride
propanol hydrochloride
Scheme 1.
O
HO
R
N
1. RMgBr
N
C
.HCl
*
in dry ether
(R)
CH3
H
H
(R)
CH3
2. aq.NH4Cl
3. dry HCl
α-Alkylated/arylated-1-phenyl-2-(1-
pyrrolidinyl)-1-propanol hydrochloride
(R)-(+)-1-Phenyl-2-(1-pyrrolidinyl)-1-
propanone
Scheme 2. (*Absolute configuration to be ascertained)
Table 1
It was observed that the Grignard products formed from the
enantiomeric ketones are mirror images as can be expected. The
stereochemical consequence of the Grignard product from (SR)-
( )-1-phenyl-2-(1-pyrrolidinyl)-1-propanone is given in Scheme 5.
Similar observations were also made in the case of benzyl, phen-
ethyl and 1-naphthyl in Grignard reagents Table 3.
List of Grignard products prepared and isolated as hydrochlorides
Compound No.
R
1
2
3
4
5
6
7
8
9
Methyl
Ethyl
2-Propyl
1-Butyl
2-Methylpropyl
Benzyl
Phenylethyl
3-Methoxyphenyl
1-Naphthyl
In order to provide an additional evidence for the proposed (S)-
configuration at carbon-1 in the Grignard product through chemi-
cal analogy, the Grignard alkylations of (R)- and (S)-1-phenyl-2-
methylamino-1-propanone8 with methylmagnesium bromide
have been undertaken. The specific rotation, enantiomeric purities
and ee values of the Grignard products are shown in Table 4. It can
be seen that the Grignard products obtained from the (2S)- and
(2R)- ketones are mirror images as shown by their specific rota-
tions. The configurations at carbon-1 in (1S,2R) and (1R,2S) Grig-
nard products have been inverted (Walden) via reported
procedures,9 the results of which are given in Table 4. It can again
be noticed that the two Walden-inverted products are mirror
images as shown by their specific rotations. These two products
will have (1R,2R) and (1S,2S) configurations (Scheme 6). Hence,
the configuration at carbon-1 of the Grignard products can be con-
cluded to be (S) which matches with the configuration inferred
through molecular modelling.
The Walden inversion with 1-phenyl-1-methyl-2-(1-pyrrolidi-
nyl)-1-propanol cannot be performed because of the requirement
of a hydrogen on the amino function for the procedure adopted
for the Walden inversion.9 Hence the absolute configuration at
carbon-1 of the Grignard products has been inferred as (S) by
drawing an analogy from the N-methyl compounds (Scheme 6).
In order to ascertain that the chirality at carbon-2 remains unaf-
fected during the oxidation of the hydroxyl group at carbon-1, the
(1S,2R)-(+)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol and its (1R,2R)
-isomer10 were oxidised under the same conditions. The two
oxidised products show nearly same specific rotations (Table 5)
with very high ee values.
carbonyl oxygen and nitrogen serving as bidentate ligands. This
complexation (Schemes 3 and 4) freezes the conformation of the
ketone, facilitating attack of the alkyl/aryl anions of the Grignard
reagent from the less hindered side leading to the exclusive forma-
tion of the Grignard product with an (S)-configuration at carbon-1.
The preferred diastereomer of the Grignard product is erythro-
(1S,2R)-(ꢀ)-1-phenyl-1-ethyl-2-(1-pyrrolidinyl)-1-propanol.
In order to derive additional evidence towards the absolute con-
figuration at carbon-1 in the Grignard product, the Grignard reac-
tions using ethyl magnesium bromide with (S)-(ꢀ)-1-phenyl-2-(1-
pyrrolidinyl)-1-propanone and the corresponding (SR)-ketone
were also carried out. Scheme 4 shows that the attack of the
C2H5 anion from the least hindered side as per the Cram’s rule pro-
vides the erythro-(1R,2S)-(+)-1-phenyl-1-ethyl-2-(1-pyrrolidinyl)-
1-propanol hydrochloride with the (S)-(ꢀ)-ketone.
Table 2
Physical properties of 1-phenyl-1-alkyl/aryl-2-(1-pyrrolidinyl)-1-propanol hydro-
chlorides (compounds 1–9)
½ ꢁ
a 2D5
Compound
Melting
point (°C)
Yield
(%)
Purity by
HPLC (%)
Enantiomeric
purity %
1
2
3
4
5
6
7
8
9
193–195
214–218
208–210
194–198
194–196
228–232
200–202
210–212
268–270
64
74
74
77
51
55
60
73
57
99.5
99.5
98.9
96.0
99.5
96.0
98.0
97.2
99.5
ꢀ12.5
ꢀ18.4
ꢀ6.6
100
100
100
100
100
100
100
100
100
4. Conclusion
ꢀ9.1
(R)-(+)-1-Phenyl-2-(1-pyrrodinyl)-1-propanone has been alkyl-
ated/arylated via a Grignard addition. During these reactions, the
C-1 carbon, the reaction centre experiences near total chiral induc-
tion. The driving force for this observation can be attributed to the
fact that magnesium cation, both in the reactant and in the prod-
ꢀ6.9
ꢀ71.8
+29.2
ꢀ58.4
+135.3

B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
2775
BrMg
O
CH3
H
H
BrMg
O
HO
N
H
C2H5
C2H5
N
N
C H
N
(R)
C2H5
C
O
CH3
CH3
CH3
(Least hindered side)
CH3
CH3
N
C
H
.HCl
N
C
C
H
(R)
(R)
dry HCl
HO
C
C2H5
HO
C2H5
(S)
(S)
erythro-(1S,2R)-(−)-1-Phenyl-1-ethyl-2-
(1-pyrrolidinyl)-1-propanol hydrochloride
or
BrMg
MgBr
O
H5C2
O
H5C2
OH
(R)
C
N
N
H
C
(S)
N
H
(R)
C
C
C
H
CH3
CH3
CH3
C2H5
CH3
CH3
N
C
H
H5C2
.HCl
N
C
H
OH
(R)
C
(R)
(R)
C2H5
CH3
H
C
(S)
HO
C
C2H5
(S)
HO
C
(S)
dry HCl
N
erythro-(1S,2R)-(−)-1-Phenyl-1-ethyl-2-
(1-pyrrolidinyl)-1-propanol hydrochloride
Scheme 3.
Table 3
Retention times with optical purities of (S,R), (R,S) and (S,R and R,S) isomers of 1-phenyl-1-alkyl- and (1-naphthyl)-2-(1-pyrrolidinyl)-1-propanol hydrochloride given in
parentheses
Compound Alkyl group (1S,2R)-isomer
(1R,2S)-isomer
(1SR,2RS)-racemic mixture
Retention time, ½a D25
ꢁ
, (enantiomeric purity %) Retention time, ½a D25
ꢁ
, (enantiomeric purity %)
½ ꢁ
a 2D5
Retention time, (enantiomeric purity %)
2
6
7
Ethyl
5.43
5.19
5.58
(47)
5.13
(53)
0
0
0
ꢀ18.44
(100)
6.23
ꢀ71.7
(100)
5.01
+17.8
(100)
4.51
+69.2
(97)
Benzyl
Phenethyl
6.31
(51)
4.52
(49)
4.62
5.03
(48)
4.59
(52)
+29.92
(100)
ꢀ29.2
(100)
9
1-Naphthyl 6.63 (1S, 2S) isomer
7.14 (1R, 2R) isomer
ꢀ132.0
6.63
(50)
7.21
(50)
0
+135.3
(100)
(100)
uct, complexes with the nitrogen of the pyrrolidinyl moiety and
the carbonyl oxygen forcing the formation of a particular diaste-
reomer. These alkylated/arylated compounds are expected to re-
veal higher therapeutic values with reduced toxicity.

2776
B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
BrMg
O
CH3
C
MgBr
H
H
O
C2H5
N
H
N
O
(S)
N
C2H5
C
CH3
CH3
CH3
C
CH3
H
C2H5
OH
N
H
N
H
C
N
(S)
(S)
dry HCl
C2H5
C
OH
.HCl
C2H5
C
OH
(R)
(R)
CH3
erythro-(1R,2S)-(+)-1-Phenyl-1-ethyl
-2-(1-pyrrolidnyl)-1-propanol hydrochloride
or
MgBr
-
O
O
C2H5
H5C2
OH
C
H5C2
MgBr
N
H
H
C
(R)
H
N
C
C
C
C
(S)
N
(S)
CH3
CH3
CH3
CH3
CH3
H5C2
CH3
N
OH
(S)
H
C
C
N
H
C
N
dry HCl
(S)
(S)
(R)
C2H5
OH .HCl
(R)
C2H5
C
OH
H
(R)
erythro-(1R,2S)-(+)-1-Phenyl-1-
ethyl-2-(1-pyrrolidinyl)-1-propanol
hydrochloride
Scheme 4.
CH3
CH3
H
C
N
N
C
C
H
O
(S)
(R)
Grignard
reaction
C2H5
C
(R)
OH
C
CH
CH3
N
HO
C2H5
)
(S
(SR)-( )-1-Phenyl-2-
(1-pyrrolidinyl)-1-propanone
erythro-(1S,2R)-(-)-1-Phenyl-1-
ethyl-2-(1-pyrrolidinyl)-1-propanol
erythro-(1R,2S)-(+)-1-Phenyl-1-
ethyl-2-(1-pyrrolidinyl)-1-propanol
dry HCl
mixture of enantiomeric erythro-isomers
as hydrochlorides
Scheme 5.

B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
2777
Table 4
(0.107 mol) of sulfuric acid was added dropwise at 15–20 °C. Next,
12.5 g (0.04 mol) of sodium dichromate dissolved in 12.5 mL of
water was added to the reaction mass over a period of 20 min.
While maintaining the temperature between 15 and 20 °C, the
reaction mass was stirred for 12 h at the same temperature. To this
reaction mixture, 10 mL of water and 25 mL of toluene were added
while maintaining the temperature at 5 °C. The pH of the mixture
was adjusted to 10.5 by adding 50% of sodium hydroxide and the
temperature was kept below 20 °C. The undissolved chromate salts
were filtered through hyflo and the salts were washed with 10 mL
of toluene. The organic layer was separated from the filtrate and
washed with 20 mL of water. The organic layer was acidified with
dilute hydrochloric acid to a pH of 2.0. The product was extracted
into the aqueous layer which was concentrated under reduced
pressure, until an oily residue was obtained. Acetone (25 mL)
was added to the residue, when (+)-1-phenyl-2-(1-pyrrolidinyl)-
1-propanone hydrochloride crystallised. The mixture was cooled
further and the crystals were filtered to obtain the keto-product.
8.4 g (84%): HPLC purity 99.64%; mp (acetone): 182–84 °C;
Physical properties of the stereoisomers of 1-phenyl-1-methyl-2-methylamino-1-
propand hydrochloride
½ ꢁ
a 2D5
Compound
Melting
point
(°C)
Enantiomeric
purity by HPLC
(%)
ee (%)
(2%,
H2O)
(1S,2R)-1-Phenyl-1-
methyl-2-
methylamino-1-
propanol
(1R,2S)-1-Phenyl-1-
methyl-2-methylamino
-1-propanol
(1R,2R)-1-Phenyl-1-
methyl-2-methylamino
-1-propanol
210–214
99.92
+15.6
99.84
210–213
98.52
ꢀ16.5
97.92
263–
265
100.00
ꢀ54.15 100.00
(1S.2S)-1-Phenyl-1-
methyl-2-
methylamino-1-
propanol
260–263 100.00
+53.15 100.00
½
a 2D5
ꢁ
¼ þ64:6 (c 1.0, H2O).
Table 5
Physical properties of stereoisomers of 1-phenyl-2-(1-pyrrolidinyl)-1-propanone
hydrochloride
5.2. General procedure for the Grignard reactions of (+)-1-phe
nyl-2-(1-pyrrolidinyl)-propanone-1 with alkyl/ aryl magnesium
bromides
½ ꢁ
a 2D5
Compound
Oxidised from
Melting Purity
ee
point
by
(°C)
HPLC
(%)
The Grignard reagents (alkyl/aryl magnesium bromides in
ether) were prepared from 0.14 mol of magnesium in 25 mL of
diethyl ether and 0.14 mol of alkyl/ aryl bromide. To a stirred solu-
tion of the Grignard reagent in ether, (+)-1-phenyl-2-(1-pyrrolidi-
nyl)-propanone-1 base (prepared from 10.0 g, 0.04 mol of the
hydrochloride salt of the ketone and sodium hydroxide solution)
in 25 mL of ether was added slowly keeping the temperature be-
tween 20 and 25 °C. The reaction mixture was stirred for 12 h at
20–25 °C. The progress of the reaction was monitored by TLC.
The reaction mixture was quenched, at the end of the reaction,
with 20 mL of saturated solution of ammonium chloride in water
keeping the temperature below 20 °C. The ether layer was sepa-
rated, dried over anhydrous sodium sulfate and concentrated un-
der reduced pressure to yield an oil. The oily product was
dissolved in 20 mL of acetone and was acidified to a pH of 2.0–
3.0 by bubbling dry HCl gas. The precipitated product was filtered,
washed with acetone and recrystallised from 2-propanol.
(R)-1-Phenyl-2-
(1-
pyrrolidinyl)-
1-propanone
(S)-1-Phenyl-2-
(1-
pyrrolidinyl)-
1-propanone
(R)-1-Phenyl-2-
(1-
pyrrolidinyl)-
1-propanone
(RS)-1-Phenyl-2-
(1-
(1S,2R)-1-Phenyl-
2-(1-pyrrolidinyl)-
1-propanol
182–
184
100
100
99.0
99.0
+64.6 99.47
ꢀ62.4 97.92
+62.9 99.70
(1R,2S)-1-Phenyl-
2-(1-pyrrolidinyl)-
1-propanol
182–
185
(1R,2R)-1-Phenyl-
2-(1-pyrrolidinyl)-
1-propanol
181–
184
(1SR,2RS)-1-
Phenyl-2-(1-
pyrrolidinyl)-1-
propanol
182–
185
0
—
pyrrolidinyl)-
1-propanone
5. Experimental
5.1. Oxidation of (+)-1-Phenyl-2-(1-pyrrolidinyl)-1-propanol
5.3. General procedure for Walden inversion
To a solution of 10 g (0.04 mol) of (1S,2R)-(+)-1-phenyl-2-(1-
pyrrolidinyl)-1-propanol hydrochloride in 30 mL of water, 10.5 g
(1S,2R)- and (1R,2S)-erythro-1-Phenyl-1-methyl-2-methylamino-
1-propanol hydrochloride 5 g (0.0232 mol) and 12.0 mL of acetic
(1S,2R)-1-Phenyl-2-methylamino-1-propanol
Mirror Image
(1R,2S)-1-Phenyl-2-methylamino-1-propanol
Oxidation
Oxidation
Mirror Image
(R)-1-Phenyl-2-methylamino-1-propanone
(S)-1-Phenyl-2-methylamino-1-propanone
Grignard reaction
Grignard reaction
Mirror Image
(1S,2R)-1-Phenyl-1-methyl-2-methylamino-1-propanol
(1R,2S)-1-Phenyl-1-methyl-2-methylamino-1-propanol
Walden inversion
Walden inversion
Mirror Image
(1S,2S)-1-Phenyl-1-methyl-2-methylamino-1-propanol
(1R,2R)-1-Phenyl-1-methyl-2-methylamino-1-propanol
Scheme 6.

2778
B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
anhydride were heated to 120–130 °C for 1 h. The reaction mass
was concentrated under reduced pressure to yield an oil. To the oily
residue, 20 mL of 10% hydrochloric acid was added and heated at
reflux for 3 h. The reaction mass was concentrated under reduced
pressure to yield an oily residue, which was triturated with acetone
to obtain a white precipitate. The precipitated product was filtered
and washed with acetone to obtain (1R,2R)- and (1S,2S)-threo-1-
phenyl-1-methyl-2-methylamino-1-propanol hydrochlorides.
1H NMR (300 MHz, CDCl3) dH 0.82 (t, 3H, CH2–CH3), 1.25 (d,
J = 6.4 Hz, 3H, CH–CH3), 1.38 (m, 2H, CH2–CH3), 1.64 (m, 1H, HO–
C–CH1H2), 1.90 (m, 1H, HO–C–CH1H2, H1 and H2 are diastereotopic
þ
protons), 2.00–2.31 (m, 7H,þ NH–CH2–CH2–CH2, –CH2–CH2–CH3,
þ
NH–CHe), 3.02 (m, 2H, HþaC–NH–CHa), 4.06 (q, J = 6.6 Hz, 1H, CH–
CH3), 4.34 (m, 1H, HeC-NH), þ5.69 (br s, 1H, OH), 7.27–7.60 (m,
5H, Harom), 10.30 (br s, 1H, N–H); 13C NMR (300 MHz, CDCl3) dc
9.4, 14.1, 22.9, 23.9, 25.0, 25.5, 38.8, 48.6, 56.5, 70.5, 77.2, 126.8,
127.4, 128.4, 139.9; MS (EI) m/z (rel. intens.) 261 (M+), 98 (100),
56 (6). Anal. Calcd for C17H27NOꢂHCl: C, 68.55; H, 9.47; N, 4.70.
Found: C, 69.12; H, 9.48; N, 4.63. The ee was determined by CSP
HPLC to be 100% (Chiralpak AD-H, 1% n-hexane/2-propanol/0.1%
dimethylamine, 1.0 mL/ min) tR (1S,2R) = 4.0 min (100%).
5.3.1. (1S,2R)-(ꢀ)-1-Phenyl-1-methyl-2-(1-pyrrolidinyl)-1-pro
panol hydrochloride 1
Compound 1 (6.76 g, 63.8%): ½a D25
ꢁ
¼ ꢀ12:5 (c 1.0, H2O); mp (2-
þ
propanol): 193–195 °C; IR (KBr, cmꢀ1): 3200 (OH), 2646 (N–H); 1H
NMR (300 MHz, DMSO-d6) dH 0.98 (d, J = 6.7 Hz, 3H, CH–CH3), 1.71
þ
5.3.5. (1S,2R)-(ꢀ)-1-Phenyl-1-(2-methylpropyl)-2-(1-pyrroli
(s, 3H, C(OH)–CH3), 1.75–1.87 (m, 4þH, NH–CH2–CH2–CH2), 2.90 (m,
þ
þ
dinyl)-1-propanol hydrochloride 5
1H, NH–CHe)11, 3.31 (m, 2H, HaC–N–CHa), 3.68 (m, 1H, HeC–NH),
Compound 5 (7.56 g, 51.2%): ½a D25
ꢁ
¼ ꢀ6:9 (c 1.0, H2O); mp (2-
þ
3.82 (q, J = 6. 5 Hz, 1H, CH3–CH), 6.10 (br s, 1H,OH), 7.25–7.52 (m,
þ
propanol) 194–196 °C; IR (KBr, cmꢀ1): 3292 (OH), 2716 (N–H);
1H NMR (300 MHz, DMSO-d6) dH 0.56 (d, 3H, CH3–CH–CH3), 0.89
(d, 3H, CH3–CH–CH3, the two methyl groups of the isobutyl func-
5H, Harom), 9.76 (br s, 1H, NH); 13C NMR (DMSO-d6): 8.6, 23.0,
24.4, 28.7, 48.5, 55.0, 67.0, 74.3, 125.3, 126.8, 127.9, 145.4; MS (CI,
CH3OH), m/z (rel. intens.): 220 (M+H+, 100), 202 (16), 98 (17). Anal.
Calcd for C14H21NOꢂHCl: C, 65.74; H, 8.67; N, 5.47. Found: C, 66.23;
H, 8.64; N, 5.50. The ee was determined by CSP HPLC to be 100%
(Chiralpak AD-H, 1% n-hexane/2-propanol/0.1% diethylamine, 1.0
mL/min) tR (1S,2R) = 6.4 min (100%).
tion appear to be diastereotopic), 1.06 (d, J = 6.2 Hz, 3H, HO–C–
þ
CH–CH3), 1.48 (m, 1H, H3C–CH–CH3), 1.80 (m, 4H, NH–CH2–CH2–
CH2–), 1.85 (d of d, J = 6.1, 1.0 Hz, 1H, HO–C–CH1H2–CH–CH3),
2.02 (d of d, J = 6.0, 1.2 Hz, 1H, HO–C–CH1H2–CH–CH3, H1 and H2
þ
are diastereþotopic protons), 2.48 (m, 1H, HeCHa–NH), 2.69 (m,
þ
1H, HeCHa–þNH–CHeHa–CH2), 3.14 (m, 1H, HeCHa–NH), 3.65 (m,
5.3.2. (1S,2R)-(ꢀ)-1-Phenyl-1-ethyl-2-(1-pyrrolidinyl)-1-propa
1H, HeCHa–NH–CHeHa), 3.78 (q, J = 6.3 Hz, 1H, –CH–CH3), 5.86 (br
þ
s, 1H, OH), 7.27–7.54 (m, 5H, Harom), 9.29 (br s, 1H, N–H); 13C
NMR (300 MHz, DMSO-d6) dc 8.6, 22.8, 23.6, 24.0, 24.2, 39.4,
46.3, 48.2, 55.5, 69.0, 77.2, 126.3, 127.0, 127.8, 141.5; MS(CI,
CH3OH) m/z (rel. intens.) 262 (M+H+, 100), 244 (10), 98 (11). Anal.
Calcd for C17H27NOꢂHCl: C, 68.55; H, 9.47; N, 4.70. Found: C, 68.20;
H, 9.50; N, 4.75. The ee was determined by CSP HPLC to be 100%
(Chiralpak AD-H, 1% n-hexane/2-propanol/0.1% dimethylamine,
1.0 mL/ min) tR (1S,2R) = 3.8 min (100%).
nol hydrochloride 2
Compound 2 (8.24 g, 73.6%): ½a D25
ꢁ
¼ ꢀ18:4 (c 1.0, H2O); mp (2-
þ
propanol) 214–218 °C; IR (KBr, cmꢀ1): 3271 (OH), 2718 (N–H); 1H
NMR (300 MHz, CDCl3) dH 0.77 (t, 3H, CH2–CH3) 1.25 (d, J = 6.5 Hz,
3H, CH–CH3), 1.68 (m, 1H, HO–C–CH1H2–CH3), 1.89 (m, 1H, HO–C–
CH1H2–CH3, H1 and H2 are diastereotopic protons), 2.02–2.36 (m,
þ
þ
5H, NH–CHe–CH2–CH2), 3.16 (m, 2H, HþaC–NH–CHa), 4.08 (q,
J = 6.4 Hz, 1H, HC–CH3), 4.33 (m, 1H, HeC–N), 5.63 (br s, 1H, OH),
þ
7.26–7.60 (m, 5H, Harom), 10.29 (br s, 1H, NH); 13C NMR (CDCl3)
dC 7.5, 9.4, 23.9, 25.5, 31.9, 48.7, 56.4, 70.3, 77.6, 126.9, 127.4,
128.4, 139.9; MS (EI) m/z (rel. intens.): 233 (M+), 98 (100), 56 (8).
Anal. Calcd for C15H23NOꢂHCl: C, 66.77; H, 8.96; N, 5.19. Found: C,
66.89; H, 8.85; N, 5.16. The ee was determined by CSP HPLC to be
100% (Chiralpak AD-H, 1% n-hexane/2-propanol/0.1% diethylamine,
1.0 mL/ min) tR (1S,2R) = 5.4 min (100%).
5.3.6. (1S,2R)-(ꢀ)-1-Phenyl-1-benzyl-2-(1-pyrrolidinyl)-1-propa
nol hydrochloride 6
Compound 6 (7.62 g, 55.2%): ½a D25
ꢁ
¼ ꢀ71:8 (c 1.0, H2O); mp (2-
þ
propanol) 228–232 °C; IR (KBr, cmꢀ1): 3183 (OH), 2675 (N–H);
1H NMR (300 MHz, CDCl3) dH 1.29 (d, J = 6.1 Hz, 3H, CH–CH3),
þ
þ
1.63–2.17 (m, 4H, NH–CH2–CH2–CH2), 2.58 (m, 1H, N H–CHe),
þ
þ
2.99 (m, 1H, NH–CHa), 3.21 (m, 1H, HaC–NH), 3.45 (d, 1H,
J = 1.5 Hz, HO–C–CH1H2–C6H5), 3.70 (d, 1H, J = 1.5 Hz, HO–C–
CH1H2–C6H5, H1 and H2 are diastereotopic protons), 4.12 (q,
5.3.3. (1S,2R)-(ꢀ)-1-Phenyl-1-(2-propyl)-2-(1-pyrrolidinyl)-1-
þ
þ
propanol hydrochloride 3
Compound 3 (10.37 g, 73.7%): ½a D25
ꢁ
¼ ꢀ6:6 (c 1.0, H2O); mp (2-
J = 6.3 Hz, NH–CH–CH3), 4.24 (m, 1H, HeC–NH), 4.99 (br s, 1H, C–
þ
OH), 7.08–7.52 (10H, m, Harom), 10.50 (br s, 1H, N–H); 13C NMR
(300 Hz, CDCl3) dc 9.6, 23.8, 25.4, 44.9, 48.9, 56.2, 69.1, 77.6,
126.5, 126.8, 127.7, 128.3, 131.0, 135.1, 140.2; MS(EI) m/z (rel. in-
tens.) 295 (M+), 98 (100), 56 (7). Anal. Calcd for C20H25NOꢂHCl: C,
72.38; H, 7.90; N, 4.22. Found: C, 72.14; H, 7.88; N, 4.26. The ee
was determined by CSP HPLC to be 100% (Chiralpak AD-H, 1% n-
hexane/2-propanol/0.1% dimethylamine, 1.0 mL/min) tR (1S,2R) =
6.2 min (100%).
þ
propanol) 208–210 °C; IR (KBr, cmꢀ1): 3276 (OH), 2703 (N–H); 1H
NMR (300 MHz, DMSO-d6) dH 0.67 (d, 3H, HO–C–CH–CHa ), 1.02 (d,
3
3H, HO–C–CH–CHb3, CH3a and CH3b are diastereotopic methyl groups),
1.28 (d, J = 6.3 Hz, 3H, CH–CH3), 1.62 (m, 1H, Ha C–CH–CHb), 1.73–
3
3
þ
þ
2.23 (m, 4H, NH–CH2–CH2–CH2), 2.34–2.52 (m, 2H, HaC–NH–CHe),
þ
þ
3.16 (m, 1H, H2C–NH–CHa), 3.74 (m, 1H, HeC–NH–CH2), 3.95 (q,
J = 6.4 Hz, 1H, HC–CH3), 5.85 (br s, 1H, OH), 7.36–7.64 (m, 5H, Har-
þ
om), 9.18 (br s, 1H, NH); 13C NMR (300 MHz, DMSO-d6) dc 8.1,
15.9, 17.3, 22.9, 24.4, 32.9, 47.8, 55.6, 66.7, 78.5, 126.8, 127.3,
127.9, 140.5; MS (CI,CH3OH), m/z (rel. intens.): 248 (M+H+, 100),
230 (8), 98 (14). Anal. Calcd for C16H25NOꢂHCl: C, 67.46; H, 9.55;
N, 4.91. Found: C, 67.74; H, 9.28; N, 4.98. The ee was determined
by CSP HPLC to be 100% (Chiralpak AD-H, 1% n-hexane/2-propa-
nol/0.1% diethylamine, 1.0 mL/min) tR (1S,2R) = 3.9 min (100%).
5.3.7. (1S,2R)-(+)-1-Phenyl-1-phenylethyl-2-(1-pyrrolidinyl)-1-
propanol hydrochloride 7
Compound 7 (8.68 g, 60.3%): ½a D25
ꢁ
¼ þ29:2 (c 1.0, H2O); mp (2-
þ
propanol) 200–202 °C; IR (KBr, cmꢀ1): 3275 (OH), 2656 (N–H);
1H NMR (300 MHz, CDCl3) dH 1.24 (d, J = 6.6 Hz, 3H, CH–CH3),
1.65 (m, 1H, HO–C–CH1H2–CH2–C6H5), 1.91 (m, 2H, HO–C–
CH1H2–CH2–C6H5), 2.01 (m, 1H, HO–C–CH1H2–CH2–C6H5, H1 and
þ
H2 are diastereotopic protons), 2.23 (m, 4H, NH–CH2–CH2–CH2),
5.3.4. (1S,2R)-(ꢀ)-1-Phenyl-1-butyl-2-(1-pyrrolidinyl)-1-propa
þ
þ
nol hydrochloride 4
2.62 (m, 1H, NH–CHe), 2.92 (m, 3H, HaHeC-NH-CHa), 4.12 (1H, q,
þ
Compound 4 (9.50 g, 76.6%): ½a D25
ꢁ
¼ ꢀ9:1 (c 1.0, H2O); mp (2-
J = 6.4 Hz, NH–CH–CH3), 6.08þ (br s, 1H, C–OH), 7.11–7.69 (10H,
þ
propanol) 194–198 °C; IR (KBr, cmꢀ1): 3316 (OH), 2644 (N–H);
m, Harom), 10.44 (br s, 1H, N–H), 13C NMR (300 MHz, CDCl3) dc

B. N. Hitesh Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 2773–2779
2779
9.3, 24.0, 25.6, 29.5, 40.9, 48.6, 56.6, 70.8, 77.1, 125.6, 127.0, 127.7,
128.2, 128.5, 128.6, 139.4, 142.3; MS(CI, CH3OH) m/z (rel. intens.)
310 (M+H+, 100), 293 (9), 98 (9). Anal. Calcd for C21H27NOꢂHCl: C,
72.92; H, 8.15; N, 4.05. Found: C, 73.13; H, 8.18; N, 4.06. The ee
was determined by CSP HPLC to be 100% (Chiralpak AD-H, 1% n-
CHe), 4.74 (q,þJ = 6.3 Hz, 1H, CH–CH3), 7.18–7.93 (m, 12H, Harom),
the OH and N–H protons have disappeared on exchange with D
from CF3COOD; 13C NMR (300 MHz, CDCl3+CF3COOD) dc 10.6,
23.2, 25.1, 50.6, 57.3, 67.7, 79.6, 123.3, 124.2, 126.3, 126.4, 126.6,
126.8, 128.7, 128.8, 129.5, 130.7, 131.3, 135.8, 136.5, 140.6; MS(CI,
CH3OH) m/z (rel. intens.) 332 (M+H+, 100), 315 (83), 233 (12), 98
(31). Anal. Calcd for C23H25NOꢂHCl: C, 75.08; H, 7.12; N, 3.81.
Found: C, 75.13; H, 7.21; N, 3.84. The ee was determined by CSP
HPLC to be 100% (Chiralpak AD-H, 1% n-hexane/ 2-propanol/0.1%
dimethylamine, 1.0 mL/ min) tR (1R,2R) = 7.1 min (100%).
hexane/2-propanol/0.1%
dimethylamine,
1.0 mL/min)
tR
(1S,2R) = 5.01 min (100%).
5.3.8. (1R,2R)-(ꢀ)-1-Phenyl-1-(3-methoxyphenyl)-2-(1-pyrroli
dinyl)-1-propanol hydrochloride 8
Compound 8 (10.38 g, 72.6%): ½a D25
¼ ꢀ58:4 (c 1.0, H2Oþ); mp (2-
ꢁ
propanol) 210–213 °C; IR (KBr, cmꢀ1): 3258 (OH), 2668 (N–H); 1H
NMR (300 MHz, DMSO-d6) dH 1.20 (d, J = 6.1 Hz, 3H, CH–CH3), 1.79
Acknowledgement
þ
þ
(m, 4H, NH–CH2–CH2–CH2), 3.02 (m, 1H, HeC–NH–CH2), 3.22–3.33
The authors thank Mr. K. Loganathan for analytical support ex-
tended during this investigation.
þ
(m, 3H, HaC–NH–CHaHe), 3.75 (s, 3H, C6H4–O–CH3), 5.00 (q,
J = 6.3 Hz, 1H, CH–CH3), 6.76 (br s, 1H, C6H5–C–OH), 6.83–7.56
þ
(m, 9H, Harom), 8.89 (br s, 1H, N–H); 13C NMR (300 MHz, DMSO-
d6) dc 11.7, 22.7, 22.9, 51.6, 54.8, 55.0, 65.2, 79.0, 111.8, 112.3,
118.0, 125.3, 126.7, 128.0, 129.4, 145.3, 146.5, 159.2; MS(CI,
CH3OH) m/z (rel. intens.) 312 (M+H+, 100), 295 (15), 98 (19). Anal.
Calcd for C20H25NO2ꢂHCl: C, 69.06; H, 7.48; N, 4.03. Found: C,
68.31; H, 7.74; N, 3.99. The ee was determined by CSP HPLC to
be 100% (Chiralpak AD-H, 1% n-hexane/2-propanol/0.1% dimethyl-
amine, 1.0 mL/ min) tR (1R,2R) = 7.9 min (100%).
References
1. The Merck Index, Monograph No. 7257 and 7279, Merck and Co.: Rahway, New
Jersey, USA, 1989, 1157 and 1160.
2. Suter, C. M.; Weston, A. W. J. Am. Chem. Soc. 1942, 64, 533–536.
3. Shelton, R. A. Chirotechnology: Industrial Synthesis of Optically Active Compounds;
Marcel Dakker: New York, 1993.
4. Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G. Angew. Chem., Int. Ed. 1999, 38, 1755–
1758.
5. Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G. Chirality 2002, 14, 534–540.
6. (1S,2R)- and (1R,2S)-1-Phenyl-2-amino-1-propanols were obtained from
Malladi Drugs & Pharmaceuticals Ltd, Chennai.
7. Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828–5835.
8. These ketones have been prepared through oxidation of the corresponding
(1S,2R)- and (1R,2S)-1-phenyl-2-methylamino-1-propanols which were
obtained from Malladi Drugs & Pharmaceuticals Ltd, Chennai.
9. DE 3230333.
10. The (1R,2R)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol was prepared from the
(1S,2R)-isomer through a process involving Walden inversion at C-1.
11. The pyrrolidinyl ring protons and carbons appear to be experiencing magnetic
anisotropy being in the vicinity of a chiral environment.
5.3.9. (1R,2R)-(+)-1-Phenyl-1-(1-naphthyl)-2-(1-pyrrolidinyl)-
1-propanol hydrochloride 9
Compound 9 (8.60 g, 56.6%): ½a D25
¼ þ135:25 (c 1.0, 7:3 of dim-
ꢁ
ethylacetimide and H2O); mp (7:3 of CH3OH and H2O) 268–270 °C;
þ
IR (KBr, cmꢀ1): 3124 (OH), 2784 (N–H); 1H NMR (300 MHz,
CDCl3+CF3COOD) dH 1.38 (d, J = 6.0 Hz, 3H, CH–CH3), 1.98 (m, 4H,
NH–CH2–CH2–CH2), 2.95 (m, 1H, HeC–NH–CH2), 3.23 (m, þ1H,
HaC–NH–CH2), 3.42 (m, 1H, H2C–NH–CHa), 4.16 (m, 1H, H2C–NH–
þ
þ
þ
þ