Stereospecific synthesis of mexiletine and related compounds: Mitsunobu versus Williamson reaction

Article abstract of DOI:10.1016/S0957-4166(00)00332-3

Mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral, orally effective antiarrhythmic agent, and several analogues substituted on either the stereogenic centre or the xylyloxy moiety, were prepared in both, highly enriched, optically active forms. According to the 'chiral pool' approach, the appropriate amino alcohols, protected as the corresponding phthalimide derivatives, were condensed with the desired phenols under either Mitsunobu (method A) or Williamson (method B) conditions. Generally, method A provided the most efficient route, both in terms of yields and number of steps necessary. Only when an isopropyl group was present on the stereogenic centre, i.e. when 2-amino-3-methylbutanol was used as the starting alcohol, method B proved to be the only available route, method A giving no product other than the starting phthalimide derivative. Regardless of the method used, enantiomeric excesses ranged from 91 to 99%. Given the availability of both variously substituted phenols and optically active amino alcohols, the two methods described herein, taken together, may serve as a versatile approach, useful to meet the needs of new chiral, optically active mexiletine analogues, possibly endowed with higher potency in exerting a use-dependent block on sodium channels and/or more resistant to biotransformations. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00332-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3619–3634
Stereospecific synthesis of mexiletine and related
compounds: Mitsunobu versus Williamson reaction
Alessia Carocci,a Alessia Catalano,a Filomena Corbo,a Andrea Duranti,b Rosa Amoroso,c
Carlo Franchini,a Giovanni Lentinia,* and Vincenzo Tortorellaa
aDipartimento Farmaco-Chimico, Universita` degli Studi di Bari, via E. Orabona 4, 70125 Bari, Italy
bIstituto di Chimica Farmaceutica e Tossicologica, Facolta` di Farmacia, Piazza del Rinascimento 6,
Universita` degli Studi di Urbino, 61029 Urbino, Italy
cIstituto di Scienze del Farmaco, Universita` ‘G. D’Annunzio’, Via dei Vestini, 66100 Chieti, Italy
Received 26 July 2000; accepted 22 August 2000
Abstract
Mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral, orally effective antiarrhythmic agent,
and several analogues substituted on either the stereogenic centre or the xylyloxy moiety, were prepared
in both, highly enriched, optically active forms. According to the ‘chiral pool’ approach, the appropriate
amino alcohols, protected as the corresponding phthalimide derivatives, were condensed with the desired
phenols under either Mitsunobu (method A) or Williamson (method B) conditions. Generally, method A
provided the most efficient route, both in terms of yields and number of steps necessary. Only when an
isopropyl group was present on the stereogenic centre, i.e. when 2-amino-3-methylbutanol was used as the
starting alcohol, method B proved to be the only available route, method A giving no product other than
the starting phthalimide derivative. Regardless of the method used, enantiomeric excesses ranged from 91
to 99%. Given the availability of both variously substituted phenols and optically active amino alcohols,
the two methods described herein, taken together, may serve as a versatile approach, useful to meet the
needs of new chiral, optically active mexiletine analogues, possibly endowed with higher potency in
exerting a use-dependent block on sodium channels and/or more resistant to biotransformations. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
Mexiletine 1a (Fig. 1) is a chiral therapeutically relevant compound, clinically used as an
antiarrhythmic,1 antimyotonic,2 and analgesic3 agent, in its racemic form. However, several lines
of evidence have shown that mexiletine enantiomers differ in both pharmacodynamics4 and
pharmacokinetics.5 In the last decade, starting a program aimed at the discovery of sodium
channel blockers effective as antimyotonic agents,4d,6 we needed a convenient and facile
stereospecific route to mexiletine and analogues of general formula 1 (Fig. 1).
* Corresponding author. E-mail: glentini@farmchim.uniba.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00332-3

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
Figure 1. Chemical structure of mexiletine 1a and general formula of 1a analogues 1
Since the resolution methods are in our opinion solvent-wasting, time-consuming, and
tedious,4a,7 we reviewed the ‘chiral pool’ approach syntheses reported for 1a (illustrated by
disconnections in Fig. 2). In the early 1990’s, a method based on the relatively expensive chiral
starting material, (+)-(S)-3-bromo-2-methyl-1-propanol, was reported to allow the synthesis of
(−)-(R)-1a.7a The key step was the stereospecific Hoffmann degradation (disconnection a) of
2-methyl-3-(2,6-xylyloxy)propanamide ultimately obtained by Williamson reaction on the start-
ing bromo alcohol (disconnection b). This four-step route does not give the target molecule in
satisfactory overall yield (7%) and can not be extended to mexiletine analogues bearing
substituents other than methyl on the stereogenic centre since the corresponding chiral starting
alcohols are not commercially available.
Figure 2. Retrosynthetic analysis on mexiletine 1a
Recently, a concise procedure has been proposed: starting from 2 equiv. of both commercially
available enantiomers of 2-amino-1-propanol and 1 equiv. of 1,3-dimethyl-2-fluorobenzenetri-
carbonylchromium, Loughhead et al.8 obtained enantiomerically pure 1a enantiomers in 32–41%
yields referred to the above aryl chromium tricarbonyl complex (disconnection c).
Several related 2,6-xylyl aminoalkyl ethers were also prepared in optically active form, but the
enantiomeric excess (ee) values for these analogues were not given. This elegant two-step route
was not suitable for our goal, being tainted with a few drawbacks. It starts with the preparation
of 1,3-dimethyl-2-fluorobenzenetricarbonylchromium from the relatively expensive 2-fluoro-m-
xylene. Loughhead et al. did not report the yield relative to this step but referred to Mahaffy
and Hamilton,9 who prepared the above aryl chromium tricarbonyl complex in 28% yield. Thus,
overall yields are not supposed to be higher than 15% and are expected to be even lower when
passing to further substituted 2-fluoro-1,3-dimethylbenzenes, due to steric hindrance and/or
electron-withdrawing effects.10 Furthermore, 4-substituted 2-fluoro-1,3-dimethylbenzenes are not
commercially available. Very recently, a facile synthesis of both 1a enantiomers in moderate
overall yields (24–34%) and acceptable ee (93–96%) has been proposed.11 The key step was the
stereospecific OH/NH2 exchange by Mitsunobu’s Gabriel-type synthesis-reaction of phthalimide
with 1-(2,6-xylyloxy)-2-propanol (disconnection a), in turn obtained by regiospecific SN2 propyl-
ene oxide ring opening by 2,6-xylenol (disconnection b). This route suffers from the limited

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3621
number of commercially available chiral epoxides, actually being only applicable to 1a ana-
logues bearing a phenyl group on the stereogenic centre.12
Considering the above routes as not completely satisfactory, we tried to distil the best from
each of them, i.e. the use of widely available phenols to be coupled to relatively inexpensive
optically active a-amino alcohols, in order to develop a new versatile route to 1. Thus, we got
inspiration from a patent by Synthelabo scientists13 who condensed (S)-N-tert-butyloxycar-
bonyl(Boc)-2-aminopropanol with 2-bromo-5-fluorophenol under Mitsunobu conditions (dis-
connection b) to obtain intermediates in the synthesis of polycyclic 5-HT3 and 5-HT4
antagonists. The same reaction has been recently reported to allow the synthesis of (R)- and
(S)-1-phenoxy-2-propanamine as intermediates to N-substituted adenosines.14
Herein we propose the modification of this route, and its application to the preparation of our
target molecules 1. The key step is an etherification reaction, which was performed under both
Mitsunobu (method A) and Williamson (method B) conditions. The relative merits are
discussed.
2. Results and discussion
The synthetic route adopted is shown in Scheme 1. It starts from commercially available
homochiral a-amino alcohols 2a–c which were to be submitted to a condensation step with the
suitable phenols 7a–c. We did not succeed in directly condensing 2a with 2,6-dimethylphenol 7a
under Mitsunobu conditions, this reaction affording a complex mixture in which the desired
product was absent, as stated by gas chromatograph/mass (GMS) analysis. Nor can the
conversion of 2a–c into the corresponding halides, to be submitted to Williamson reaction, be
run on the amino alcohols in their free base form. Thus, a protection for the amino group of
2a–c was needed. Instead of Boc-protection,13,14 phthalic anhydride 3a, a low cost solid, was
chosen as the N-protecting agent, in our opinion being more convenient than normally used
N-tert-butyloxycarbonylating agents which are liquid or relatively expensive solid reagents.
Indeed, condensation of primary amines with 3a generally gives the corresponding phthalimide
derivatives in high yields,15 and the same is true for the relative standard deprotection reaction.16
Furthermore, phthalimide derivatives of amino alcohols have no acidic hydrogen but the
alcoholic one, and this was supposed to enhance yields in the successive Mitsunobu step, where
a possible competition between the N-Boc-amino alcohol carbamic NH and the hindered
xylenolic OH might be feared. In our hands, phthalimido alcohols 4a–c were obtained in high
yields (78–94%, 72–87% after recrystallization). Two 3a analogues, i.e. 3-nitro- and 4-methyl-
phthalic anhydrides (3b and 3c, respectively) may also be used in this step. When 3b was used,
about 40% of the starting 2a was recovered as the corresponding 2-carboxy-3-nitrobenzoyl
derivative 5,17 which may be converted into the desired phthalimide adduct 4b by refluxing 5 in
acidic milieu. Considering 4b coming from the last step together with the first amount directly
obtained from the condensation of 2a with 3b, yields were in the same range observed with 3a,
and the same is true for the condensation of 2c with 3a to give 4e. However, considering the
lower cost of 3a, the latter was taken as the protecting reagent of choice. The phthalimide
derivative 4a was submitted to condensation with the desired phenols 7a–c under Mitsunobu
conditions18 (method A) to obtain the corresponding aryl ethers 8a–c. Yields were generally
moderate (23–65%, see Table 1) and, in this respect, diisopropyl azodicarboxylate (DIAD) seems

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
Scheme 1. Stereospecific synthesis of mexiletine 1a and analogues 1b–e. Reagents and conditions: (i) toluene/Et3N/
reflux/3 h; (ii) toluene/p-TsOH/reflux/6 h or EtOH/HCl/reflux/24 h; (iii) THF/PPh3/DEAD or DIAD (see text)/rt/24
h; (iv) toluene/HBr(g) or HI (g)/−5°C“rt, 18 h“80°C, 2 h (when X=Br or I); THF/SOCl2/pyridine/60°C/6 h (when
X=Cl); pyridine/p-TsCl/rt/18 h (when X=TsO); (v) DMF/Na2CO3/130°C/24 h; (vi) N2H4/AcOH/EtOH/reflux/2 h

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3623
Table 1
Aryloxy alkylamines 1 and phthalimidoalkyl aryl ether intermediates 8 from either phthalimido alcohols 4 or
phthalimido alkyl halogenides 6
Entry Substrate
Substitution Methoda
Phthalimido ether Substitution
Amine
R1
X
% Yield
29
R2
% Overall yield (% ee)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(−)-(R)-4a
(−)-(R)-4a
(+)-(S)-4a
(+)-(S)-4a
(−)-(R)-4a
(+)-(S)-4a
(−)-(R)-4a
(+)-(S)-4a
(+)-(R)-4d
(−)-(S)-4d
(+)-(R)-6h
(−)-(S)-6i
(−)-(R)-6l
(+)-(S)-6m
Me
Me
Me
Me
Me
Me
Me
Me
Bzl
Bzl
Bzl
Bzl
i-Pr
i-Pr
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
I
Ab
Ac
Ab
Ac
Ab
Ab
Ab
Ab
Ac
Ac
B
(R)-8a
(R)-8a
(S)-8a
(S)-8a
(R)-8b
(S)-8b
(R)-8c
(S)-8c
(R)-8d
(S)-8d
(R)-8d
(S)-8d
(R)-8e
(S)-8e
H
H
H
(−)-(R)-1a
(−)-(R)-1a
(+)-(S)-1a
(+)-(S)-1a
(−)-(R)-1b
(+)-(S)-1b
(−)-(R)-1c
(+)-(S)-1c
(−)-(R)-1d
(+)-(S)-1d
22 (98)e
65
28
55
22
31
52
41
43
48 (98)e
17 (99)e
40 (91)e
17 (97)e
25 (95)e
25 (98)e
26 (97)e
13 (93)f
14 (99)g
H
Me
Me
Cl
Cl
H
H
H
H
H
54
57
60
(−)-(R)-1d·HCl 7h (n.d.)d
(+)-(S)-1d·HCl 8h (n.d.)d
Br
I
Br
B
B
B
n.d.d
n.d.d
(−)-(R)-1e·HI
(+)-(S)-1e·HI
8h (99)g
9h (99)g
H
a Method A: Mitsunobu dehydration in THF at room temperature, in the presence of PPh3 and either DEAD or
DIAD, as specified by notes b and c; method B: Williamson etherification.
b Azodicarboxylate: DEAD.
c
Azodicarboxylate: DIAD.
d N.d.=not determined.
e
f
1
Ee evaluated by H NMR, c.s.a.=O-p-chlorophenylmandelic acid, proton observed CHCH3.
Ee evaluated by HPLC on the corresponding N-acetyl derivative, c.s.p.=CHIRALCEL OD-R.
g Ee evaluated by HPLC, c.s.p.=CHIRALCEL OD.
h On the corresponding recrystallized hydrohalides.
to afford higher yields than diethyl azodicarboxylate (DEAD) (cf entries 1 and 2; 3 and 4).
Considering also its lower cost and ease of handling, DIAD should be the preferred reagent.
However, regardless from the azodicarboxylate used, the Mitsunobu dehydration run on
N-phthalylvalinol 4e failed to give the corresponding 2,6-xylyl ether 8e, leaving 4e unreacted.
Fortunately, 8e could be obtained in a sufficiently chemically pure form, as stated by GMS
analysis, by a Williamson reaction19 (method B, entries 13 and 14) of 7a with 4e iodo or bromo
derivative (6l and 6m, respectively), obtained in high yield from 4e by using a procedure

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
previously reported for benzyl alcohols,20 and recently applied to phthalimido alcohols.19b
Method B, in turn, was not satisfactory in giving 8a, regardless of the leaving group used (Br,
Cl, I, TsO). The reaction, indeed, is tainted by competing elimination, which lowers yields and
gives, after work up, an unresolved mixture presenting the desired product together with
2-phthalimidopropene. Neither the yields nor the work up benefited from the use of 3b or 3c as
the protecting agent. However, 1a enantiomers may be obtained directly submitting to hydrazi-
nolysis the mixture resulting from the previous step. Thus method B provided 1a enantiomers in
overall yields lower (<5%) than those observed running method A (40–48%). Method B was
successful also in affording 8d enantiomers, and overall yields were about as moderate as those
observed with method A (7–8%, based on the corresponding recrystallized hydrochlorides,
entries 11 and 12, and 13–14%, entries 9 and 10, respectively), no significant difference being
observed when reacting iodides in lieu of bromides. The final products 1a–e, obtained by
hydrazinolysis16b of the corresponding phthaloylated intermediates 8a–e, were purified and
stored as the corresponding hydrohalides (see Section 4). Free amine samples obtained by
extraction from each of these salts underwent enantiomeric excess (ee) evaluation, which was
1
performed by either chiral H NMR 1a–c or HPLC analysis on chiral stationary phase (c.s.p.)
1
1d–e under the conditions described in the experimental section. For H NMR enantiomeric
excess (ee) evaluation, O-p-chlorophenylmandelic acid was used as the chiral solvating agent
(c.s.a.).21 HPLC analyses were performed on the free base forms of (+)-(S)-1d, (−)-(R)-1e, and
(+)-(S)-1e (c.s.p.: CHIRALCEL OD) and on the N-acetyl derivative of (−)-(R)-1d (c.s.p.:
CHIRALCEL OD-R). Regardless of the method used to obtain 1a–e, ee values ranged from 91
to 99%.
3. Conclusion
In summary, the utilization of Mitsunobu (method A) and Williamson (method B) reactions
for the aryl ether bond formation has allowed the synthesis of mexiletine analogues in highly
enriched optically active forms. Generally, method A provided the most efficient route, both in
terms of yields and number of steps necessary. However, method A failed when applied to the
preparation of 1e, i.e. when 2-amino-3-methylbutanol 2c was used as the starting alcohol; in this
case, method B proved to be the only available route. Regardless of the method used, ee values
found for both enantiomers of 1a–e were acceptable (91–99%). Some of the mexiletine analogues
here reported 1d,e have already shown interesting features in exerting a potent and use-depen-
dent block on skeletal muscle sodium channels6b,c and may be considered as possible candidate
antimyotonic agents. Being the 4-position of mexiletine metabolically hydroxylated, 4-substi-
tuted mexiletine analogues 1b,c might show higher resistance to biotransformation, thus being
potentially preferable to mexiletine for the therapy of myotonic disorders, which are chronic
diseases.
The most enticing aspect of the synthesis reported herein seems to be the possibility to
generate a variety of mexiletine analogues, given the plethora of available phenols and the
availability of relatively not expensive optically active a-amino alcohols. The adaptability of the
Mitsunobu reaction to solid phase synthesis22 provides the potential for vast chemical diversity
when preparing aryloxy alkylamines.
The extension of the route here presented to the preparation of mexiletine major metabolites
in their optically active forms is currently under study.

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3625
4. Experimental
4.1. General
The structures of the compounds were confirmed by routine spectrometric analyses. Only
spectra for compounds to our knowledge never previously described are given. Compounds used
as starting materials were purchased from either Aldrich or Lancaster in the highest commer-
cially available quality. O-p-Chlorophenylmandelic acid used as the c.s.a. was prepared in our
laboratories.21b,c Solvents were RP grade, unless otherwise indicated. Melting points were
determined on a Gallenkamp melting point apparatus in open glass capillary tubes and are
uncorrected. The infrared spectra were recorded on a Perkin–Elmer 283 spectrophotometer and
1
band positions are given in reciprocal centimetres (cm−1). H NMR spectra were recorded on
either an FT Bruker Aspect 3000 (300 MHz) spectrometer or a Varian XL 200 spectrometer (90
MHz) using CDCl3 as solvent, unless otherwise indicated. Chemical shifts are in parts per
million (ppm) relative to either the solvent or tetramethylsilane as internal references, respec-
tively. When determining ee values, 1a–c free base forms were recovered by extraction of a
sample of the corresponding hydrochlorides and dissolved with 2 equiv. of c.s.a. in benzene-d6.
Spectra were registered at 20°C and the splitting of a-methyl groups was observed (Dl=0.080
ca). MS spectra were recorded with a Hewlett-Packard 5995c gas chromatograph/mass spec-
trometer at low resolution. Elemental analyses were performed on a Carlo Erba mod. 1106.
Optical rotations were measured on a Perkin–Elmer 241 MC spectropolarimeter; concentrations
are expressed in g/100 mL and the cell length is 1 dm. HPLC was performed on a Waters
chromatograph (Waters Assoc., Milford, MA) model 600 equipped with a U6K model injector
and a 481 model variable wavelength detector. When CHIRALCEL OD (DAICEL Co.) was
used as the c.s.p., the mobile phase was n-hexane/i-PrOH=99/1 (flow rate: 1.0 mL/min). When
CHIRALCEL OD-R (DAICEL Co.) was used as the c.s.p., the mobile phase was MeOH/
H2O=99/1 (flow rate: 0.4 mL/min). Chromatographic separations were performed on silica gel
columns by flash chromatography (Kieselgel 60, 0.040–0.063 mm, Merck) using the technique
described by Still et al.23 TLC analyses were performed on precoated silica gel on glass or
aluminium sheets (Kieselgel 60 F254, Merck).
4.2. General procedure for the preparation of phthalimido alcohols 4a–e15
A mixture of 2-amino-1-alcanol 2a–c (13.4 mmol), anhydride 3a–c (13.4 mmol), triethylamine
(1.34 mmol), and 20 mL of toluene is heated under reflux in a flask fitted with a Dean–Stark
tube for 3 h. During this period, the temperature of the oil bath is maintained at about 130°C
and water separates. All volatile matter are then evaporated under vacuum and the solid residue
is taken up with EtOAc and washed with 2N HCl, NaHCO3, and H2O. The organic phase is
dried (Na2SO4) and concentrated under vacuum. The crude solid is recrystallized to give 4a–e.
When 3-nitrophthalic anhydride 3b was used to protect 2a, about 40% of the starting amino
alcohol was recovered as the corresponding 2-carboxy-3-nitrobenzoyl derivative 5. The latter
was converted into the desired phthalimide adduct 4b by refluxing a suspension of 5 in either
toluene, separating water for 6 h in the presence of a catalytic amount of p-toluensulphonic acid
(yield from 5 to 4b: 49%), or EtOH/HCl 4% (24 h, yield from 5 to 4b: 78%).

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
4.2.1. (−)-(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione (−)-(R)-4a
Yield: 90% (86% after recrystallization); mp 84–85°C (EtOAc–petroleum ether), lit.:24 80°C
(toluene); [h]2D0=−14.6 (c 3.2, CHCl3), lit.:24 −12.2 (c 1.13, CHCl3); MS: m/z 205 (M+, <1), 174
(100). Spectroscopic data were according to those reported for the enantiomer (+)-(S).25
4.2.2. (+)-(S)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione (+)-(S)-4a
Yield: 94% (87% after recrystallization); mp 84–85°C (EtOAc–petroleum ether), lit.:24 86–87°C
(acetone–hexane); [h]2D0=+16.5 (c 2, CHCl3), lit.:25 +13.7 (c 4.2, CHCl3); MS: m/z 205 (M+, <1),
174 (100). Spectroscopic data were according to those reported in the literature.25
4.2.3. ( )-(RS)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione ( )-(RS)-4a
Yield: 95% (88% after recrystallization); mp 97–98°C (EtOAc–petroleum ether). Spectroscopy
data were identical to those found for (+)-(S)-4a.
4.2.4. (+)-(S)-2-(2-Hydroxy-1-methylethyl)-4-nitro-1H-isoindole-1,3(2H)-dione (+)-(S)-4b
Yield: 49%; mp 113–114°C (EtOAc–hexane); [h]2D0=+21.4 (c 2, CHCl3); IR (KBr pellet): 3520
1
(OH), 1770, 1720 (CꢀO), 1540 (NO2); H NMR (90 MHz): l 1.5 (d, 3H, J=7.5 Hz, CH3CH),
2.6 (br s, 1H, OH), 3.7–4.3 (m, 2H, CH2CH), 4.4–4.7 (m, 1H, CH), 7.8–8.3 (m, 3H, Ar); MS:
m/z 219 ([M−31]+, 100).
4.2.5. ( )-(RS)-2-(2-Hydroxy-1-methylethyl)-4-nitro-1H-isoindole-1,3(2H)-dione ( )-(RS)-4b
Yield: 58%; mp 112–114°C (EtOAc–hexane). All other nonchiroptical physical characteristics
were identical to those found for (+)-(S)-4b.
4.2.6. (+)-(S)-2-(2-Hydroxy-1-methylethyl)-5-methyl-1H-isoindole-1,3(2H)-dione (+)-(S)-4c
Yield: 69%; mp 105–107°C (EtOAc–petroleum ether); [h]2D0=+17.8 (c 2, CHCl3); IR (KBr
1
pellet): 3502 (OH), 1766, 1693 (CꢀO); H NMR (90 MHz): l 1.4 (d, 3H, J=7.5 Hz, CH3CH),
2.5 (s, 3H, CH3Ar), 3.7–4.2 (m, 2H, CH2CH), 4.2–4.7 (m, 1H, CH), 7.5 (d, 1H, J=9 Hz, Ar
HC-7), 7.6 (s, 1H, Ar HC-4), 7.7 (d, 1H, J=9 Hz, Ar HC-6); MS: m/z 219 (M+, <1), 188 (100).
4.2.7. (+)-(R)-2-(1-Benzyl-2-hydroxyethyl)-1H-isoindole-1,3(2H)-dione (+)-(R)-4d
Yield: 93% (77% after recrystallization); mp 110–112°C (EtOAc–petroleum ether), lit.:26
95–97°C (Et2O); [h]2D0=+132 (c 2, CHCl3), lit.:26 +145 (c 2, EtOH). Spectrometry data were
according to those reported in the literature.26 Anal. calcd for (C17H15NO3): C, 72.58; H, 5.37;
N, 4.98. Found: C, 72.68; H, 5.44; N, 4.89.
4.2.8. (−)-(S)-2-(1-Benzyl-2-hydroxyethyl)-1H-isoindole-1,3(2H)-dione (−)-(S)-4d
Yield: 96% (82% after recrystallization); mp 111–112°C (EtOAc–petroleum ether), lit.:26
96–98°C (Et2O); [h]2D0=−119 (c 2, CHCl3), lit.:26 −136 (c 2, EtOH). Spectrometry data were
according to those reported in the literature.26 Anal. calcd for (C17H15NO3): C, 72.58; H, 5.37;
N, 4.98. Found: C, 73.00; H, 5.60; N, 4.95.
4.2.9. (R)-2-[1-(Hydroxymethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (R)-4e
1
Yield: 81%; mp 36–38°C; [h]2D0=−11.5 (c 3.1, EtOH); [h]2D0=+2.8 (c 2, CHCl3). H NMR and
MS spectra were according to those reported in the literature for the enantiomer (S).25

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3627
4.2.10. (S)-2-[1-(Hydroxymethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (S)-4e
Yield: 78% (72% after recrystallization); mp 36–37°C (EtOAc–petroleum ether); [h]2D0=+11.7
1
(c 3.2, EtOH), lit.:25 +8.33 (c 2.924, EtOH); [h]D20=−2.9 (c 2, CHCl3); H NMR and MS spectra
were according to those reported in the literature.25
4.2.11. ( )-(RS)-2-(2-Hydroxy-1-methylethylaminocarbonyl)-6-nitrobenzoic acid ( )-(RS)-5
1
Yield: 39%; mp 148–149°C (EtOAc–petroleum ether); IR (KBr pellet): 1720 (CꢀO); H NMR
(90 MHz, CDCl3/DMSO-d6): l 1.2 (d, 3H, J=7.5 Hz, CH3CH), 3.5 (d, 2H, J=6.0 Hz,
CH2CH), 3.9–4.3 (m, 1H, CH), 7.4–8.1 (m, 5H, Ar+OH+NH).
4.3. General procedure for the preparation of phthalimidoalkyl aryl ethers (8a–e) through
Mitsunobu coupling18 (method A)
To a stirred solution of the suitable phthalimidoalcohol (4a–d, 12.5 mmol), phenol (7a–c, 18.7
mmol), and triphenylphosphine (18.7 mmol), in dry THF (120 mL) under N2 atmosphere, a
solution containing 18.7 mmol of DEAD or DIAD, as indicated below for each product, in dry
THF (120 mL) is added dropwise. The mixture is stirred at room temperature for 24 h. The
solvent is then evaporated under vacuum, ether is added and the precipitate formed is filtered
off. The filtrate is evaporated and the residue is purified by silica gel column chromatography
(EtOAc/petroleum ether 2:8).
4.3.1. (−)-(R)-2-[2-(2,6-Dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione
(−)-(R)-8a
Azodicarboxylate used: DIAD. Yield: 65%; [h]2D0=−50 (c 2.5, CHCl3), lit.:11 −55 (c 2.2,
CHCl3). Spectrometry data were in agreement with the literature.11
4.3.2. (+)-(S)-2-[2-(2,6-Dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione (+)-(S)-8a
Azodicarboxylate used: DIAD. Yield: 55%; [h]2D0=+55 (c 3.1, CHCl3), lit.:11 +55 (c 2.5,
CHCl3). Spectrometry data were in agreement with the literature.11
4.3.3. (−)-(R)-2-[1-Methyl-2-(2,4,6-trimethylphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione
(−)-(R)-8b
Azodicarboxylate used: DEAD. Yield: 22%; [h]2D0=−42 (c 2.0, CHCl3); IR (film): 1774, 1711
1
(CꢀO); H NMR (90 MHz): l 1.5 (d, 3H, J=7.5 Hz, CH3CH), 2.2 (s overlap s at 2.25, 6H,
CH3C-2,6), 2.25 (s, 3H, CH3C-4), 3.9 (dd, 1H, J=9 and J=6, CHHCH), 4.3 (apparent t, 1H,
J=9, CHHCH), 4.7–5.1 (m, 1H, CH), 6.8 (br s, 2H, ArO HC), 7.8–8.0 (m, 4H, Ar CH); MS:
m/z 323 (M+, 11), 188 (100).
4.3.4. (+)-(S)-2-[1-Methyl-2-(2,4,6-trimethylphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione
(+)-(S)-8b
Azodicarboxylate used: DEAD. Yield: 31%; [h]2D0=+40 (c 2.6, CHCl3). Spectrometry data
were identical to those found for (−)-(R)-8b.
4.3.5. (−)-(R)-2-[2-(4-Chloro-2,6-dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione
(−)-(R)-8c
Azodicarboxylate used: DEAD. Yield: 52%; [h]2D0=−38 (c 3.0, CHCl3); IR (film): 1772, 1709

3628
A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
(CꢀO); 1H NMR (90 MHz): l 1.6 (d, 3H, J=7.5 Hz, CH3CH), 2.2 (s, 6H, 2CH3Ar), 3.9 (dd, 1H,
J=9 and 6, CHHCH), 4.4 (apparent t, 1H, J=9, CHHCH), 4.7–5.1 (m, 1H, CH), 7.0 (s, 2H,
ArO HC), 7.7–8.0 (m, 4H, Ar CH); MS: m/z 343 (M+, 8), 188 (100).
4.3.6. (+)-(S)-2-[2-(4-Chloro-2,6-dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione
(+)-(S)-8c
Azodicarboxylate used: DEAD. Yield: 41%; [h]2D0=+35 (c 3.3, CHCl3). Spectrometry data
were identical to those found for (−)-(R)-8c.
4.3.7. (+)-(R)-2-[1-Benzyl-2-(2,6-dimethylphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione
(+)-(R)-8d
Azodicarboxylate used: DIAD. Yield: 43% (33% after recrystallization); mp 115–116°C
1
(EtOAc–petroleum ether); [h]2D0=+33.7 (c 2.0, CHCl3); IR (KBr pellet): 1768, 1700 (CꢀO); H
NMR (300 MHz): l 2.2 (s, 6H, CH3Ar), 3.2–3.4 (m, 2H, ArCH2CH), 3.8–4.1 (m, 1H,
CHCHHO), 4.4–4.6 (m, 1H, CHCHHO), 4.8–5.3 (m, 1H, CH), 7.0 (s, 3H ArO HC), 7.3 (s, 5H,
Ph HC), 7.6–7.9 (m, 4H, Ar HC); MS: m/z 385 (M+, 9), 264 (100).
4.3.8. (−)-(S)-2-[1-Benzyl-2-(2,6-dimethylphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione (−)-(S)-8d
Azodicarboxylate used: DIAD. Yield: 54% (46% after recrystallization); mp 114–115°C
(EtOAc–petroleum ether); [h]2D0=−36.4 (c 2, CHCl3). Spectrometry data were identical to those
found for (+)-(R)-8d.
4.4. General procedure for the preparation of bromo- or iodoalkyl phthalimides 6a–c,f,h–m19b,20
Into a stirred ice-cooled solution of the suitable phthalimido alcohol 4a–e (6 mmol) in dry
toluene (30 mL) under N2 atmosphere, HBr or HI is bubbled until saturation occurred. The
mixture is stirred at −5°C for 1 h, at room temperature for 18 h, and at 80°C for 2 h. The
solvent is then evaporated under vacuum and the residue, taken up with EtOAc, is washed with
6N NaOH, 2N HCl, and H2O. The organic layer is dried (Na2SO4) and concentrated under
vacuum to give a solid which may be purified by silica gel column chromatography (EtOAc/
petroleum ether 2:8) and/or by recrystallization.
4.4.1. (−)-(R)-2-(2-Bromo-1-methylethyl)-1H-isoindole-1,3(2H)-dione (−)-(R)-(6a)
Yield: 92% (78% after recrystallization); mp 70–71°C (benzene–hexane); [h]2D0=−20.6 (c 2,
1
CHCl3); IR (KBr pellet): 1769, 1699 (CꢀO); H NMR (90 MHz): l 1.6 (d, 3H, J=7.5 Hz,
CH3CH), 3.5–4.2 (m, 2H, CH2CH), 4.4–4.9 (m, 1H, CH), 7.8–8.3 (m, 4H, Ar). MS: m/z 267
(M+, 1), 174 (100).
4.4.2. (+)-(S)-2-(2-Bromo-1-methylethyl)-1H-isoindole-1,3(2H)-dione (+)-(S)-(6a)
Yield: 95% (90% after recrystallization); mp 71–72°C (benzene–hexane); [h]2D0=+22.4 (c 2,
CHCl3). All other nonchiroptical physical characteristics were identical to those found for
(−)-(R)-6a.
4.4.3. ( )-(RS)-2-(2-Bromo-1-methylethyl)-1H-isoindole-1,3(2H)-dione ( )-(RS)-(6a)
Yield: 98% (92% after recrystallization); mp 61–62°C (benzene–hexane). All other nonchirop-
tical physical characteristics were identical to those found for both enantiomers.

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3629
4.4.4. (+)-(S)-2-(2-Bromo-1-methylethyl)-5-methyl-1H-isoindole-1,3(2H)-dione (+)-(S)-(6b)
Yield: 77% (68% after recrystallization); mp 84–85°C (benzene–hexane); [h]2D0=+25.8 (c 2,
1
CHCl3); IR (KBr pellet): 1770, 1699 (CꢀO); H NMR (90 MHz): l 1.6 (d, 3H, J=7.5 Hz,
CH3CH), 2.5 (s, 3H, CH3Ar), 3.6 (dd, 1H, J=9 Hz and J=6 Hz, CHHCH), 4.1 (apparent t,
1H, J=9 Hz, CHHCH), 4.5–4.9 (m, 1H, CH), 7.5 (d, 1H, J=9 Hz, Ar HC-7), 7.6 (s, 1H, Ar
HC-4), 7.7 (d, 1H, J=9 Hz, Ar HC-6); MS: m/z 281 (M+, 1), 188 (100).
4.4.5. (+)-(S)-2-(2-Bromo-1-methylethyl)-4-nitro-1H-isoindole-1,3(2H)-dione (+)-(S)-(6c)
Yield: 70% (46% after recrystallization); mp 91–92°C (AcOEt-i-Pr2O); [h]2D0=+22.9 (c 2.3,
1
CHCl3); IR (KBr pellet): 1801, 1732 (CꢀO), 1537 (NO2); H NMR (90 MHz): l 1.5 (d, 3H,
J=7.5 Hz, CH3CH), 3.5 (dd, 1H, J=9 Hz and J=6 Hz, CHHCH), 4.0 (apparent t, 1H, J=9
Hz, CHHCH), 4.4–4.7 (m, 1H, CH), 7.8–8.3 (m, 3H, Ar); MS: m/z 312 (M+, 3), 219 (100).
4.4.6. (−)-(R)-2-(2-Iodo-1-methylethyl)-1H-isoindole-1,3(2H)-dione (−)-(R)-(6f)
Yield: 80% (67% after recrystallization); mp 57–58°C (MeOH); [h]2D0=−23.6 (c 2, CHCl3); IR
(KBr pellet): 1766, 1697 (C=O); 1H NMR (90 MHz): l 1.7 (d, 3H, J=7.5 Hz, CH3CH), 3.5 (dd,
1H, J=9 Hz and J=6 Hz, CHHCH), 3.9 (apparent t, 1H, J=9 Hz, CHHCH), 4.3–4.8 (m, 1H,
CH), 7.7–8.0 (m, 3H, Ar); MS: m/z 315 (M+., 6), 188 (100).
4.4.7. (+)-(S)-2-(2-Iodo-1-methylethyl)-1H-isoindole-1,3(2H)-dione (+)-(S)-(6f)
Yield: 95% (77% after recrystallization); mp 58–59°C (MeOH); [h]2D0=+21.3 (c 2, CHCl3). All
other nonchiroptical physical characteristics were identical to those found for (−)-(R)-6f.
4.4.8. ( )-(RS)-2-(2-Iodo-1-methylethyl)-1H-isoindole-1,3(2H)-dione ( )-(RS)-(6f)
Yield: 72% (68% after recrystallization); mp 64–65°C (MeOH). All other nonchiroptical
physical characteristics were identical to those found for both enantiomers.
4.4.9. (+)-(R)-2-(1-Benzyl-2-iodoethyl)-1H-isoindole-1,3(2H)-dione (+)-(R)-(6h)
Yield: 89% (79% after recrystallization); mp 140–141°C (MeOH), lit.:27 141–142°C (MeOH);
[h]2D0=+96.0 (c 2, CHCl3), lit.:27 +99.1 (c 1, acetone); MS: m/z 391 (M+, 1), 300 (100).
Spectroscopy data were corresponding to the literature.27
4.4.10. (−)-(S)-2-(1-Benzyl-2-iodoethyl)-1H-isoindole-1,3(2H)-dione (−)-(S)-(6h)
Yield: 65% (54% after recrystallization); mp 140–141°C (MeOH), lit.:28 138–140°C; [h]D20=−
97.8 (c 2, CHCl3); MS: m/z 391 (M+, 1), 300 (100). Spectroscopy data were corresponding to the
literature.28
4.4.11. (+)-(R)-2-(1-Benzyl-2-bromoethyl)-1H-isoindole-1,3(2H)-dione (+)-(R)-(6i)
Yield: 83% (77% after recrystallization); mp 119–120°C (MeOH), lit.:29 119–121°C; [h]D20=+
105 (c 2, CHCl3), lit.:29 +120.2 (c 1.896, CH2Cl2); MS: m/z 343 (M+, 1), 264 (100). Spectroscopy
data were in agreement with those reported in the literature.29
4.4.12. (−)-(S)-2-(1-Benzyl-2-bromoethyl)-1H-isoindole-1,3(2H)-dione (−)-(S)-(6i)
Yield: 70% (62% after recrystallization); mp 118–119°C (MeOH), lit.:28 118–119°C (MeOH);
[h]2D0=−107 (c 2, CHCl3), lit.:29 −112.2 (c 1.274, CH2Cl2); MS: m/z 343 (M+, 1), 264 (100).
Spectroscopy data were in agreement with the literature.29

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
4.4.13. (−)-(R)-2-[1-(Iodomethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (−)-(R)-6l
Yield: 95% (80% after recrystallization); mp 107–108°C (MeOH); [h]2D0=−11.0 (c 2, CHCl3);
1H NMR (300 MHz): l 0.91 (d, 3H, J=6.7 Hz, CH3CHCH3), 1.07 (d, 3H, J=6.8 Hz,
CH3CHCH3), 2.33–2.46 (m, 1H, CH3CHCH3), 3.66 (dd, 1H, J=10 Hz and J=3.6 Hz,
CHꢁCHHI), 3.97 (dd, 1H, J=12 Hz and J=9.9 Hz, CHꢁCHHI), 4.06–4.14 (m, 1H, NCHCH2),
7.69–7.75 (m, 2H, Ar HC-5,6), 7.82–7.88 (m, 2H, Ar HC-4,7); MS: m/z 343 (M+, 6), 300 (100).
4.4.14. (+)-(S)-2-[1-(Iodomethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (+)-(S)-6l
Yield: 91% (68% after recrystallization); [h]2D0=+10.8 (c 2, CHCl3). Nonchiroptical physical
characteristics are identical to those found for (−)-(R)-6l.
4.4.15. (−)-(R)-2-[1-(Bromomethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (−)-(R)-6m
Yield: 84% (62% after recrystallization); mp 70–71°C (MeOH), lit.:29 61–63°C; [h]D20=−19.4 (c
2, CHCl3), lit.:29 −11.3 (c 1.380, CH2Cl2);29 MS: m/z 295 (M+, 9), 252 (100). Spectroscopy data
were in agreement with those reported in the literature.29
4.4.16. (+)-(S)-2-[1-(Bromomethyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (+)-(S)-6m
Yield: 95% (81% after recrystallization); mp 70–71°C (MeOH), lit.:29 61–64°C; [h]D20=+18.2 (c
2, CHCl3), lit.:29 +10.0 (c 3.218, CH2Cl2);29 MS: m/z 295 (M+, 8), 252 (100). Spectroscopy data
were in agreement with those reported in the literature.29
4.5. General procedure for the preparation of cloroalkyl phthalimides 6d,e
A solution of the suitable phthalimido alcohol (1.20 mmol, 1 equiv.), pyridine (0.1 mL, 1.32
mmol, 1.1 equiv.), and thionyl chloride (0.1 mL, 1.26 mmol, 1.05 equiv.) in anhydrous THF (2
mL) is stirred under nitrogen at 60°C for 6 h. Volatile components are removed under vacuum
and the crude residue is taken up with Et2O. The solution is washed with water, dried (Na2SO4)
and concentrated under vacuum to give an oil which is purified by silica gel column chromatog-
raphy (EtOAc/petroleum ether 2:8).
4.5.1. ( )-(RS)-2-(2-Chloro-1-methylethyl)-1H-isoindole-1,3(2H)-dione ( )-(RS)-6d
1
Yield: 50%; H NMR (90 MHz): l 1.6 (d, 3H, J=7.5 Hz, CH3CH), 3.7 (dd, 1H, J=9 Hz and
J=6 Hz, CHHCH), 4.2 (apparent t, 1H, J=9 Hz, CHHCH), 4.4–4.8 (m, 1H, CH), 7.7–8.0 (m,
4H, Ar); MS: m/z 223 (M+, 1), 174 (100).
4.5.2. ( )-(RS)-2-(2-Chloro-1-methylethyl)-4-nitro-1H-isoindole-1,3(2H)-dione ( )-(RS)-6e
1
Yield: 56%; H NMR (90 MHz): l 1.7 (d, 3H, J=7.5 Hz, CH3CH), 3.7 (dd, 1H, J=9 Hz and
J=6 Hz, CHHCH), 4.2 (apparent t, 1H, J=9 Hz, CHHCH), 4.4–4.8 (m, 1H, CH), 7.8–8.2 (m,
3H, Ar); MS: m/z 268 (M+, 2), 219 (100).
4.6. Preparation of (+)-(S)-2-phthalimidopropyl toluene-p-sulphonate (+)-(S)-6g
The procedure proposed by Casara et al. was followed.30 Yield: 82% (65% after recrystalliza-
tion); mp 144–145°C (CH2Cl2–petroleum ether), lit:30 135°C (ether–CH2Cl2); [h]D20=+22.0 (c 2,
CHCl3), lit.:30 +20.0 (c 0.504, CHCl3);30 MS: m/z 359 (M+, 2), 174 (100). Spectroscopy data were
in agreement with those reported in the literature.30

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3631
4.7. General procedure for the preparation of phthalimidoalkyl aryl ethers 8a–e through
Williamson coupling19 (method B)
A stirred mixture of 2,6-dimethylphenol (4.0 mmol) and Na2CO3 (4.4 mmol) in dry DMF (70
mL), is heated under N2 atmosphere until the temperature of 130°C is reached. Then the suitable
haloalkyl phthalimide 6a–c,f,h–m is added and heating is maintained for 24 h. The solvent is
then evaporated under vacuum, taken up with EtOAc, and washed with 0.5N NaOH, and H2O.
The organic layer is dried (Na2SO4) and concentrated under vacuum. Purification of the crude
oil residue by column chromatography (EtOAc/petroleum ether 2:8) gives a crude solid which is
checked for purity by GMS analysis and judged suitable for the next step. MS data for 8e
enantiomers: m/z 337 (M+, 13), 216 (100).
4.8. General procedure for the removal of the phthalimido protecting group16b
To a stirred solution of the phthalimidoalkyl aryl ether 8a–e (1 mmol) in absolute EtOH (10
mL), glacial AcOH (3 mmol), and N2H.4H2O (3 mmol) is added. The mixture is heated under
reflux for 1.5 h and then is filtered on a Celite pad; the solvent is evaporated under vacuum. The
residue is taken up with EtOAc and extracted with 2N HCl, then the aqueous phase is made
alkaline with 2N NaOH and extracted twice with EtOAc. The combined organic layers are dried
(Na2SO4) and concentrated under vacuum. The final product is an uncoloured oil which is
purified by crystallization of the corresponding hydrohalide, obtained treating with a few drops
of the suitable hydrohalide aqueous solution and azeotropically removing water.
4.8.1. (−)-(R)-1-(2,6-Dimethylphenoxy)-2-propanamine (−)-(R)-1a
Yield: 78%; [h]2D0=−2.1 (c 3.0, CHCl3), lit.:11 −2.7 (c 4.7, CHCl3); spectrometry data were in
agreement with the literature.11,7a (−)-(R)-1a·HCl, yield: 28%; mp 203–204°C (EtOH–Et2O),
lit.:11 204–205°C (EtOH–Et2O); [h]D20=−2.4 (c 2.0, MeOH), 98% ee (1H NMR), lit.:8 −2.9 (c 1.00,
MeOH, >99% ee). Anal. calcd for (C11H18ClNO): C, 61.85; H, 8.41; N, 6.49. Found: C, 60.93;
H, 8.56; N, 6.39.
4.8.2. (+)-(S)-1-(2,6-Dimethylphenoxy)-2-propanamine (+)-(S)-1a
Yield: 76%; [h]2D0=+2.6 (c 3.0, MeOH), lit.:11 +2.5 (c 4.9, CHCl3); spectrometry data were in
agreement with the literature.11,7a (+)-(S)-1a·HCl, yield: 25%; mp 196–198°C (EtOH–Et2O), lit.:11
193–194°C (EtOH–Et2O); [h]2D0=+2.2 (c 2.0, MeOH), 91% ee (1H NMR), lit.:8 +2.6 (c 1.00,
MeOH, 99% ee). Anal. calcd for (C11H18ClNO): C, 61.25; H, 8.41; N, 6.49. Found: C, 61.52; H,
8.66; N, 6.46.
4.8.3. (−)-(R)-1-(2,4,6-Trimethylphenoxy)-2-propanamine (−)-(R)-1b
1
Yield: 80%; [h]2D0=−1.6 (c 3.0, CHCl3); H NMR (300 MHz): l 1.57 (d, 3H, J=7.5 Hz,
CH3CH), 1.73 (br s, 2H, NH2), 2.22 (s, 6H, CH3C-2,6), 2.23 (s, 3H, CH3C-4), 3.67–3.80 (m, 1H,
CH), 3.81–3.98 (m, 2H, CH2), 6.63 (s, 2H, Ar); MS: m/z 193 (M+, 6), 58 (100). (−)-(R)-1b·HCl,
yield: 34%; mp 184–185°C (EtOH–Et2O); [h]2D0=−2.0 (c 2.6, MeOH), 97% ee (1H NMR). Anal.
calcd for (C12H20ClNO): C, 62.73; H, 8.77; N, 6.10. Found: C, 62.82; H, 8.93; N, 6.16.
4.8.4. (+)-(S)-1-(2,4,6-Trimethylphenoxy)-2-propanamine (+)-(S)-1b
Yield: 87%; [h]2D0=+1.8 (c 2.6, CHCl3). All spectrometry data were identical to those obtained
from (−)-(R)-1b analyses. (+)-(S)-1b·HCl, yield: 27%; mp 187–188°C (EtOH–Et2O); [h]2D0=+1.8

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A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
(c 2.4, MeOH), 95% ee (1H NMR). Anal. calcd for (C12H20ClNO): C, 62.73; H, 8.77; N, 6.10.
Found: C, 62.37; H, 9.13; N, 6.01.
4.8.5. (−)-(R)-1-(4-chloro-2,6-dimethylphenoxy)-2-propanamine (−)-(R)-1c
1
Yield: 51%; [h]2D0=−1.2 (c 2.2, CHCl3); H NMR (300 MHz): l 1.38 (d, 3H, J=6.0 Hz,
CH3CH), 1.6 (bs, 2H, NH2) 2.25 (s, 6H, CH3Ar), 3.61–3.72 (m, 2H, CH2), 3.88–3.99 (m, 1H,
CH), 7.8–8.2 (m, 3H, Ar); MS: m/z 213 (M+, 3), 58 (100). (−)-(R)-1c·HCl, yield: 16%; mp
256–257°C (EtOH–Et2O); [h]2D0=−2.1 (c 2.0, MeOH), 98% ee (1H NMR). Anal. calcd for
(C11H17Cl2NO): C, 52.81; H, 6.85; N, 5.60. Found: C, 53.02; H, 7.01; N, 5.68.
4.8.6. (+)-(S)-1-(4-chloro-2,6-dimethylphenoxy)-2-propanamine (+)-(S)-1c
Yield: 67%; [h]2D0=+0.9 (c 2.8, CHCl3). All spectrometry data were identical to those obtained
from (−)-(R)-1c analyses. (+)-(S)-1c·HCl, yield: 35%; mp 257–258°C (EtOH–Et2O); [h]2D0=+2.2
(c 2.0, MeOH), 97% ee (1H NMR). Anal. calcd for (C11H17Cl2NO): C, 52.81; H, 6.85; N, 5.60.
Found: C, 52.68; H, 7.26; N, 5.77.
4.8.7. (−)-(R)-a-[(2,6-dimethylphenoxy)methyl]benzeneethanamine (−)-(R)-1d
Yield: 33%; [h]2D0=−3.3 (c 2.0, CHCl3); MS: m/z 255 (M+, 2), 120 (100). (−)-(R)-1d·HCl, yield:
20%; mp 195–197°C (EtOH–Et2O), lit.:8 186–187°C (EtOH–Et2O); [h]2D0=−23 (c 2.0, MeOH),
93% ee (HPLC analysis on the corresponding N-Ac-derivative, obtained by standard acetylation
reaction19b of the free base, CHIRALCEL OD-R, tR 14.8 min), lit.:8 [h]2D0=−20.1 (c 0.40,
MeOH, enantiomeric purity not given). Spectroscopy data were in agreement with the litera-
ture.8 Anal. calcd for (C17H22ClNO): C, 68.56; H, 7.67; N, 4.70. Found: C, 58.76; H, 7.58; N,
4.77.
4.8.8. (+)-(S)-a-[(2,6-dimethylphenoxy)methyl]benzeneethanamine (+)-(S)-1d
Yield: 28%; [h]2D0=+4.7 (c 2.0, CHCl3); MS data identical to those obtained from (−)-(R)-1d.
(+)-(S)-1d·HCl, yield: 18%; mp 194–196°C (EtOH–Et2O), lit.:8 185–186°C (EtOH–Et2O); [h]D20=
+20 (c 2.0, MeOH), 99% (HPLC, CHIRALCEL OD, tR 19.1 min), lit.:8 +24.5 (c 0.07, MeOH,
enantiomeric purity not given). Spectroscopy data were in agreement with the literature.8 Anal.
calcd for (C17H22ClNO): C, 68.56; H, 7.67; N, 4.70. Found: C, 68.65; H, 7.32; N, 4.67.
4.8.9. (−)-(R)-1-(2,6-dimethylphenoxy)-3-methyl-2-butanamine (−)-(R)-1e
[h]2D0=−1.4 (c 2.5, CHCl3); MS: m/z 207 (M+, 1), 72 (100). (−)-(R)-1e·HI, yield: 10%; mp
196–198°C (CHCl3-i-Pr2O); [h]2D0=−3.0 (c 2.0, MeOH), 99% ee (HPLC, CHIRALCEL OD, tR
12.7 min); 1H NMR (300 MHz): l 1.12 (d, 3H, J=6.9 Hz, CH3CHCH3), 1.21 (d, 3H, J=7.0 Hz,
CH3CHCH3), 2.29 (s, 6H, CH3Ar), 2.45–2.52 (m, 1H, CH3CHCH3), 3.62–3.68 (m, 1H,
CHCHCH2), 3.96 (dd, 1H, J=10.3 Hz and J=4.5 Hz, CHCHHO), 4.13 (dd, 1H, J=10.3 Hz
and J=7.6 Hz, CHCHHO), 6.88–6.97 (m, 3H, Ar). Anal. calcd for (C13H22INO·0.5H2O): C,
45.36; H, 6.73; N, 4.07. Found: C, 45.76; H, 6.58; N, 4.16.
4.8.10. (+)-(S)-1-(2,6-dimethylphenoxy)-3-methyl-2-butanamine (+)-(S)-1e
[h]2D0=+1.9 (c 2.6, CHCl3); MS data identical to those obtained from (−)-(R)-1e. (+)-(S)-
1e·HI, yield: 11%; mp 198–200°C (CHCl3–hexane); [h]2D0=+2.4 (c 1.0, MeOH), 99% ee (HPLC,
CHIRALCEL OD, tR 15.1 min); 1H NMR data were identical to those obtained from
(−)-(R)-1e·HI. Anal. calcd for (C13H22INO·0.5H2O): C, 45.36; H, 6.73; N, 4.07. Found: C, 45.78;
H, 6.50; N, 4.20.

A. Carocci et al. / Tetrahedron: Asymmetry 11 (2000) 3619–3634
3633
Acknowledgements
We thank the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (MURST)
for financial support. Thanks are also due to Dr. Giuseppe Carbonara for helpful hints.
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