Remarkable enantioselective α-amination in 1-phenyl-2-(N-alkylamino)- 1-propanol

Article abstract of DOI:10.1002/chir.21996

(1R,2R)-1-Phenyl-1-alkyl/arylamino-2-(N-alkylamino)propane hydrochloride salts have been synthesized with high degree of enantiomeric purity from (1S,2R)-(+)-1-phenyl-2-(N-alkylamino)-1-propanol through the corresponding chloro derivatives. This reaction sequence involves three inversions with overall inversion of configuration at C-1. Copyright

Full text of DOI:10.1002/chir.21996

CHIRALITY 24:262–270 (2012)
Remarkable Enantioselective a-Amination in
1-Phenyl-2-(N-alkylamino)-1-propanol
BORKATTE N. HITESH KUMAR,1,2 VELAYUTHAM MURUGESAN,2 TANGIRALA PRAKASAM,1
1
PATHANGI S. SRINIVASAN,1 AND DEVALLA V. RAMANA
*
1Research and Development Centre, Malladi Drugs and Pharmaceuticals Ltd., No. 788/1, Irulapalayam, Kuthambakkam,
Chennai 602107, Tamil Nadu, India
2Department of Chemistry, College of Engineering, Guindy, Anna University, Chennai 600025, Tamil Nadu, India
ABSTRACT
(1R,2R)-1-Phenyl-1-alkyl/arylamino-2-(N-alkylamino)propane hydrochloride salts
have been synthesized with high degree of enantiomeric purity from (1S,2R)-(1)-1-phenyl-2-(N-
alkylamino)-1-propanol through the corresponding chloro derivatives. This reaction sequence
involves three inversions with overall inversion of configuration at C-1. Chirality 24:262–270,
C
VV
2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric 1,2-chloroamines; asymmetric 1,2-diamines; aziridinium chloride;
SN2 mechanism; 1-amino-2-N-tosylpropanes
INTRODUCTION
metric synthesis19 of Tamiflu which is a very important
anti-influenza drug containing a chiral 1,2-diamino function-
ality.
a-Amination reactions constitute an important class of
regiospecific and stereospecific substitution reactions as a
result of their impact in commercial applications. The prod-
ucts of a-amination such as diamines, triamines and their
derivatives have important applications such as chelating
agents in radiopharmaceuticals,1,2 precursors of aza-macro-
cycles3 and heterocycles in medicinal chemistry.4 They also
play a vital role as chiral auxiliaries in a variety of asymmetric
transformations involving chiral phosphonamides,5 Lewis
acids,6 metal enolates,7 dienophiles,8 and transition metal
reagents.9,10
Chiral 1-phenyl-1-methylamino-2-(1-pyrrolidinyl)propane is
synthesized20 from the corresponding 1-phenyl-2-amino-1-
propanol through the intermediacy of mesyloxy derivative.
Considering the enormous utility of the chiral 1,2-diamines,
the syntheses of several stereospecific and regiospecific
1,2-diamines are undertaken in this work from (1S,2R)-nor-
ephedrine through the corresponding chloro derivatives.
EXPERIMENTAL
General Remarks
The methods available for preparing vicinal diamines are
rather limited, particularly when other sensitive functional-
ities are present elsewhere in the molecule. Olefins react
with azide anions oxidatively to form vicinal diazides11,12
which on reduction afford diamines. But this method
requires careful selection of reductants to avoid possible
explosion. Iodoisocyanation of olefins followed by hydrolysis
results in the formation of aziridine which can be opened up
with ammonia to give vicinal diamines13 stereospecifically.
Cycloaddition of chlorosulphonylisocyanate to olefins fol-
lowed by Curtius rearrangement and hydrolysis of the result-
ing cyclic urea gives vicinal diamines.14 Reductive amination
of a-aminoketones, Michael addition of urethanes of dehy-
droalanine derivatives, reduction of a-aminonitriles and
a-aminoamides15 lead to vicinal diamines. Diamines are also
prepared from dienes through a Diels Alder adduct of sul-
phone bisimides15 and also from 1,3-diamino-2-propanols.1
A highly stereoselective and regioselective synthetic route
to a series of chiral diamines and triamines for use as ligands
in organocopper conjugate addition reactions has been devel-
oped with ephedrine and pseudoephedrine as starting amino-
alcohols by Dieter et al.16 Synthesis of stereospecific-substi-
tuted 1-pyrrolidinyl-2-benzylaminoethane has been achieved
starting from 1,2-diphenylethene.17
All reactions were carried out under nitrogen atmosphere unless other-
wise noted. Solvents are dried according to established procedures. Reac-
tions were monitored by thin layer chromatography (TLC). Optical rota-
tions were recorded on a Jasco DIP-370 digital polarimeter. Melting points
were measured on Scientific Melting Point Apparatus and were uncor-
rected. The chromatographic purity and enantiomeric excess (ee) values
were determined by using high performance liquid chromatography
(HPLC), Shimadzu LC-10ATVP and SPD-M10AVP. Infrared (IR) spectra
were recorded on a FTIR spectrometer Shimadzu IR Prestige 21.1H nuclear
magnetic resonance (NMR) spectra were recorded on Brucker Avance 300
MHz spectrometer, and 13C NMR spectra were recorded on Brucker
Avance 75 MHz using trimethylsilane as internal standard and hexadeuter-
ated dimethyl suphoxide (DMSO-d6) or deuterochloroform (CDCl3) unless
otherwise noted. Data are presented as follows: chemical shift, integration,
multiplicity (br s 5 broad singlet, s 5 singlet, d 5 doublet, t5 triplet, q 5
quartet, and m 5 multiplet). Mass spectra (MS) was measured using Agi-
lent Liquid Chromatograpy - Mass Spectra (LCMS) using chemical ionisa-
tion (CI) or Electro Spray Ionisation (ESI) as specified.
Typical procedure for the synthesis of 1-phenyl-2-(1-piperidinyl/
pyrrolidinyl)-1-propanol hydrochloride. To a solution of 0.66 mol of
1-phenyl-2-amino-1-propanol hydrochloride in 150 ml of water, 50%
sodium hydroxide was added to attain a pH of 12–13. The liberated nore-
*Correspondence to: Devalla V. Ramana, Research and Development Centre,
Malladi Drugs and Pharmaceuticals Ltd., No. 788/1, Irulapalayam, Kutham-
bakkam, Chennai 602 107, Tamil Nadu, India.
E-mail: dvramana@malladi.co.in
Received for publication 29 September 2010; accepted 13 July 2011; Accepted
21 October 2011
DOI: 10.1002/chir.21996
Published online 23 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
Chiral salicyl-1,2-diamines18 show great promise as anti-
cancer molecules. These compounds have been shown to
induce inhibition of the growth of cancer cells. These vici-
nal diamines display pharmaceutical potency in the treat-
ment of human breast cancer. Enantiomerically enriched
1,2-diamines are powerful drug intermediates in the asym-
C
VV
2012 Wiley Periodicals, Inc.

ꢀ-AMINATION IN 1-PHENYL-2-(N-ALKYLAMINO)-1-PROPANOL
263
phedrine base was extracted in dichloromethane. The organic layer was
dried over anhydrous sodium sulfate and the solvent was evaporated
under reduced pressure to yield an oily residue that was dissolved in
400 ml of toluene. To this solution, 0.8 mol of 1,5-dibromopentane/1,4-
dibromobutane and 1.0 mol of sodium carbonate were added, and the
resulting suspension was heated to reflux for 12 h. The progress of the
reaction was monitored by TLC. After cooling to room temperature, the
solids were removed by filtration. The toluene filtrate was washed with
water, dried over anhydrous sodium sulfate, and evaporated to dryness
under reduced pressure to yield an oil. The oily product was dissolved
in 300 ml of acetone and acidified to pH 2–3 by bubbling HCl gas. The
precipitated product was removed by filtration and was washed with ace-
tone to obtain white crystalline 1-phenyl-2-(1-piperidinyl/1-pyrrolidinyl)-
1-propanol hydrochloride.
dinyl)-1-propanol hydrochloride, 0.021 mol, was dissolved in 15 ml of
H2O. The solution was stirred at room temperature for 12 h. The pro-
gress of the reaction was monitored by TLC. The reaction mass was
evaporated under reduced pressure to remove excess of water, when a
white solid was obtained. The solid was triturated with acetone, filtered,
and dried.
Characterization of the Products
(1R,2R)-(1)-1-Phenyl-1-methylamino-2-(1-piperidinyl)propane
hydrochloride 1. Compound 1 (3.13 g, 64%); [a]2D5 5 18.7 (c5 1.0,
CH3OH); mp (2-propanol) 250–2548C. The ee was determined by CSP
HPLC to be 100% (Chiral AGP, 95% 0.01 M ammonium acetate pH 4.5
using acetic acid, 5% 2-propanol, 0.5 ml/min); tR (1R,2R) 5 3.6 min
(100%); IR (KBr, cm21): 3428, 3005, 2943, 2662, 1576, 1464, 1379, 1171,
704; 1H NMR (400 MHz, DMSO-d6) dH 1.21 (d, J 5 6.4 Hz, 3H,
CHꢀꢀCH3), 1.32–2.24 (6H, m, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2),* 2.45 (s,
Typical procedure for N-tosylation of (1S,2R)-(1)-1-phenyl-2-
amino-1-propanol. About 0.662 mol of (1S,2R)-(1)-1-phenyl-2-amino-
1-propanol was taken in a round bottom flask and 500 ml of tetrahydrofu-
ran was added and the mixture was stirred under nitrogen atmosphere.
Triethylamine (0.79 mol) was added and cooled to 108C. Tosylchloride
(0.795 mol) dissolved in 150 ml of tetrahydrofuran was added slowly
over 30–40 min by maintaining the temperature at 10–158C. The reaction
mixture was stirred overnight at 15–208C. The reaction was monitored
for the completion by TLC. Then 150 ml of water and 300 ml of chloro-
form were added and the product was extracted into chloroform layer.
Chloroform layer was separated. Chloroform layer was dried over anhy-
drous sodium sulfate, filtered, and concentrated to yield an oily residue.
The oily residue was dissolved in 50 ml of chloroform and 240 ml of n-
hexane. White crystals formed were filtered, and the crystals were
washed with 60 ml of n-hexane.
3H,CHꢀꢀNHꢀꢀCH3),
2.80–3.82,
(m,
4H,CH2ꢀꢀNꢀꢀCH2),
4.59
(m,1H,CHꢀꢀCH3), 5.28 (d, J 5 þ6.5 Hz, 1H, CHꢀꢀC6H5), 7.47–7.92 (m, 5H,
H aromatic), 10.56 (br s, CHꢀꢀN H2ꢀꢀCH3); 13C NMR (100 MHz, DMSO-
d6) dC 11.5, 21.5, 22.6, 31.0, 48.1, 53.4, 62.1, 63.8, 78.5, 129.4, 129.6,
129.9, 130.8; MS (CI, CH3OH) m/z (rel. intens.) 233 (M1H1, 100), 202
(31), 112 (16); Anal. Calcd for C15H24N2ꢁHCly: C, 67.16; H, 9.33; N, 10.45.
Found: C, 66.93; H, 9.40; N, 10.43.
(1R,2R)-(1)-1-Phenyl-1-ethylamino-2-(1-piperidinyl)propane
hydrochloride 2. Compound 2 (2.83 g, 55%); [a]2D5 5 12.2 (c 5 1.0,
CH3OH); mp (2-propanol) 220–2268C. The ee was determined by CSP
HPLC to be 100% (Chiral AGP, 95% 0.01 M ammonium acetate pH 4.5
using acetic acid, 5% 2-propanol, 0.5 ml/min); tR (1R,2R) 5 3.8 min (100
%); IR (KBr, cm21): 3474, 3406, 3022, 2945, 2667, 1649, 1575, 1458, 1369,
1096, 710; 1H NMR (400 MHz, CDCl3) dH 1.08 (d, J 5 6.6 Hz, 3H,
CHꢀꢀCH3), 1.43 (t, J 5 6.5 Hz, 3H, CH2ꢀꢀCH3), 1.95–2.70 (m, 6H,
NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.73, (q, J 5 6.4 Hz, 2H, ꢀꢀCH2ꢀꢀCH3),
2.75–3.15 (m, 4H,CH2ꢀꢀNꢀꢀCH2), 4.79 (m, 1H, CHꢀꢀCH3), 5.00 (d, J 5
Typical procedure for chlorination of 1-phenyl-2-(N-alkyl/tosyla-
mino)-1-propanol hydrochloride. To a suspension of 0.45 mol of 1-
phenyl-2-(N-alkyl)-1-propanol hydrochloride or 1-phenyl-2-(N-tosyl)-1-pro-
panol, 600 ml of chloroform and 3 ml of dimethylformamide heated to
458C and 0.68 mol of thionyl chloride were added slowly over a period of
2 h by maintaining the temperature at 45 to 508C. The reaction was
monitored by TLC. Chloroform was evaporated under reduced pressure
yielding a white solid that was triturated with acetone or hexane, filtered,
and washed with acetone/hexane to obtain white crystalline chloro de-
rivative.
6.4 Hz, 1H, CHꢀꢀC6H5), 7.30–7.50 (m, 5H, H aromatic), 10.96 (br s, 2H,
þ
CHꢀꢀN H2ꢀꢀCH2); 13C NMR (100 MHz, CDCl3) dC 11.2, 12.0, 21.8, 22.8,
42.0, 48.5, 54.4, 61.5, 64.2, 77.7, 129.7, 130.2, 130.9; MS (CI, CH3OH)
m/z (rel. intens.) 247 (M1H1, 100), 202 (27), 112 (12); Anal. Calcd for
C16H26N2ꢁHCl: C, 68.09; H, 9.57; N, 9.93. Found: C, 67.97; H, 9.63; N, 9.93.
(1R,2R)-(1)-1-Phenyl-1-(N,N-diethylamino)-2-(1-piperidinyl)pro-
pane dihydrochloride 3. Compound 3 (3.85 g, 68%); [a]2D5 5 112.0 (c
5 1.0, CH3OH); mp (2-propanol) 188–1918C. The ee was determined by
CSP HPLC to be 100% (Chiral AGP, 95% 0.01 M ammonium acetate pH
4.5 using acetic acid, 5% 2-propanol, 0.5 ml/min); tR (1R,2R) 5 2.4 min
(100%); IR (KBr, cm21): 3545, 3462, 2953, 2872, 2660, 1636, 1541, 1458,
1391, 1305, 1130, 1070, 714; 1H NMR (300 MHz, CDCl3) dH 1.27 (t, J 5
6.5 Hz, 3H, NꢀꢀCH2ꢀꢀCH3), 1.60 (t, J 5 6.5 Hz, 3H, NꢀꢀCH2ꢀꢀCH3), 1.83
Typical procedure for the synthesis of 1-phenyl-1-alkyl/aryla-
mino-2-(N-alkyl/tosylamino)propane
hydrochloride. 1-Phenyl-1-
chloro-2-(N-alkylamino)propane hydrochloride or 1-phenyl-1-chloro-2-
(tosyl amino)propane (0.02 mol) was dissolved in 50 ml of dichlorome-
thane/acetonitrile and cooled to 58C. Alkyl/arylamine, 0.08 mol in 10 ml
of dichloromethane, was added slowly to the mixture over a period of 2
h. The resulting solution was stirred overnight at room temperature.
The progress of the reaction was followed by TLC. The reaction mixture
was washed with water followed by brine. The organic layer was sepa-
rated, and the solvent was removed under reduced pressure. The oily
residue was dissolved in 2-propanol and acidified with HCl in 2-propanol
(d,
J
5
6.4 Hz, 3H, CHꢀꢀCH3), 1.90–2.21 (m, 6H,
NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.35 (m, 2H,CH2ꢀꢀNꢀꢀCH2), 2.78 (m, 2H,
CH2ꢀꢀNꢀꢀCH2), 3.13 (m, 2H, NꢀꢀCH2ꢀꢀCH3), 3.60 (m, 2H,
NꢀꢀCH2ꢀꢀCH3), 4.07 (q, J 5 6.6 Hz, 1H, CHꢀꢀCH3), 6.32 (d, J 5 6.4 Hz,
1H, C6H5ꢀꢀCH), 7.52–8.13 (m, 5H, H aromatic), 11.94 (br s, 1H,
þ
þ
to
obtain
1-phenyl-1-alkyl/arylamino-2-(N-alkyl/tosylamino)propane
CH3ꢀꢀCH2ꢀꢀN H), 12.08 (br s, 1H, CH2ꢀꢀN HꢀꢀCH2); 13C NMR (75
MHz, CDCl3) dC 7.9, 8.7, 10.2, 21.9, 22.3, 23.2, 44.8, 48.7, 56.2, 61.4, 65.2,
77.2, 129.7, 129.9, 130.1, 131.1; MS (ESI) m/z (rel. intens.) 275 (M1H1,
100); Anal. Calcd for C18H30N2ꢁ2HCl: C, 62.25; H, 9.22; N, 8.07. Found:
C, 62.39; H, 9.18; N, 8.03.
hydrochloride. The product was filtered and recrystallized from 2-propa-
nol. The crude samples in the case of all the diamines prepared con-
tained only achiral impurities.
Typical procedure for Walden inversion. To (1S,2R)-1-phenyl-2-
amino-1-propanol hydrochloride (5 g, 0.0232 mol), 12.0 ml of acetic anhy-
dride was added and heated to 120–1308C for 1 h. The reaction mass
was concentrated under reduced pressure to yield an oil. To the oily resi-
due, 20 ml of 10% hydrochloric acid was added and heated to reflux for 3
h. The reaction mass was concentrated under reduced pressure to give
an oily residue that was triturated with acetone to obtain a white precipi-
tate. The precipitated product was filtered and washed with acetone to
obtain (1R,2R)-1-phenyl-2-amino-1-propanol hydrochlorides.
(1R,2R)-(–)-1-Phenyl-1-(propan-2-yl-amino)-2-(1-piperidinyl)pro-
pane dihydrochloride 4. Compound 4 (4.30 g, 80%); [a]2D5 5 2 7.0 (c
5 1.0, CH3OH); mp (2-propanol) 232–2368C. The ee was determined by
CSP HPLC to be 100% (Chiral AGP, 95% 0.01 M ammonium acetate pH
*The protons and carbons of the piperidinyl/pyrrolidinyl rings and the N,N-
dialkyl groups at C-1 appear to be experiencing magnetic anisotropy being in
the vicinity of chiral environment.
yThe number of HCl molecules associated with each diamine is ascer-
tained by nonaqueous titrimetry and confirmed by proton NMR spectros-
copy.
Reaction of (1R,2R)-1-chloro-1-phenyl-2-(1-piperidinyl)-1-propa-
nol hydrochloride with H2O. (1R,2R)-1-Chloro-1-phenyl-2-(1-piperi-
Chirality DOI 10.1002/chir

264
HITESH KUMAR ET AL.
Chirality DOI 10.1002/chir

ꢀ-AMINATION IN 1-PHENYL-2-(N-ALKYLAMINO)-1-PROPANOL
265
Scheme 1. Formation of aziridinium chloride.
þ
4.5 using acetic acid, 5% 2-propanol, 0.5 ml/min); tR (1R,2R) 5 14.6 min
5H, H aromatic), 9.47 (br s, 1H, CH2ꢀꢀN HꢀꢀCH2), 10.29–11.60 (br s, 2H,
þ
(100%); IR (KBr, cm21): 3522, 3462, 2978, 2870, 2671, 1566, 1456, 1443,
C6H5CHꢀꢀN H2); 13C NMR (75 MHz, CDCl3) dC 10.7, 21.9, 22.4, 23.1,
27.4, 48.6, 55.0, 58.5, 62.0, 64.0, 129.5, 130.3, 130.7, 132.0; MS (CI,
CH3OH) m/z (rel. intens.) 275 (M1H1, 100), 202 (91), 112 (82), 56
(32); Anal. Calcd for C18H30N2ꢁ2HCl: C, 62.43; H, 9.25; N, 8.09. Found:
C, 62.36; H, 9.18; N, 7.95.
1
1400, 1304, 1128, 1084, 710; H NMR (300 MHz, CDCl3) dH 1.02 (d, J 5
6.5 Hz, 3H, CHꢀꢀCH3), 1.31 (d, J 5 6.5 Hz, 3H, CH3ꢀꢀCHꢀꢀCH3), 1.56 (d,
J
5
6.4 Hz, 3H, CH3ꢀꢀCHꢀꢀCH3), 1.95–2.63 (m, 6H,
NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.84 (m, 1H,CH3ꢀꢀCHꢀꢀCH3), 3.01 (m, 2H,
CH2ꢀꢀNꢀꢀCH2), 3.76 (m, 2H, CH2ꢀꢀNꢀꢀCH2), 4.79 (m, 1H, CHꢀꢀCH3),
5.15 (d, J 5 6.5 Hz, 1H, C6H5ꢀꢀCH), 7.47–8.30 (m, 5H, H aromatic),
(1R,2R)-(–)-1-Phenyl-1-phenylamino-2-(1-piperidinyl)propane
hydrochloride 7. Compound 7 (5.0 g, 83%); [a]2D5 5 299.0 (c 5 1.0,
CH3OH); mp (2-propanol) 236–2398C. The ee was determined by CSP
HPLC to be 100% (Chiralcel OD-R, 62% of 0.1% perchloric acid, pH 5.0
using sodium hydroxide, 38% acetonitrile, 0.5 ml/min); tR (1R,2R) 5 22.8
min (100%); IR (KBr, cm21): 3406, 3252, 3017, 2947, 2675, 1601, 1560,
1456, 1258, 708; 1H NMR (400 MHz, CF3COOH) dH 1.36 (d, J 5 6.7 Hz,
3H, CHꢀꢀCH3), 1.54–2.37 (m, 6H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 3.05–3.75
(m, 4H, CH2ꢀꢀNꢀꢀCH2), 4.70 (m, 1H, CHꢀꢀCH3), 5.20 (d, J 5 6.6 Hz, 1H,
þ
þ
10.56 (br s, 1H, CH2ꢀꢀN HꢀꢀCH2), 11.14 (d, 2H, CHꢀꢀN H2ꢀꢀCH); 13C
NMR (75 MHz, CDCl3) dC 12.4, 17.2, 20.3, 21.9, 22.3, 23.0, 48.2, 49.7,
54.7, 59.6, 64.3, 129.5, 129.8, 130.2, 130.8; MS (CI, CH3OH) m/z (rel.
intens.) 261 (M1H1, 100), 202 (72), 112 (55), 56(25); Anal. Calcd for
C17H28N2ꢁ2HCl: C, 61.44; H, 9.04; N, 8.43. Found: C, 61.55; H, 9.22; N,
8.34.
(1R,2R)-(–)-1-Phenyl-1-(1-butylamino)-2-(1-piperidinyl)propane
dihydrochloride 5. Compound 5 (5.10 g, 90%); [a]2D5 5 27.0 (c 5 1.0,
CH3OH); mp (2-propanol) 240–2448C. The ee was determined by CSP
HPLC to be 100% (Chiral AGP, 95% 0.01 M ammonium acetate pH 4.5
using acetic acid, 5% 2-propanol, 0.5 ml/min); tR (1R,2R) 5 10.5 min
(100%); IR (KBr, cm21): 3482, 3038, 2936, 2879, 2691, 1574, 1497, 1460,
1400, 1379, 1112, 1087, 700; 1H NMR (300 MHz, DMSO-d6) dH 0.78 (t, J
5 6.6 Hz, 3H, CH2ꢀꢀCH3), 0.94 (d, J 5 6.4 Hz, 3H, CHꢀꢀCH3), 1.23 (m,
2H, ꢀꢀCH2ꢀꢀCH3), 1.41–1.67 (2H, m, ꢀꢀCH2ꢀꢀCH2ꢀꢀCH3), 1.69–2.16 (m,
6H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.19–2.38 (m, 2H, CH2ꢀꢀNꢀꢀCH2),
C6H5ꢀꢀCH), þ7.25–7.47 (m, 10H,
H aromatic), 9.06 (br s, 2H,
C6H5ꢀꢀCHꢀꢀN H2); 13C NMR (100 MHz, CF3COOH) dC 12.7, 22.5, 24.0,
24.6, 50.0, 57.1, 66.2, 70.2, 111.6, 114.5, 117.3, 120.1, 124.6, 129.8, 131.7,
133.4; MS (CI, CH3OH) m/z (rel. intens.) 295 (M1H1, 100), 202 (33),
112 (36); Anal. Calcd for C20H26N2ꢁHCl: C, 72.62; H, 8.17; N, 8.47.
Found: C, 72.60; H, 8.23; N, 8.36.
(1R,2R)-(–)-1-Phenyl-1-(1-(S)-phenylethylamino)-2-(1-piperidinyl)
propane dihydrochloride 8. Compound 8 (5.0 g, 76%); [a]2D5 5 240.4
(c 5 1.0, CH3OH); mp (2-propanol) 218–2208C. The ee was determined
by CSP HPLC to be 100% (Chiralcel OD-R, 80% of 0.1 M KH2PO4 using
orthophosphoric acid, 20% acetonitrile, 0.5 ml/min); tR (1R,2R, 10S) 5
37.5 min (100%); IR (KBr, cm21): 3445, 3026, 2880, 2662, 1570, 1499,
1458, 1240, 1200, 704; 1H NMR (400 MHz, CDCl3) dH 0.94 (d, 3H,
C6H5ꢀꢀCHꢀꢀCH3), 1.82 (d, J 5 6.5 Hz, 3H, CHꢀꢀCHꢀꢀCH3), 1.89–2.61
(m, 6H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.98–3.87 (m, 4H, CH2ꢀꢀNꢀꢀCH2),
3.95 (q, J 5 6.4 Hz, 1H, C6H5ꢀꢀCHꢀꢀCH3), 4.05 (m, 1H, CHꢀꢀCHꢀꢀCH3),
5.07 (d, J 5 6.6 Hz, 1H, C6H5ꢀꢀCHꢀꢀCH),þ7.28–7.45 (m, 10H, H aro-
matic),þ 11.12 (br s, 2H, C6H5ꢀꢀCHꢀꢀN H2), 11.29 (br s, 1H,
CH2ꢀꢀN HꢀꢀCH2); 13C NMR (100 MHz, CDCl3) dC 12.6, 21.3, 21.7, 22.1,
22.7, 47.4, 54.3, 58.4, 60.4, 63.9, 127.3, 128.3, 129.0, 129.3, 130.1, 130.4,
132.3, 135.2; MS (CI, CH3OH) m/z (rel. intens.) 323 (M1H1, 100), 202
(18), 112 (27), 56(5); Anal. Calcd for C22H30N2ꢁ2HCl: C, 67.00; H, 8.12;
N, 7.11. Found: C, 67.33; H, 7.97; N, 7.32.
2.70–3.00 (m, 2H, CH2ꢀꢀNꢀꢀCH2), 3.50 (t,
J 5 6.7 Hz, 2H,
C6H5ꢀꢀCHꢀꢀNHꢀꢀCH2), 4.40 (m, 1H, CHꢀꢀCH3), 5.12 (d, J 5 6.5 Hz, 1H,
C6H5ꢀꢀCH), 7.49–7.74 (m, 5H,
H aromatic), 10.44 (br s, 2H,
þ
þ
CHꢀꢀN H2ꢀꢀCH2), 10.62 (br s, 1H, CH2ꢀꢀN HꢀꢀCH2); 13C NMR (75
MHz, DMSO-d6) dC 11.4, 13.3, 19.2, 21.0, 21.8, 22.4, 27.0, 45.4, 46.9, 52.8,
60.3, 63.0, 129.1, 129.3, 129.6, 131.7; MS (CI, CH3OH) m/z (rel. intens.):
275 (M1H1, 100), 202 (43), 112 (37), 56(15); Anal. Calcd for
C18H30N2ꢁ2HCl: C, 62.43; H, 9.25; N, 8.09. Found: C, 62.52; H, 9.14; N,
7.91
(1R,2R)-(1)-1-Phenyl-1-(1,1-dimethylethylamino)-2-(1-piperi-
dinyl) propane dihydrochloride 6. Compound 6 (3.80 g, 67.0%);
[a]2D5 5 1 2.5 (c 5 1.0, H2O); mp (2-propanol) 184–1868C. The ee was
determined by CSP HPLC to be 100% (Chiral AGP, 95% 0.01 M ammo-
nium acetate pH 4.5 using acetic acid, 5% 2-propanol, 0.5 ml/min); tR
(1R,2R) 5 7.2 min (100%); IR (KBr, cm21): 3482, 3377, 3017, 2882, 2650,
1576, 1504, 1458, 1375, 1188, 714; 1H NMR (300 MHz, CDCl3) dH 1.37
(s, 9H, t-bu protons), 1.48 (d, J 5 6.6 Hz, 3H, CHꢀꢀCH3), 1.71–2.61 (m,
6H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 2.96–3.26 (m, 4H, CH2ꢀꢀNꢀꢀCH2), 4.94
(m, 1H, CHꢀꢀCH3), 5.62 (d, J 5 6.5 Hz, 1H, C6H5ꢀꢀCH), 7.31–8.30 (m,
(1R,2R)-(1)-1-Phenyl-1-(1-(R)-phenylethylamino)-2-(1-piperidi-
nyl)propane dihydrochloride 9. Compound 9 (3.80 g, 58%); [a]D25
1 4.7 (c 5 1.0, CH3OH); mp (2-propanol) 222–2268C. The ee was deter-
mined by CSP HPLC to be 100% (Chiralcel OD-R, 80% of 0.1 M KH2PO4
5
Scheme 2. Formation of the diamine.
Chirality DOI 10.1002/chir

266
HITESH KUMAR ET AL.
HPLC to be 100% (chiralpak AD-H, 99% n-hexane, 1% 2-propanol, 0.1%
diethylamine, 2.0 ml/min, 210 nm); tR 5 5.13 min (100%); IR (KBr,
cm21): 3429, 3042, 2914, 2681, 2486, 1721, 1601, 1589, 1489, 1460, 1402,
1383, 1312, 1196, 746, 708; 1H NMR (200 MHz, CDCl3): dH 0.76 (d, J 5
6.6 Hz, 3H, C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 1.12 (s, 9H, ꢀꢀC(CH3)3, 1.84–1.92
Scheme 3. Stereochemical pathway from aminoalcohol to diamine.
(m,
4H,
NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2),
2.76–2.95,
(m,
4H,
NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 3.51 (m, 1H, C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 3.70 (d, J
pH 2.0 using orthophosphoric acid, 20% acetonitrile, 0.5 ml/min); tR
(1R,2R, 10R) 5 49.8 min (100%); IR (KBr, cm21): 3534, 3445, 3026, 2881,
2666, 1580, 1497, 1456, 1306, 1208, 706; 1H NMR (300 MHz, CDCl3) dH
0.96 (d, J 5 6.7 Hz, 3H, C6H5ꢀꢀCHꢀꢀCH3), 1.68 (d, J 5 6.8 Hz, 3H,
CHꢀꢀCHꢀꢀCH3), 1.91–2.75 (m, 6H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2), 3.00–
3.93 (m, 4H, CH2ꢀꢀNꢀꢀCH2), 3.94 (q, J 5 6.4 Hz, 1H, CHꢀꢀCHꢀꢀCH3),
4.89 (q, J 5 6.4 Hz, 1H, C6H5ꢀꢀCHꢀꢀCH3), 5.36 (d, J 5 6.6 Hz, 1H,
5 6.5 Hz, 1H,þC6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 7.26–7.5 (m, 5H, H aromatic), 8.72 (br
þ
s, 3H, CH2ꢀꢀN HꢀꢀCH2, C6H5ꢀꢀCHꢀꢀN H2); 13C NMR (50 MHz, CDCl3):
dC 9.7, 24.5, 29.1, 48.5, 56.3, 59.9, 63.3, 129.1–137.8, 164.0; MS (ESI) m/z
(rel. intens.): 261 (M1H1,100); Anal. Calcd for C17H28N2ꢁC2H2O4: C,
65.12; H, 8.63; N, 7.99. Found: C, 64.91; H, 8.48; N, 8.13.
(1R,2R)-(1)-1-Phenyl-1-(1-butylamino)-2-(N-ethyl-N-methylami-
no)propane dihydrochloride 13. Compound 13 (5.2 g, 62%); [a]D25
5
C6H5ꢀꢀCHꢀꢀCH), 7.28–7.53 (m, 10H, H aromatiþc), 10.54 (br s, 1H,
þ
CH2ꢀꢀN HꢀꢀCH2), 11.44 (br s, 2H, C6H5ꢀꢀCHꢀꢀN H2); 13C NMR (75
MHz, CDCl3): dC 12.2 17.8, 22.0, 22.6, 23.0, 47.9, 54.5, 57.9, 61.2, 63.9,
128.3, 128.8, 129.0, 129.7, 130.0, 131.3, 133.7, 136.7; MS (CI, CH3OH) m/
z (rel. intens.) 323 (M1H1, 100), 202 (46), 112 (30), 56(11); Anal. Calcd.
for C22H30N2.2HCl: C, 67.00; H, 8.12; N, 7.11. Found: C, 67.29; H, 8.13;
N, 7.27.
24.9 (c 5 1.0, CH3OH); mp 215–2188C. The ee was determined by CSP
HPLC to be 100% (chiralpak AD-H, 99% n-hexane,1% 2-propanol, 0.1% dieth-
ylamine, 1.0 ml/min,210 nm); tR 5 6.49 min (100%); IR (KBr, cm21): 3496,
3036, 2932, 2664, 1570, 1470, 1381, 702; 1H NMR (300 MHz, CDCl3): dH
0.81 (t, J 5 6.5 Hz, 3H, CH2ꢀꢀCH2ꢀꢀCH3), 1.07 (d, J 5 6.3 Hz, 3H,
NꢀꢀCHꢀꢀCH3), 1.25 (m, 2H, CH3ꢀꢀCH2ꢀꢀCH2), 1.63 (t, J 5 6.6 Hz, 3H,
NꢀꢀCH2ꢀꢀCH3), 1.86 (m, 2H, NHꢀꢀCH2ꢀꢀCH2), 2.62 (t, J 5 6.5 Hz, 2H,
NHꢀꢀCH2), 2.90 (s, 3H, NꢀꢀCH3), 3.35 (q, J 5 6.5 Hz, 2H, NꢀꢀCH2ꢀꢀCH3),
3.66 (m, 1H, NꢀꢀCHꢀꢀCH3), 4.82 (d, J 5 6.5 Hþz, 1H, C6H5ꢀꢀCHꢀꢀNH)
(1R,2R)-(2)-(1-phenyl-1-cyclohexylamino-2-(1-pyrrolidinyl)pro-
pane dihydrochloride 10. Compound 10 (10.6 g, 75.0%); [a]D25
5
213.0 (c 5 5.0, H2O); mp 144–1478C. The ee was determined by CSP
HPLC to be 100% (chiralpak AD-H, 99% n-hexane,1% 2-propanol, 0.1% dieth-
ylamine, 2.0 ml/min,210 nm); tR 5 5.27 min (100%); IR (KBr, cm21): 3429,
2986, 2940, 2673, 2434, 1572, 1501, 1352, 775, 714; 1H NMR (200 MHz,
D2O): dH 1.26–1.91 (m,17 H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2, CHꢀꢀ(CH2)5,
C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 3.09–3.34 (m, 5H, CH2ꢀꢀNꢀꢀCH2, CHꢀꢀ(CH2)5),
7.45–7.91 (m, 5H, H aromatic), 10.27 (br s, 1H, N HꢀꢀCH3), 11.19 (br s,
þ
2H, CHꢀꢀN H2ꢀꢀCH2); 13C NMR (75 MHz, CDCl3): dC 10.4, 11.7, 13.4,
19.9, 27.8, 34.9, 46.6, 52.8,61.9, 62.7, 129.4, 130.0, 130.4, 130.6; MS (ESI)
m/z (rel. intens.): 249 (M1H1, 100); Anal. Calcd for C16H28N2ꢁ2HCl: C,
59.81; H, 9.41; N, 8.72. Found: C, 59.77; H, 9.38; N, 8.69.
4.12 (m, 1H, C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 4.70 (d,
J 5 6.5 Hz, 1H,
(1R,2R)-(1)-1-Phenyl-1-(2-fluorophenylamino)-2-(N-ethyl-N-meth-
ylamino)propane hydrochloride 14. Compound 14 (5.8 g, 70%); [a]D25
5 2141.1 (c 5 1.0, CH3OH); mp 205–2108C. The ee was determined by
CSP HPLC to be 100% (chiralpak AD-H, 99% n-hexane, 1% 2-propanol,
0.1% diethylamine, 1.0 ml/min, 210 nm); tR 5 14.14 min (100%); IR (KBr,
C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 7.56 (s, 5H, H aromatic); 13C NMR (50 MHz,
D2O): dC 8.8, 21.0, 22.4, 26.4, 27.9, 48.6, 55.5, 57.2, 59.3, 126.0–129.4; MS
(ESI) m/z (rel. intens.): 287 (M1H1, 100); Anal. Calcd for C19H30N2ꢁ2HCl:
C, 63.50; H, 8.98; N, 7.79. Found: C, 63.64; H, 8.65; N, 7.57.
1
cm21): 3264, 3032, 2992, 2635, 1618, 1456, 1329, 748, 712; H NMR (300
(1R,2R)-(-)-1-phenyl-1-(propan-2yl amino)-2-(1-pyrrolidinyl)pro-
pane dihydrochloride 11. Compound 11 (9.2 g, 72.0%); [a]D25
MHz, CDCl3): dH 1.21 (d, J 5 6.8 Hz, 3H, NꢀꢀCHꢀꢀCH3), 1.52 (t, J 5 6.4
Hz, 3H, NꢀꢀCH2ꢀꢀCH3), 2.91 (s, 3H, NꢀꢀCH3), 3.13 (q, J 5 6.4 Hz, 2H,
NꢀꢀCH2ꢀꢀCH3), 3.46 (m, 1H, CH3ꢀꢀCHꢀꢀN), 4.21 (d, J 5 6.4 Hz, 1H,
5
211.0 (c 5 5.0, H2O); mp 247–2508C. The ee was determined by CSP
HPLC to be 100% (chiralpak AD-H, 99% n-hexane,1% 2-propanol, 0.1%
diethylamine, 2.0 ml/min, 210nm); tR 5 6.67 min (100%); IR (KBr,
cm21): 3456, 2980, 2941, 2668, 2479, 1566, 1458, 1396, 781, 718; 1H NMR
(200 MHz, D2O): dH 1.14–1.21 (m, 6H, CH3ꢀꢀCHꢀꢀCH3), 1.47 (d, J 5 6.6
Hz, 3H C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 1.88 (m, 4H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2),
3.25 (m, 5H, NꢀꢀCH2ꢀꢀCH2ꢀꢀCH2ꢀꢀCH2, CH3ꢀꢀCHꢀꢀCH3), 3.96 (m, 1H,
C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3), 4.71 (d, J 5 6.5 Hz, 1H, C6H5ꢀꢀCHꢀꢀCHꢀꢀCH3),
7.49 (s, 5H, H aromatic); 13C NMR (50 MHz, D2O): dC 11.5, 18.7, 19.8, 23.5,
51.5, 54.1, 60.3, 61.9, 128.4–132.1; MS (ESI) m/z (rel. intens.): 247 (M1H1,
100); Anal. Calcd for C16H26N2ꢁ2HCl: C, 60.18; H, 8.84; N, 8.77. Found: C,
60.36; H, 9.03; N, 8.52.
C6H5ꢀꢀCHꢀꢀNH), 6.71 (m, 5H, C6H5), 7.40 (m, 4H, C6H4F), 9.98 (br s,
þ
1H, C6H5ꢀꢀCHꢀꢀNH), 10.47 (br s, 1H, N HꢀꢀCH3); 13C NMR (75 MHz,
CDCl3): dC 9.7–64.3 (six signals due to nonaromatic carbons), 115.0–
154.5 (10 signals due to aromatic carbons (both 1H and 13C NMR spectra
contain signals due to short and long range HꢀꢀF and CꢀꢀF coupling);
MS (ESI) m/z (rel. intens.): 287(M1H1, 100); Anal. Calcd for
C18H23N2ꢁHCl: C, 66.96; H, 7.49; N, 8.68. Found: C, 66.93; H, 7.45; N,
8.66.
(1S,2R)-(1)-1-Phenyl-1-phenylamino-2-(tosylamino)propane
15. Compound 15 (2.8 g, 56%); [a]2D5 5 19.5 (c 5 1.0, CH3OH); mp
161–1638C. The ee was determined by CSP HPLC to be 100% (chiralpak
AD-H, 99% n-hexane, 1% 2-propanol, 0.1% diethylamine,1.0 ml/min, 210
nm); tR 5 5.10 min (100%); IR (KBr, cm21): 3416, 3223, 3049, 2982, 1603,
1516, 1332, 1321, 1143, 815, 700; 1H NMR (300 MHz, CDCl3): dH 0.88 (d,
(1R,2R)-(2)-1-phenyl-1-(1,1-dimethylethylamino)-2-(1-pyrrolidi-
nyl)propane oxalate 12. Compound 12 (7.3 g, 55.0%); [a]2D5 5 230.0
(c 5 1.0, 1 N HCl); mp 190–1928C. The ee was determined by CSP
TABLE 2. Retention time, specific rotation, and enantiomeric purities (in parentheses) of (1R,2R), (1S,2S), and (1RS,2SR) isomers
of 1-phenyl-1-alkyl/arylamino-2-(1-piperidinyl)propane hydrochlorides
(1R,2R) isomer
(1S,2S) isomer
(1SR,2RS) isomer
RT, [a]2D5, enantiomeric
RT, [a]2D5, enantiomeric
RT, [a]2D5, enantioneric
Compound
1-Amino group
purity (%)
purity (%)
purity (%)
5
7
1-Butyl
Phenyl
11.60, 27.00, (100)
20.30, 2101.50, (100)
(1R,2R,10S,) isomer
37.96, 240.70, (100)
_
13.18, 16.64, (100)
22.77, 198.50, (100)
(1S,2S,10R) isomer
–
11.93, 0, (49)
13.03, 0, (51)
23.37, 0, (52)
20.54, 0, (48)
(1SR,2RS,10SR) isomera
8
9
(S)-10-Phenylethyl
(R)-10-Phenylethyl
49.80, 137.70, (100)
38.20, 0, (48)
48.0, 0, (52)
aPrepared from the (S/R)-phenyethylamine.
Chirality DOI 10.1002/chir

ꢀ-AMINATION IN 1-PHENYL-2-(N-ALKYLAMINO)-1-PROPANOL
267
Scheme 4. Stereochemical pathway for the enantiomeric diamines.
J 5 6.4 Hz, 3H, NHꢀꢀCHꢀꢀCH3), 2.44 (s, 3H, C6H4ꢀꢀCH3), 3.76–3.87 (m,
1H, CHꢀꢀCHꢀꢀCH3), 4.26–4.33, (m, 2H, NHꢀꢀCHꢀꢀCHꢀꢀNH), 4.73 (d, J
5 6.4 Hz, 1H, CHꢀꢀCHꢀꢀCH3), 6.76–7.79 (m, 14H, H aromatic); 13C
NMR (75 MHz, CDCl3): dC 18.0, 21.5, 53.4, 60.7, 113.4, 117.4, 127.0,
127.6,127.7, 128.5, 128.9, 129.9, 137.6, 138.2, 143.7, 146.4; MS (ESI) m/z
(rel. intens.): 381 (M1H1, 100), High Resolution Mass Spectra- Electro
Spray Ionisation (HRMS-ESI) (m/z): calcd for C22H25N2O2S (M1H):
381.1637; found 381.1637, 0.0 ppm.
(1S,2R)-(2)-1-Phenyl-1-(4-fluorophenylamino)-2-(tosylamino)-
propane 16. Compound 16 (3.4 g, 68%); [a]2D5 5 25.1 (c 5 1.0,
CH3OH); mp 160–1628C. The ee was determined by CSP HPLC to be 100%
TABLE 3. Physical properties and HPLC retention times of 1-phenyl-1-alkyl/arylamino-2-(N-tosylamino)propane
(compounds 15–18)
Chemical purity by HPLC using
RP C18 column (%)
Enantiomeric excess (%)
using chiral column
1S,2R
isomer
1S,2R isomer
1R,2S isomer
Melting
R2 point (8C)
Yield
(%)
Content of 1R,2R isomer
Compound No.
R1
[a]2D5
19.5
RT
Content
(diastereomer)
RT
ee
RT
Content
15
16
17
18
Aniline
H
H
H
H
161–163
160–162
124–128
131–135
56
68
57
62
28.3
98.37
100
98.6
8.2 (RT) Nil
Nil
3.05 100
6.23 100 13.95
3.96 100
4.12 100
7.17
Nil
Nil
Nil
Nil
4-Fluoro aniline
Benzyl-amine
N,N-Diethyl
25.05 29.12
238.9 29.45
132.0 31.35
Nil
4.62
6.73
99.31
20.00 (RT) Nil
Chirality DOI 10.1002/chir

268
HITESH KUMAR ET AL.
Scheme 5. Formation of the diamines through N-tosylation.
(1S,2R)-(1)-1-phenyl-2-amino-1-propanol{ and the correspond-
ing dibromoalkanes in the presence of sodium carbonate. The
hydroxyl function in the aminoalcohols is converted as a chloro
derivative using thionyl chloride. The 1-chloro compounds are
used for the preparation of the diamines using various alkyl/
aryl amines.
The diamines have been isolated as hydrochlorides with
high ee and their physical properties along with the details
of the HPLC retention times are reported in Table 1. It can
be noticed that many 1,2-diamines of varying nature are pre-
pared to show the generality of this method.
The chlorination of a chiral alcohol with thionyl chloride
proceeds through an inversion of configuration21,22 in the
presence of an amino function. The alkyl/aryl amination
reaction of the chloro compound at C-1 is performed in the
less-polar solvent, dichloromethane, and hence is expected
to go through a SN2 reaction mechanism inducing another
inversion. It can be seen that an overall retention of configu-
ration at C-1 would have taken place during the reactions
from the alcohol to alkyl/aryl amino compounds.
(chiralpak AD-H, 99% n-hexane, 1% 2-propanol, 0.1% diethylamine, 1.0 ml/
min, 210 nm); tR 5 14.10 min (100%); IR (KBr, cm21): 3412,3227, 3030,
2982, 1597,1518, 1332, 1321, 1144, 816, 700; H NMR (300 MHz, CDCl3):
dH 0.86 (d, J 5 6.4 Hz, 3H, CHꢀꢀCH3), 2.43 (s, 3H, C6H4ꢀꢀCH3), 3.75–3.86
(m, 1H,CHꢀꢀCHꢀꢀCH3), 4.22–4.40, (m, 2H, NHꢀꢀCHꢀꢀCHꢀꢀNH), 4.68 (d,
J 5 6.5 Hz 1H,CHꢀꢀCHꢀꢀCH3), 6.27–7.78 (m, 13H, H aromatic); 13C NMR
(75 MHz, CDCl3): dC 17.8, 21.5, 53.5, 61.3, 114.1–157.2 (12 aromatic); MS
(ESI) m/z (rel. intens.): 399 (M1H1, 100), HRMS-ESI (m/z): calcd for
C22H24N2O2SF (M1H): 399.1543; found 399.1537, 1.5 ppm.
1
(1S,2R)-(-)-1-Phenyl-1-(1-benzylamino)-2-(tosylamino)propane
17. Compound 17 (3.5 g, 57%); [a]2D5 5 239.9 (c 5 1.0, CH3OH); mp
124–1288C. The ee was determined by CSP HPLC to be 100% (chiralpak
AD-H, 99% n-hexane, 1% 2-propanol, 0.1% diethylamine,1.0 ml/min,210
nm); tR 5 5.95 min (100%); IR (KBr, cm21): 3331, 3231, 3059, 2938, 1597,
1491, 1331, 1308, 818, 700; 1H NMR (300 MHz, CDCl3): dH 0.88 (d, J 5
6.5 Hz, 3H,CHꢀꢀCH3), 2.40 (s,3H,C6H4ꢀꢀCH3), 3.36 (m, 1H,
CH3ꢀꢀCHꢀꢀNH), 3.44–3.52, (m, 2H, NHꢀꢀCH2ꢀꢀC6H5), 3.65 (s, 1H,
SO2ꢀꢀNH), 5.05 (d, J 5 6.6 Hz 1H, C6H5ꢀꢀCHꢀꢀCH), 7.08–7.67 (m, 14H,
H aromatic); 13C NMR (75 MHz, CDCl3): dC 16.6, 21.5, 51.0, 53.4, 64.6,
127.1–143.2 (12 aromatic); MS (ESI) m/z (rel. intens.): 395 (M1H1,
100), HRMS-ESI (m/z): calcd for C23H27N2O2S (M1H): 395.1793; found
395.1805, 3.0 ppm.
STEREOCHEMICAL ASPECTS
(1S,2R)-(-)-1-Phenyl-1-(N,N-diethylamino)-2-(tosylamino)
propane 18. Compound 18 (2.29 g, 65%); [a]2D5 5 232.0 (c 5 1.0,
CH3OH); mp 131–1358C. The ee was determined by CSP HPLC to be
100% (chiralpak AD-H, 99% n-hexane,1% 2-propanol, 0.1% diethyl-
amine,1.0 ml/min,210 nm); tR 5 5.11 min (100%); IR (KBr, cm21): 3240,
3059, 2974, 1597, 1493, 1331, 1169, 826, 704; 1H NMR (300 MHz,
CDCl3): dH 0.89 (t, J 5 6.7 Hz, 6H, Nꢀꢀ(CH2ꢀꢀCH3)2), 1.00 (d, J 5 6.4
Hz, 3H, CHꢀꢀCH3), 2.20 (m, 2H, NꢀꢀCH2ꢀꢀCH3), 2.43 (m, 5H,
NꢀꢀCH2ꢀꢀCH3, C6H5ꢀꢀCH3), 3.38 (d, J 5 6.5 Hz, 1H, C6H5ꢀꢀCHꢀꢀN),
3.68 (m, 1H, CH3ꢀꢀCHꢀꢀCH), 5.09 (br s, 1H, NHꢀꢀSO2), 7.07–7.67 (m,
9H, H aromatic); 13C NMR (75 MHz, CDCl3): dC 11.6, 19.4, 21.5, 42.2,
49.5, 68.8, 127.2–143.1 (eight aromatic); MS (ESI) m/z (rel. intens.): 361
(M1H1, 100); Anal. Calcd for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77;
S, 8.89. Found: C, 66.68; H, 7.86; N, 7.72; S, 8.91.
It is known that a-chloroamines readily form aziridinium
chlorides16,17,20 through an intramolecular substitution reac-
tion. This reaction takes place through an inversion of configu-
ration at C-1 (Scheme 1). The reaction of the amine nitrogen
to displace the chlorine at C-1 during the formation of the 1,2-
diamine, infact, takes place through the aziridinium chloride.
The incoming amine nitrogen can, in principle, attack at C-
1 or C-2 in the aziridinium chloride. But it is reported23 that
the nucleophile attacks the benzylic carbon in the aziridi-
nium intermediate during the reaction of phenols with ami-
noindanols. Hence the approach of the nitrogen of the amine
will be preferably toward more electrophilic benzylic carbon
(C-1) (Scheme 2) during the reactions leading to 1,2-dia-
mines in this work.
It can be observed that there are three inversions during
the reactions starting from aminoalcohols to the diamines
(Scheme 3) giving rise to overall inversion of configuration.
The 1,2-diamines are also prepared from (1R,2S)-(1)-1-
phenyl-2-(1-piperidinyl)-1-propanol and from the correspond-
ing racemic aminoalcohol using n-butylamine, aniline, and
RESULTS AND DISCUSSION
(1S,2R)-(1)-1-Phenyl-2-(1-piperidinyl)-1-propanol and (1S,2R)-
(1)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol are prepared from
{The (1S,2R)- and (1R,2S)-1-phenyl-2-amino-1-propanols were obtained from
Malladi Drugs & Pharmaceuticals Ltd., Chennai.
Chirality DOI 10.1002/chir

ꢀ-AMINATION IN 1-PHENYL-2-(N-ALKYLAMINO)-1-PROPANOL
269
TABLE 4. Specific rotation, retention times, and melting points of 1-phenyl-1-diethylamino-2-(1-piperidinyl)propane
dihydrochloride
Configuration of the
amino alcohol
Configuration of the
diamine
Melting
point (8C)
Synthetic route
Overall stereochemistry [a]D25
Retention time
1S,2R
1S,2R
1S,2R
Aziridinium chloride 1R,2R (compound 3)
Inversion
Retention
Partial racemization
112.0
132.0
118.0
188–191
131–135
148–154
3.69
43.92
N-detosylation
1S,2R (compound 19)
1S,2R and 1R,2R
Walden inversion
3.72 (29) and 43.56 (69)
(R)-1-phenylethylamine through the chloro derivative. The
retention times in the HPLC analysis, specific rotations, and
the enantiomeric purities of the products are given in Table
2. It can be noticed that the 1,2-diamines prepared from
(1S,2R)-aminoalcohol are mirror images of the 1,2-diamines
obtained from (1R,2S)-aminoalcohol (Scheme 4 and Table 2).
These observations strongly support the absolute configura-
tion assigned to C-1 of the 1,2-diamine.
(1S,2R)-(1)-1-Phenyl-2-amino-1-propanol is tosylated to
obtain the N-tosyl derivative. This compound is chlorinated
at C-1 followed by amination (compounds 15–18; Table 3). It
is expected in the N-tosylated chloro compound the lone pair
of electrons on the nitrogen gets delocalized to oxygen and
not available for the formation of the aziridinium intermedi-
ate. Hence the amino derivative should form with overall
retention of configuration at C-1 (Scheme 5). When the dia-
mine (compound 18) is detosylated and the piperidinyl ring
is constructed on NH2 function, the compound obtained is
(1S,2R)-(1)-1-phenyl-1-diethylamino-2-(1-piperidinyl)propane
(compound 19) which is a diastereomer of compound 3. It
can be observed from Table 4 that the specific rotations,
melting points, and the HPLC retention times of compounds
3 and 19 are different.
tions support the absolute configuration assigned to C-1 in the
diaminated product (compounds 1–14).
To establish the occurrence of SN2 mechanism in the reac-
tion of the aziridinium chloride intermediate with the alkyl/
arylamine during the formation of the 1,2-diamine, (1R,2R)-1-
phenyl-2-(1-piperidinyl)-1-chloropropane hydrochloride} is
treated with triethyl amine to release the base facilitating the
formation of aziridinium chloride before heating with water
overnight with stirring. The alcohol thus obtained shows the
specific rotation ([a]2D5) as 254.5 which agrees with the value
of 252.4 for the (1R,2R)-1-phenyl-2-(1-piperdinyl)-1-propanol
(Table 5). This observation confirms the absolute configura-
tion at C-1 to be ‘‘R’’ in the alcohol, formed through the aziri-
dinium chloride, which is in agreement with the proposed
inversion of configuration at C-1 during the amination of the
aziridinium chloride intermediate.
Furthermore, (1R,2R)-1-phenyl-2-(1-piperdinyl)-1-chloropro-
pane hydrochloride is heated at 40 8C overnight with water
to obtain the 1-alcohol back. In this experiment, the forma-
tion of the aziridinium salt is prevented. The HPLC analysis
of the 1-alcohol as the hydrochloride shows the presence of
two diastereomeric alcohols which must be (1S,2R)-alcohol
(48%) with inversion at C-1 and (1R,2R)-alcohol (51%) with
retention at C-1.
Furthermore,
the
(1S,2R)-1-phenyl-2-amino-1-propanol
hydrochloride is subjected to Walden inversion§ at C-1 and the
piperidinyl ring is built at C-2 with 1,5-dibromopentane. The
diamine is prepared from (1R,2R)-1-phenyl-2-(1-piperidinyl)-1-
propanol hydrochloride with diethylamine through the chloro
derivative. But it is known22 that (1R,2R)- and (1S,2S)-1-phenyl-
2-methylamino-1-propanol hydrochlorides give the 1-chloro
derivatives on treatment with SOCl2 with inversion and reten-
tion with partial racemization at C-1. Hence the diamine pre-
pared from the 1-chloro compound shows partial racemization
with inversion of configuration at C-1 as shown by the reten-
tion times of the diamine products (Table 4). These observa-
This observation indicates the occurrence of racemization
at C-1 during the reaction of H2O with the 1-chloro com-
pound as hydrochloride proceeding through SN1 mechanism
in the aqueous medium.
CONCLUSION
(1R,2R)-1-Phenyl-1-alkyl/arylamino-2-(N-alkyl)propane hydro-
chlorides have been prepared from (1S,2R)-(1)-1-phenyl-2-(N-
alkyl)-1-propanol hydrochloride through the chloro derivative.
When the base is liberated from the hydrochloride salt of the
chloro derivative, aziridinium chloride intermediate is formed
which reacts with the alkyl/aryl amine at the benzylic carbon
with inversion of configuration. The 1,2-diamines are formed
with overall inversion of configuration at C-1. But in the case of
(1S,2R)-(1)-1-phenyl-2-N-tosyl-1-propanol, the aziridinium inter-
mediate is not formed and the diamine is formed with overall
retention of configuration at C-1. In all these cases, the chiral pu-
rity obtained is remarkably enantioselective.
TABLE 5. Specific rotation, chemical purity (HPLC), retention
time, and configuration of the products of the reaction of
(1R,2R)-1-phenyl-2-(1-piperidinyl)-1-chloropropane hydro-
chloride (PPCPꢁHCl) with H2O
Chemical
purity (%)
(HPLC)
Retention
time
Configuration
of the product
Reaction
[a]2D5
ACKNOWLEDGMENTS
PPCPꢁHCl
and H2O
PPCPꢁHCl,
triethylamine
and H2O
222.0
51, 48
99
3.22, 6.00
6.10
1S,2R, 1R,2R
1R,2R
The authors thank Mr. K. Loganathan for analytical sup-
port extended during this investigation.
254.5
252.4
§The (1R,2R)-1-phenyl-2-amino-1-propanol was prepared from the (1S,2R)-iso-
mer through a process involving Walden inversion at C-1.
}The chloro derivative was obtained from (1S,2R)-1-phenyl-2-(1-piperdinyl)-1-
Walden
100
6.05
1R,2R
inversiona
aProduct of Walden inversion of (1S,2R)-1-phenyl-2-(1-piperidinyl)-1-propanol.
propanol on treatment with thionyl chloride.
Chirality DOI 10.1002/chir

270
HITESH KUMAR ET AL.
11. Fristad WE, Brandvold TA, Peterson JR, Thompson SR. Conversion of
LITERATURE CITED
alkenes to 1,2-diazides and 1,2-diamines. J Org Chem 1985;50:3647–3649.
1. Jones DS, Srinivasan A, Kasina S, Fritzberg AR, Wilkening DW. Conven-
ient synthesis of vicinal diamines. J Org Chem 1989;54:1940–1943.
12. Moriarty RM, Khosrowshahi JS. A versatile synthesis of vicinal diazides
using hypervalent iodine. Tetrahedron Lett 1986;27:2809–2812.
2. De Reimer LH, Meares CF, Goodwin DA, Diamanti CI. BLEDTA II: syn-
thesis of a new tumor-visualizing derivative of cobalt (III)-bleomycin. J
Label Compd Radiopharm 1981;18:1517–1534.
13. Swift G, Swern D. Stereospecific synthesis of erythro- and threo-9,10-dia-
minooctadecanoic acids and derivatives. J Org Chem 1966;31:4226–4229.
14. Jones DS. Method of synthesis of vicinal diamines. US Patent
1991;4:933–470.
3. Lehn JM. Cryptates: the chemistry of macropolycyclic inclusion com-
plexes. Acc Chem Res 1978;11:49–57.
15. Garigipati RS, Freyer AJ, Whittle RR, Weinreb SM. Diastereoselective
synthesis of unsaturated vicinal amino alcohols via Diels-Alder reactions
of N-sulfinyl dienophiles. J Am Chem Soc 1984;106:7861–7867.
4. Kasina S, Fritzberg AR, Johnson DL, Eshima D. Tissue distribution prop-
erties of technetium-99m-diamide-dimercaptide complexes and potential
use as renal radiopharmaceuticals. J Med Chem 1986;29:1933–1940.
16. Dieter RK, Deo N, Lagu B, Dieter JW. Stereo- and regioselective synthe-
sis of chiral diamines and triamines from pseudoephedrine and ephed-
rine. J Org Chem 1992;57:1663–1671.
5. Hanessian S, Delorme D, Beavdoin S, Leblanc Y. Design and reactivity of
topologically unique, chiral phosphonamides. Remarkable diastereofacial
selectivity in asymmetric olefination and alkylation. J Am Chem Soc
1984;106:5754–5756.
17. Carter C, Fletcher S, Nelson A. Towards phase-transfer catalysts with a
chiral anion: inducing asymmetry in the reactions of cations. Tetrahe-
dron: Asymmetry 2003;14:1995–2004.
6. Corey EJ, Imwinkelried R, Pikul S, Xiang YB. Practical enantioselective
Diels-Alder and aldol reactions using a new chiral controller system. J
Am Chem Soc 1989;111:5493–5495.
18. Gao J, Liu Y-G, Zhou Y, Zingaro RA. ChemMedChem 2007;2:1723–1729.
19. Fukuta Y, Mita T, Fukuda N, Kanai M, Shibasaki M. De novo synthesis
of Tamiflu via a catalytic asymmetric ring-opening of Meso-aziridines
With TMSN3. J Am Chem Soc 2006;128:6312–6313.
7. Corey EJ, Kim SS. Versatile chiral reagent for the highly enantioselective
synthesis of either anti or syn ester aldols.
1990;112:4976–4977.
J Am Chem Soc
20. Colman B, De Sousa SE, O’Brien P, Towers TD, Watson W. Enantiose-
lective rearrangement of a meso-cyclohexene oxide using norephedrine-
derived chiral bases. Tetrahedron: Asymmetry 1999;10:4175–4182.
8. Gruseck U, Heuschmann M. Asymmetric induction in the inverse Diels-
Alder reaction of chiral 2-methylene-imidazolidines. Tetrahedron Lett
1987;28:2681–2684.
21. March J. Advanced Organic Chemistry: Reactions, Mechanisms and
Structure. New York: Mc Graw-Hill, 1968; p269.
9. Onuma K, Ito T, Nakamura A. Asymmetric hydrogenation with chiral
aminophosphine–rhodium complexes and chiral recognition by bisphos-
phine–rhodium complexes in the asymmetric hydrogenation of olefins
through the chiral helical conformation of phenyl groups on the phospho-
rus atom. Bull Chem Soc Jpn 1980;53:2016–2019.
22. Flores-Parra A, Suarez-Moreno P, Sanchez-Ruiz SA, Tlahuexti M, Jaen-
Gaspar J, Tlahuexti H, Salas-coronado R, Cruz A, Noth H, Contreras R.
Chlorination reactions of ephedrines revisited. Stereochemistry and func-
tional group effect on the reaction mechanisms. Tetrahedron: Asymmetry
1998;9:1661–1671.
10. Fiorini M, Giongo GM. Aminophosphine–rhodium complexes as cata-
lysts in asymmetric hydrogenation. The dependence of the enantiose-
lectivity on the structure of the chiral ligands. J Mol Catal 1979;5:
303–310.
23. Freedman J, Vaal MJ, Huber EW. The Mitsunobu reaction of some Indan
amino alcohols. J Org Chem 1991;56:670–672.
Chirality DOI 10.1002/chir