Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine, one of the major metabolites of mexiletine

Article abstract of DOI:10.1016/j.tetasy.2007.10.002

Hydroxymethylmexiletine (HMM), one of the main metabolites of mexiletine, has been synthesized in both racemic and optically active forms following two alternative routes. The ee values for both HMM enantiomers were 98%, as assessed by ¹H NMR analysis in the presence of (-)-(R)-(2-naphthyloxy)phenylacetic acid as a chiral solvating agent and electrophoretic analysis using β-cyclodextrine sulfated sodium salt as a chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2007.10.002

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2409–2417
Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine,
one of the major metabolites of mexiletine
Maria Maddalena Cavalluzzi, Alessia Catalano, Claudio Bruno, Angelo Lovece,
Alessia Carocci, Filomena Corbo, Carlo Franchini,
Giovanni Lentini* and Vincenzo Tortorella
`
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari, via E. Orabona n. 4, 70125 Bari, Italy
Received 23 July 2007; accepted 1 October 2007
Abstract—Hydroxymethylmexiletine (HMM), one of the main metabolites of mexiletine, has been synthesized in both racemic and opti-
cally active forms following two alternative routes. The ee values for both HMM enantiomers were 98%, as assessed by 1H NMR analysis
in the presence of (ꢀ)-(R)-(2-naphthyloxy)phenylacetic acid as a chiral solvating agent and electrophoretic analysis using b-cyclodextrine
sulfated sodium salt as a chiral auxiliary.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
NH2
NH2
NH2
Mexiletine, 1-(2,6-dimethylphenoxy)-2-propanamine (Mex,
Fig. 1), is a chiral therapeutically relevant compound, clin-
ically used as an antiarrhythmic,1 antimyotonic,2 and anal-
gesic agent.3 Recently, mexiletine has also been proposed
for the treatment of tinnitus.4 All these clinical applications
require doses falling within a narrow therapeutic window
(400–1200 mg/die); when doses near the higher limit are
used, severe side-effects may occur.1,5 In therapy, mexile-
tine is administered as a racemate, generally in the form
of its hydrochloride salt. However, it has been reported
that mexiletine enantiomers differ in both pharmaco-
dynamic and pharmacokinetic properties. (ꢀ)-(R)-Mex is
more potent than its enantiomer on experimental arrhyth-
mias,6 in binding studies on cardiac sodium channels,7 and
in blocking skeletal muscle sodium channels.8–10 With
regards to the analgesic action of Mex enantiomers, only
controversal data may be found in the literature, in turn
presenting (ꢀ)-(R)-,11 (+)-(S)-Mex,12 or neither13,14 as the
eutomer. Whenever pharmacodynamic prevalence of (ꢀ)-
(R)-Mex was observed in vivo,6,11 stereospecific indexes
(SSI) were low (62). Whether enantioselective disposition,
which favors the elimination of the eutomer,15–18 may
cause partial compensation of the clinical outcome remains
unanswered. However, the switch from the clinical use of
OH
HO
Mex
PHM
HMM
Figure 1.
racemic Mex to that of its (R)-enantiomer (chiral switch-
ing)19 might be pursued given the higher toxicity of (+)-
(S)-Mex.13,14,20 Another possible way to overcome the
Mex toxicity may be metabolite switching,19 that is, the
replacement of the parent compound with one of its
metabolites. Mexiletine is extensively metabolized in
humans21,22 and the major metabolites formed by aliphatic
and aromatic hydroxylation are referred to as hydroxy-
methylmexiletine (HMM, Fig. 1) and p-hydroxymexiletine
(PHM, Fig. 1), respectively. Levy-Prades et al.,23 following
a personal communication of Danneberg and Haselbarth,
reported that Mex metabolites are inactive as antiarrhythmic
agents. Kamei studied the antinociceptive effects of (RS)-
HMM in steptozocine-induced diabetic mice using the
tail-pinch test and did not find any significant effect.13
However, when sodium channel blocking activity on skele-
tal muscles was studied, both PHM and HMM were still
able to reduce INa
on single fibers of frog skeletal
max
*
muscle, under both tonic and phasic (use-dependent)
Corresponding author. Tel.: +39 080 5442744; fax: +39 080 5442724;
e-mail: glentini@farmchim.uniba.it
conditions.24 IC50 values for the use-dependent blocking
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.002

2410
M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
action of the metabolite were only 3–4 times higher than
that of the parent compound and denoted only low SSI.
In view of a possible dissociation of pharmacological activ-
ities, these preliminary in vitro results deserve further stud-
ies, which might be aided by easy access to homochiral
PHM and HMM. Both resolution methods6,25–28 and
‘chiral pool’ approach based syntheses25,29–31 have been
reported for Mex enantiomers. The synthesis of (+)-(R)-
and (ꢀ)-(S)-PHM has already been reported.32 Herein we
report two alternative routes to homochiral HMM, which
allow unambiguous attribution of the (R)- and (S)-absolute
configurations to (ꢀ)- and (+)-HMM, respectively.
2. Results and discussion
The first route (Route A) to (RS)-HMM (RS)-7 and highly
enantiomerically enriched (R)- and (S)-HMM (R)- and
(S)-7 is shown in Scheme 1. It starts from the efficient
protection of the racemic and optically active 2-amino-
propanols 1 with phthalic anhydride 2.33 Alcohols 3 under-
go conversion to ethers 4 under Mitsunobu conditions,34 as
previously reported.31,32 Ethers 4 were converted into their
bromo derivatives 5 following the procedure described by
Mallory et al.35 The time-dependent formation of a
dibromo derivative of 4 was also observed. Thus, the times
O
OH
OH
O
+
H2N
COOH
O
1
2
8
i
vi
O
OH
HO
N
COOMe
3
9
O
Route A
Route B
ii
vii
O
O
O
O
N
H
O
N
COOMe
O
4
10
iii
viii
O
O
O
O
N
O
N
H
OH
11
ix
Br
O
5
iv
O
O
N
O
NH2
v
OH
OH
O
7a
6
Scheme 1. Reagents and conditions: (i) Et3N, toluene, reflux; (ii) 2,6-dimethylphenol, PPh3, DIAD, anhyd THF; (iii) N-bromosuccinimide, benzoyl
peroxide, CCl4; (iv) H2O/dioxane; (v) N2H4ÆH2O, glacial AcOH, abs EtOH; (vi) concd H2SO4, MeOH, 65 °C; (vii) t-BOCNHCH(CH3)CH2OH, PPh3,
DIAD, anhyd THF; (viii) LiAlH4, anhyd THF, 0 °C; (ix) 98% HCOOH, 0 °C. a The free amine was purified in the form of several salts (see text for details).

M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
2411
H2O
Me
H
Me
Cl
Me
H
H
O
O
O
Me
H
O
NH2
+
NH2
NH3
+Cl-
Cl-
OH2
N
OH
.HCl
H
7 .
(R)- HCl
13 .
(R)-
HCl
Scheme 2. Possible mechanism for the intramolecular condensation of (R)-7 hydrochloride to give (R)-3,9-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine
hydrochloride, (R)-13ÆHCl.
O
O
O
O
N
H
O
i
ii, iii
COOMe
N
N
H .
HCl
H
O
13.
10
14
(RS)-
(RS)-
(RS)- HCl
Scheme 3. Reagents and conditions: (i) 98% HCOOH, 0 °C; (ii) LiAlH4, anhyd THF, rt, then 85 °C, then rt; (iii) aq HCl.
of reaction should not be longer than 16 h in order to avoid
lowering the yield. The hydroxy derivatives 6 were ob-
tained by modifying a procedure reported in the patent lit-
erature for the conversion of benzyl chloride into benzyl
alcohol36 and were deprotected from the phthalimido
groups by hydrazinolysis.37 The free amines were converted
into their oxalate salts, which were fully characterized.
Given that the oxalate anion may precipitate calcium ions
contained in the buffer used for pharmacological trials,
the free amines, recovered from their oxalate salts, were
converted into their corresponding hydrochloride salts with
gaseous HCl. (RS)-HMMÆHCl was recrystallized from abs
EtOH/Et2O. When passing to (R)-HMMÆHCl we were
unable to recrystallize the salts and the solutions became
yellow. Thus, we tried to convert (R)-HMM into the corre-
sponding hydrochloride salt by treating the homochiral
free amine with a few drops of 2 M HCl and azeotropically
removing water, as we had done in the past for other ana-
logues of Mex31 and for PHM.32 Even this time, we didn’t
manage in crystallizing the hydrochloride salt from abs
EtOH/Et2O. Furthermore, in the following days, we
noticed that the solution was becoming more and more
yellow. Removal of the solvents gave a crude solid. Spec-
trometry analyses showed that there had been an intramo-
lecular condensation between the hydroxy and the amino
groups, resulting in the formation of 3,9-dimethyl-2,3,4,5-
tetrahydro-1,4-benzoxazepine (R)-13. A plausible mecha-
nism for the formation of (R)-13, passing through the benz-
yl chloride reactive intermediate 12, is given in Scheme 2.
(S)-HMM behaved similarly, when we tried to convert it
into its hydrochloride form by treatment with gaseous
HCl. The free amine (S)-13, extracted from the correspond-
ing salt, was converted into its hydrobromide salt. The
same procedure carried out on (R)-13 gave (R)-13ÆHBr.
Compound (RS)-13 was obtained following another syn-
thetic route shown in Scheme 3. Compound (RS)-10 was
treated with 98% HCOOH at 0 °C to give (RS)-14, which
was reacted with LiAlH4 to give (RS)-13. The free amine
was treated with a few drops of 2 M HCl and water was re-
moved azeotropically to give (RS)-13ÆHCl. Spectrometry
analyses of the racemate were identical to those of the
(R)-isomer, confirming our hypothesis. The ee values of
(R)- and (S)-13 were evaluated by capillary electrophoresis.
Finally, the HMM hydrobromides were obtained following
another route (Route B, Scheme 1). The commercially
available 3-methylsalicylic acid 8 was easily converted into
methyl 2-hydroxy-3-methylbenzoate 9,38 which is now
commercially available. Ester 9 was reacted with the appro-
priate N-Boc protected alaninol (which is commercially
available for the enantiomers and easily preparable as the
racemate, following the procedure routinely used for b-
aminoalchohols)39 under Mitsunobu conditions34 to give
compound 10, which was easily reduced to the correspond-
ing alcohol 11. Removal of the Boc protecting group gave
the desired product (HMM), which was purified as the
hydrobromide salt. This time, we succeded in the recrystal-
lization of (RS)-7ÆHBr and (R)-7ÆHBr, while (S)-7ÆHBr was
only obtained in a mixture containing 20% of (S)-13ÆHBr
1
as assessed by H NMR and elemental analyses. Ee values
1
of HMM enantiomers were evaluated by both chiral H
NMR analysis and capillary electrophoresis. The former
was performed on free amine samples, recovered by extrac-
tion of a sample from the corresponding hydrobromide
salts, using (ꢀ)-(R)-(2-naphthyloxy)phenylacetic acid as a
CSA.40,41 Capillary electrophoretic analyses were per-
formed directly on the oxalate salts, using b-cyclodextrin
sulfated sodium salt as a chiral selector. In both cases, ee
values were 98% for both enantiomers.
3. Conclusions
In conclusion, we have reported the synthesis of HMM in
its racemic and enantiomeric forms. (+)- and (ꢀ)-HMM
were fully characterized and were unambiguously given
(S)- and (R)-configurations, respectively. Overall yields
were moderate, but all steps were easily performed and
gave (R)- and (S)-7 oxalate salts in highly enriched opti-
cally active forms. The ee values were 98% for both enan-
tiomers, as stated by both 1H NMR and capillary

2412
M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
electrophoresis. The practical synthetic routes presented
herein may be useful to meet the needs of reliable analytical
standards in order to feed further studies on Mex disposi-
tion.42,43 It is noteworthy that the halohydrates of HMM
are not easy to crystallize because of competing intramolec-
ular condensation to give benzoxazepine 13. The formation
of this degradation product, which may be considered as a
rigid analogue of Mex, should be taken into account when
considering the pharmacological activities of HMM.
HMM as long as PHM, although less active than Mex, is
still able to reduce INa max under both tonic and phasic con-
ditions.24 Thus, we suggest to use PHM and HMM as the
key starting synthons for the preparation of dimeric com-
pounds, potentially active on the Na+ channels.32,44
gel columns by flash chromatography (Kieselgel 60,
0.040–0.063 mm, Merck, Darmstadt, Germany) using the
technique described by Still et al.45 TLC analyses were per-
formed on precoated silica gel on aluminum sheets (Kiesel-
gel 60F254, Merck).
4.1. (RS)-2-[2-(2,6-Dimethylphenoxy)-1-methylethyl]-1H-
isoindole-1,3(2H)-dione (RS)-4
Prepared as reported in the literature.31 Yield: 84%; IR
(neat): 1775, 1713 (C@O) cmꢀ1 1H NMR: d 1.55 (d,
;
J = 6.9 Hz, 3H, CH3CH), 2.19 (s, 6H, CH3Ar), 3.91 (dd,
J = 9.4, 5.5 Hz, 1H, CHH), 4.37 (apparent t, J = 9.2 Hz,
1H, CHH), 4.80–4.94 (m, 1H, CH), 6.82–6.91 (m, 1H,
ArO HC-4), 6.91–7.01 (m, 2H, ArO HC-3,5), 7.68–7.76
(m, 2H, Ar HC-5,6), 7.8–7.9 (m, 2H, Ar HC-4,7); 13C
NMR: d 14.7 (1C), 15.8 (2C), 46.9 (1C), 71.4 (1C), 122.9
(2C), 123.7 (1C), 128.6 (2C), 130.4 (2C), 132.0 (2C), 133.7
(2C), 155.1 (1C), 168.1 (2C); MS (70 eV) m/z (%) 309
(M+, 7), 188 (100).
4. Experimental
All chemicals were purchased from Sigma–Aldrich or Lan-
caster. (ꢀ)-(R)-(2-Naphthyloxy)phenylacetic acid, used as
chiral solvating agent (CSA), was prepared in house.40 Sol-
vents were RP grade unless otherwise indicated. Com-
pounds 3 and 4 were prepared as previously described.31
Yields refer to purified products and are not optimized.
The structures of the compounds were confirmed by rou-
tine spectrometric analyses. Only spectra for compounds
not previously described are given. Melting points were
determined on a Gallenkamp melting point apparatus in
open glass capillary tubes and are uncorrected. The infra-
red spectra were recorded on a Perkin-Elmer (Norwalk,
CT) Spectrum One FT spectrophotometer and band posi-
tions are given in reciprocal centimeters (cmꢀ1). 1H
NMR and 13C NMR spectra were recorded on a Varian
Mercury-VX spectrometer operating at 300 and 75 MHz
for 1H and 13C, respectively, using CDCl3 or CD3OD
(where indicated) as solvents. Chemical shifts are reported
in parts per million (ppm) relative to solvent resonance:
CDCl3, d 7.26 (1H NMR) and d 77.3 (13C NMR); CD3OD,
d 3.31, unless otherwise indicated (1H NMR) and variable
(13C NMR) as indicated below for each compound. J val-
ues are given in Hz. Electrophoretic runs were performed
on a BioFocus 3000 CE system (Bio-Rad, USA). A fused
silica capillary of 69.7 cm (effective length 65.2 cm) and
0.05 mm i.d. (Quadrex Corporation) thermostated at
20 °C was used as a separation tube. The samples
(0.1 mg/mL) were pressure injected and detected at
4.2. (RS)-2-{2-[2-(Bromomethyl)-6-methylphenoxy]-1-meth-
ylethyl}-1H-isoindole-1,3(2H)-dione (RS)-5
To a stirred solution of (RS)-2-[2-(2,6-dimethylphenoxy)-
1-methylethyl]-1H-isoindole-1,3(2H)-dione (RS)-4 (4.53 g,
14.6 mmol) in CCl4 (210 mL), N-bromosuccinimide
(2.60 g, 14.6 mmol) and benzoyl peroxide (250 mg,
1.02 mmol) were added. The reaction mixture was refluxed
for 4 h. The solid residue was filtered off. After evaporation
of the solvent under vacuum, the residue (7.50 g) was puri-
fied by flash chromatography (EtOAc/petroleum ether
0.5:9.5) and a slightly yellowish oil (3.30 g, 58%) was ob-
1
tained: IR (neat): 1774, 1708 (C@O) cmꢀ1; H NMR: d
1.56 (d, J = 6.9 Hz, 3H, CH3CH), 2.21 (s, 3H, CH3Ar),
4.06 (dd, J = 9.2, 5.4 Hz, 1H, CHHO), 4.39 (d,
J = 9.6 Hz, 1H, CHHBr), 4.58 (apparent t overlapping d
at 4.61, J = 9.3 Hz, 1H, CHHO), 4.61 (d overlapping
apparent t at 4.58, J = 9.9 Hz, 1H, CHHBr), 4.90–5.0 (m,
1H, CH), 6.96 (apparent t, J = 7.6 Hz, 1H, Ar HC-4),
7.08 (d, J = 7.4 Hz, 1H, Ar HC-5), 7.16 (d, J = 7.7 Hz,
1H, Ar HC-3), 7.68–7.74 (m, 2H, Ar HC-5,6), 7.82–7.88
(m, 2H, Ar HC-4,7); 13C NMR: d 15.3 (1C), 16.6 (1C),
28.9 (1C), 47.4 (1C), 72.5 (1C), 123.5 (2C), 124.7 (1C),
129.2 (1C), 131.4 (1C), 131.8 (1C), 132.3 (3C), 134.2 (2C),
155.3 (1C), 168.8 (2C); MS (70 eV) m/z (%) 387 (M+,
<1), 188 (100).
1
214 nm. When determining ee values by H NMR, (RS)-,
(R)-, and (S)-7 were recovered by extraction of a sample
of the corresponding hydrobromide salts and dissolved
with 1.5 equiv. of CSA in CDCl3. Spectra were registered
at 25 °C and the splitting of the a-methyl groups doublet
was observed (Dd = 0.093 ca). EIMS spectra were recorded
on a Hewlett-Packard 6890-5973 MSD gas chromato-
graph/mass spectrometer at low resolution. ESI+/MS/MS
analyses were performed with an Agilent 1100 Series LC-
MSD trap system VL workstation. Elemental analyses
were performed on a Eurovector Euro EA 3000 analyzer.
Optical rotations were measured on a Perkin Elmer (Nor-
walk, CT) Mod 341 spectropolarimeter; concentrations
4.3. (ꢀ)-(R)-2-{2-[2-(Bromomethyl)-6-methylphenoxy]-1-
methylethyl}-1H-isoindole-1,3(2H)-dione (ꢀ)-(R)-5
Prepared as above using (ꢀ)-(R)-2-[2-(2,6-dimethylphen-
oxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione (ꢀ)-(R)-4.
20
Yield: 67%; ½aꢁD ¼ ꢀ90:0 (c 2.7, CHCl3). Spectrometry
data were in agreement with those found for the racemate.
4.4. (+)-(S)-2-{2-[2-(Bromomethyl)-6-methylphenoxy]-1-
methylethyl}-1H-isoindole-1,3(2H)-dione (+)-(S)-5
are expressed in g/100 mL, and the cell length was 1 dm,
Prepared via the above reaction starting from (+)-(S)-2-[2-
20
thus ½aꢁD values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
(2,6-dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-
20
Chromatographic separations were performed on silica
dione (+)-(S)-4. Yield: 70%; ½aꢁD ¼ þ84:2 (c 2.05, CHCl3).

M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
2413
Spectrometry data were in agreement with those found for
the racemate.
4.8. (RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
(RS)-7
Method A: To a stirred solution of (RS)-2-{2-[2-(hydroxy-
methyl)-6-methylphenoxy]-1-methylethyl}-1H-isoindole-
1,3(2H)-dione (RS)-6 (0.63 g, 1.90 mmol) in absolute EtOH
(7.4 mL), glacial AcOH (5.80 mmol) and N2H4ÆH2O
(5.80 mmol) were added and the mixture was kept at reflux
for 2 h. The solid residue was then filtered off. After evap-
oration of the filtrate, the residue was taken up with EtOAc
and extracted with 2 M HCl, after which the aqueous phase
was made alkaline with 2 M NaOH and extracted several
times with EtOAc. The combined organic layers were dried
over Na2SO4 and concentrated under vacuum. The final
product was a sligthly yellowish oil (0.37 g, 99%). Method
B: (RS)-tert-Butyl{2-[2-(hydroxymethyl)-6-methylphenoxy]-
1-methylethyl}carbamate (RS)-11 (0.92 g, 3.1 mmol) was
dissolved in 98% HCOOH (30 mL) and the reaction mix-
ture was stirred at 0 °C for 5 h. After evaporation of the
solvent under reduced pressure, the residue was taken up
with EtOAc and extracted with 2 M HCl; then the aqueous
phase was made alkaline and extracted several times with
EtOAc. The combined organic layers were washed with
H2O, dried over Na2SO4 and concentrated under vacuum
to give 0.47 g of a yellow oil (77%): IR (neat): 3357
4.5. (RS)-2-{2-[2-(Hydroxymethyl)-6-methylphenoxy]-1-
methylethyl}-1H-isoindole-1,3(2H)-dione (RS)-6
(RS)-2-{2-[2-(bromomethyl)-6-methylphenoxy]-1-methyl-
ethyl}-1H-isoindole-1,3(2H)-dione (RS)-5 (3.33 g, 8.6
mmol) was dissolved in a mixture of H2O (20 mL) and
dioxane (20 mL). The reaction mixture was kept at reflux
for 19 h. Dioxane was removed by evaporation under vac-
uum and the aqueous phase was extracted several times
with EtOAc. The combined organic layers were dried over
Na2SO4, and concentrated under vacuum to give 4.27 g of
a yellow oil. Purification of the crude residue by silica gel
column chromatography (EtOAc/petroleum ether 1:1)
gave 1.56 g of a yellow oil. Yield: 56%; IR (neat): 3470
(OH), 1773, 1708 (C@O) cmꢀ1 1H NMR: d 1.51 (d,
;
J = 7.1 Hz, 3H, CH3CH), 2.18 (s, 3H, CH3Ar), 2.64 (br
s, 1H, OH), 3.92 (dd, J = 9.4, 5.5 Hz, 1H, CHHCH),
4.46 (apparent t, J = 9.4 Hz, 1H, CHHCH), 4.55 (d over-
lapping d at 4.61, J = 12.7 Hz, 1H, AB system, CHHOH),
4.61 (d overlapping d at 4.55, J = 12.7 Hz, 1H, AB system,
CHHOH), 4.78–4.92 (m, 1H, CH), 6.94 (apparent t,
J = 7.6 Hz, 1H, ArO HC-4), 7.03 (d, J = 6.9 Hz, 1H,
ArO HC-5), 7.13 (d, J = 7.4 Hz, 1H, ArO HC-3), 7.64–
7.74 (m, 2H, Ar), 7.77–7.86 (m, 2H, Ar); 13C NMR: d
15.2 (1C), 16.4 (1C), 47.4 (1C), 61.2 (1C), 72.9 (1C),
123.5 (2C), 124.5 (1C), 127.3 (1C), 131.1 (1C), 131.2
(1C), 132.1 (2C), 134.0 (1C), 134.3 (2C), 155.1 (1C), 168.9
(2C); MS (70 eV) m/z (%) 325 (M+, 6), 188 (100).
1
(NH2), 3292 (OH) cmꢀ1; H NMR: d 1.19 (d, J = 6.6 Hz,
3H, CH3CH), 2.29 (s, 3H, CH3Ar), 3.10 (br s, 3H,
NH2 + OH), 3.35–3.50 (br m, 1H, CH), 3.64 (apparent t,
J = 8.5 Hz, 1H, CHHCH), 3.94 (dd, J = 9.2, 2.9 Hz, 1H,
CHHCH), 4.55 (d, J = 12.1 Hz, 1H, CHHOH), 4.71 (d,
J = 12.4 Hz, 1H, CHHOH), 6.97 (apparent t, J = 7.4 Hz,
1H, Ar HC-4), 7.05–7.15 (m, 2H, Ar HC-3,5); 13C NMR:
d 16.9 (1C), 19.9 (1C), 47.5 (1C), 61.6 (1C), 78.4 (1C),
124.3 (1C), 128.3 (1C), 131.0 (1C), 131.6 (1C), 134.6 (1C),
156.6 (1C); MS (70 eV) m/z (%) 195 (M+, 2), 44 (100).
4.6. (ꢀ)-(R)-2-{2-[2-(Hydroxymethyl)-6-methylphenoxy]-1-
methylethyl}-1H-isoindole-1,3(2H)-dione (ꢀ)-(R)-6
4.9. (ꢀ)-(R)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
(ꢀ)-(R)-7
Prepared via the above reaction starting from (ꢀ)-(R)-2-{2-
[2-(bromomethyl)-6-methylphenoxy]-1-methylethyl}-1H-
20
isoindole-1,3(2H)-dione (ꢀ)-(R)-5. Yield: 67%; ½aꢁD
¼
Prepared via the above reaction starting from either (ꢀ)-
ꢀ53:4 (c 2.15, CHCl3); IR (CHCl3): 3565 (OH), 1774,
1709 (C@O) cmꢀ1; H NMR: d 1.53 (d, J = 7.1 Hz, 3H,
1
(R)-6 (method A, yield: 97%) or (+)-(R)-11 (method B,
20
yield: 81%): ½aꢁD ¼ ꢀ9:6 (c 2, CHCl3); IR (CHCl3): 3373
CH3CH), 2.20 (s, 3H, CH3Ar), 2.33 (br t, J = 6.0 Hz, 1H,
exch D2O, OH), 3.94 (dd, J = 9.4, 5.4 Hz, 1H, CHHCH),
4.50 (apparent t, J = 9.5 Hz, 1H, CHHCH), 4.57 (dd over-
lapping apparent t at 4.50, J = 11.9, 5.5 Hz, 1H, AB system
coupled to br t at 2.33, CHHOH), 4.61 (dd, J = 11.9,
5.5 Hz, 1H, AB system coupled to br t at 2.33, CHHOH),
4.80–4.95 (m, 1H, CH), 6.96 (apparent t, J = 7.4 Hz, 1H,
ArO HC-4), 7.06 (d, J = 6.3 Hz, 1H, ArO HC-5), 7.13 (d,
J = 7.3 Hz, 1H, ArO HC-3), 7.67–7.76 (m, 2H, Ar), 7.80–
7.88 (m, 2H, Ar); MS (70 eV) m/z (%) 325 (M+, 12), 188
(100).
1
(NH2), 3197 (OH) cmꢀ1; H NMR: d 1.18 (d, J = 6.6 Hz,
3H, CH3CH), 2.30 (s, 3H, CH3Ar), 3.06 (br s, 3H,
NH2 + OH), 3.34–3.48 (m, 1H, CH), 3.62 (dd, J = 9.2,
7.8 Hz, 1H, CHHCH), 3.93 (dd, J = 9.2, 3.2 Hz, 1H,
CHHCH), 4.57 (d, J = 12.4 Hz, 1H, AB system, CHHOH),
4.73 (d, J = 12.4 Hz, 1H, AB system, CHHOH), 6.98
(apparent t, J = 7.4 Hz, 1H, Ar HC-4), 7.11 (d overlapping
d at 7.12, J = 7.2 Hz, 1H, Ar HC-5), 7.12 (d overlapping d
at 7.11, J = 7.2 Hz, 1H, Ar HC-3); 13C NMR: d 16.7 (1C),
20.1 (1C), 47.3 (1C), 61.4 (1C), 78.6 (1C), 124.2 (1C), 128.1
(1C), 130.9 (1C), 131.4 (1C), 134.6 (1C), 156.5 (1C); MS
(70 eV) m/z (%) 195 (M+, 5), 44 (100).
4.7. (+)-(S)-2-{2-[2-(Hydroxymethyl)-6-methylphenoxy]-1-
methylethyl}-1H-isoindole-1,3(2H)-dione (+)-(S)-6
4.10. (+)-(S)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
(+)-(S)-7
Prepared via the above reaction starting from (+)-(S)-2-{2-
[2-(bromomethyl)-6-methylphenoxy]-1-methylethyl}-1H-
Prepared as reported above for (RS)-7, starting from either
20
isoindole-1,3(2H)-dione (+)-(S)-5. Yield: 56%; ½aꢁD
¼
(+)-(S)-6 (method A, yield: 88%) or (ꢀ)-(S)-11 (method B,
20
þ59:6 (c 2.4, CHCl3); Spectrometry data were in agreement
with those reported for (ꢀ)-(R)-6.
yield: 96%): ½aꢁD ¼ þ8:4 (c 2, CHCl3); MS (70 eV) m/z (%)
195 (M+, 3), 44 (100).

2414
M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
4.11. (RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
hydrochloride (RS)-7ÆHCl
(m, 1H, CH), 3.68–3.84 (m, 2H, CH2CH), 4.46 (s, 2H,
CH2OH), 6.91 (apparent t, J = 7.6 Hz, 1H, Ar HC-4),
7.02 (d overlapping d at 7.05, J = 9.2 Hz, 1H, Ar HC-5),
7.05 (d overlapping d at 7.02, J = 7.7 Hz, 1H, Ar HC-3);
Anal. Calcd for (C11H17NO2Æ0.5H2C2O4): C, 59.98; H,
7.55; N, 5.83. Found: C, 59.67; H, 7.47; N, 6.06. Other
spectroscopic data were in agreement with those of the
racemate.
(RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol (RS)-7
(0.80 g, 4.1 mmol) was treated with a few drops of hydro-
chloric aqueous solution. Removal of water by azeotropic
distillation (abs EtOH/toluene) afforded a white solid,
which was recrystallized from EtOH/Et2O to give 0.26 g
of white crystals (40%): mp 143–144 °C; 1H NMR
(CD3OD): d 1.43 (d, J = 6.9 Hz, 3H, CH3CH), 2.33 (s,
3H, CH3Ar), 3.69–3.81 (m, dd upon irradiation at 1.43,
J = 6.9, 3.6 Hz, 1H, CH), 3.94 (dd, J = 10.3, 7.0 Hz, 1H,
CHHCH), 4.04 (dd, J = 10.2, 3.6 Hz, 1H, CHHCH), 4.64
(s, 2H, CH2OH), 7.06 (apparent t, J = 7.5 Hz, 1H, Ar
HC-4), 7.18 (d, J = 7.4 Hz, 1H, Ar HC-5), 7.23 (d,
J = 7.4 Hz, 1H, Ar HC-3); Anal. Calcd for
(C11H17NO2ÆHCl): C, 57.02; H, 7.83; N, 6.04. Found: C,
56.64; H, 7.59; N, 5.93.
4.15. (RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
hydrobromide (RS)-7ÆHBr
(RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol [(RS)-
7] (0.25 g, 1.28 mmol) was dissolved in anhydrous Et2O
and treated with gaseous HBr for a few seconds to give a
white solid, which was recrystallized by abs EtOH/Et2O/
iPr2O to give 0.090 g of white crystals (25%): mp 148–
149 °C; 1H NMR (CD3OD): d 1.23 (d, J = 6.6 Hz, 3H,
CH3CH), 2.29 (s, 3H, CH3Ar), 3.30–3.42 (m, 1H, CH),
3.68 (dd, J = 9.2, 7.3 Hz, 1H, CHHCH), 3.78 (dd,
J = 9.2, 4.1 Hz, 1H, CHHCH), 4.65 (s, 2H, CH2OH),
7.02 (apparent t, J = 7.6 Hz, 1H, Ar HC-4), 7.12 (d,
J = 6.9 Hz, 1H, Ar HC-5), 7.23 (d, J = 6.9 Hz, 1H, Ar
HC-3); 13C NMR (CD3OD, d 47.8): d 15.2 (1C), 17.5
(1C), 47.0 (1C), 59.3 (1C), 77.7 (1C), 124.1 (1C), 127.1
(1C), 130.6 (1C), 130.8 (1C), 134.1 (1C), 155.1 (1C). Anal.
Calcd for (C11H17NO2Æ0.12HBr): C, 64.33; H, 8.40; N,
6.82. Found: C, 64.43; H, 8.30; N, 6.65.
4.12. (RS)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
oxalate (RS)-7ÆH2C2O4
To an ether solution of (RS)-[2-(2-aminopropoxy)-3-meth-
ylphenyl]methanol (RS)-7 (0.30 g, 1.54 mmol), a 3%
H2C2O4 ether solution (4.6 mL, 1.54 mmol) was added.
Ethyl ether was removed by evaporation under vacuum
to give (RS)-7ÆH2C2O4 as a white solid, which was recrys-
tallized from MeOH/Et2O to give 0.25 g (57%) of white
1
crystals: mp 189–190 °C; H NMR (CD3OD): d 1.40 (d,
J = 6.6 Hz, 3H, CH3CH), 2.31 (s, 3H, CH3Ar), 3.60–3.75
(m, 1H, CH), 3.90 (dd, J = 9.9, 6.9 Hz, 1H, CHHCH),
3.99 (dd, J = 10.0, 4.0 Hz, 1H, CHHCH), 4.64 (s, 2H,
CH2OH), 7.03 (apparent t, J = 7.6 Hz, 1H, Ar HC-4),
7.14 (d, J = 7.4 Hz, 1H, Ar HC-5), 7.22 (d, J = 7.4 Hz,
1H, Ar HC-3); 13C NMR (CD3OD, d 46.2): d 12.9 (1C),
13.6 (1C), 46.2 (1C), 57.9 (1C), 71.9 (1C), 122.9 (1C),
125.9 (1C), 129.3 (2C), 132.4 (1C), 153.2 (1C), 171.0 (2C);
Anal. Calcd for (C11H17NO2Æ0.5H2C2O4): C, 59.99; H,
7.55; N, 5.83. Found: C, 60.14; H, 7.56; N, 6.05.
4.16. (R)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
hydrobromide (R)-7ÆHBr
Prepared as reported above for (S)-7ÆHBr, starting from
(ꢀ)-(R)-7. Yield: 26%; mp 114–116 °C (abs EtOH/iPr2O);
98% ee (1H NMR); 1H NMR (CD3OD): d 1.46 (d,
J = 6.6 Hz, 3H, CH3CH), 2.33 (s, 3H, CH3Ar), 3.82
(apparent sextet, J = 6.0 Hz, 1H, CH), 4.07 (d,
J = 9.9 Hz, 2H, CH2CH), 4.63 (d, J = 9.9 Hz, 1H, AB sys-
tem, CHHOH), 4.67 (d, J = 9.9 Hz, 1H, AB system,
CHHOH), 7.06 (apparent t, J = 7.6 Hz, 1H, Ar HC-4),
7.21 (d, J = 6.6 Hz, 1H, Ar HC-5), 7.27 (d J = 7.2 Hz,
1H, Ar HC-3); ESI+/MS m/z 218.1 (MNa+); ESI+/MS/
MS m/z 161 (100); Anal. Calcd for (C11H17NO2Æ0.25HBr):
C, 61.31; H, 8.07; N, 6.50. Found: C, 61.45; H, 7.72; N,
6.35. Spectroscopic data were in agreement with (+)-(S)-
7ÆHBr.
4.13. (ꢀ)-(R)-[2-(2-Aminopropoxy)-3-methylphenyl]metha-
nol oxalate (ꢀ)-(R)-7ÆH2C2O4
Prepared as reported above for (RS)-7ÆH2C2O4, starting
from (ꢀ)-(R)-7. Yield: 33%; mp 203–204 °C (MeOH/
Et2O); >98% ee (capillary electrophoresis, injection:
10 psi/s; BGE: phosphate buffer 0.035 M at pH 3.0; chiral
selector: b-cyclodextrin sulfated sodium salt 5.5 mg/mL;
20
voltage: 20 kV); ½aꢁD ¼ ꢀ5:7 (c 2, MeOH); Anal. Calcd
4.17. (S)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
hydrobromide (S)-7ÆHBr
for (C11H17NO2Æ0.5H2C2O4): C, 59.98; H, 7.55; N, 5.83.
Found: C, 59.78; H, 7.50; N, 6.00. Spectroscopic data were
in agreement with (+)-(S)-7ÆH2C2O4.
(+)-(S)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol [(+)-
(S)-7] (0.80 g, 4.1 mmol) was dissolved in anhydrous Et2O
and treated with gaseous HBr for a few seconds to give a
white solid, which was recrystallized from abs EtOH/
Et2O/iPr2O to give 0.11 g of white crystals (10%): mp
4.14. (+)-(S)-[2-(2-Aminopropoxy)-3-methylphenyl]methanol
oxalate (+)-(S)-7ÆH2C2O4
1
Prepared as reported above for (RS)-7ÆH2C2O4, starting
from (+)-(S)-7. Yield: 34%; mp 197–199 °C (MeOH/
121–122 °C; 98% ee (1H NMR); H NMR (CD3OD) was
in agreement with that of the (R)-enantiomer but denoted
the presence of about 20% of (S)-13ÆHBr; ESI+/MS m/z
218.1 (MNa+); ESI+/MS/MS m/z 161 (100). Anal. Calcd
for (C11H17NO2ÆHBr + 0.2C11H15NOÆHBr): C, 48.37; H,
6.52; N, 5.13. Found: C, 48.26; H, 6.49; N, 5.12.
Et2O); >98% ee (capillary electrophoresis using the condi-
20
tions described for the R-enantiomer); ½aꢁD ¼ þ6:7 (c 2,
1
MeOH); H NMR (D2O/CD3OD 3:2, d 3.11): d 1.24 (d,
J = 6.6 Hz, 3H, CH3CH), 2.10 (s, 3H, CH3Ar), 3.55–3.67

M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
2415
4.18. Methyl 3-methylsalicylate 9
spectrometric data were in agreement with those of the
racemate.
3-Methylsalicylic acid (4.0 g, 26.3 mmol) was dissolved in
MeOH (32 mL) and treated with concd H2SO4 (12 mL).
The reaction mixture was kept at 65 °C for 30 h. Excess
MeOH was removed by evaporation under vacuum and
the aqueous phase was extracted several times with Et2O.
The organic layer was washed with a saturated aqueous
NaHCO3 solution, then dried over Na2SO4 and concen-
trated under vacuum to give 3.43 g of a yellow oil (78%):
4.22. (RS)-tert-Butyl {2-[2-(hydroxymethyl)-6-methylphen-
oxy]-1-methylethyl}carbamate (RS)-11
To a suspension of LiAlH4 (0.65 g, 17.0 mmol) in anhy-
drous THF (50 mL), (RS)-methyl 2-{2-[(tert-butoxycar-
bonyl)amino]propoxy}-3-methylbenzoate (RS)-10 (2.75 g,
8.5 mmol) was added. The reaction mixture was stirred at
0 °C for 7 h, then it was quenched by the careful addition
of cold water until the end of gas evolution. The residue
was removed by filtration and the filtrate additioned with
H2O. The aqueous phase was extracted several times with
Et2O. The combined extracts were dried over Na2SO4
and the filtrate was concentrated under vacuum to give
2.13 g of a yellow oil (85%), which was recrystallized from
EtOAc/petroleum ether: mp 79–80 °C; IR (CHCl3): 3446
IR (neat): 3423 (OH), 1676 (C@O) cmꢀ1 1H NMR: d
;
2.26 (s, 3H, CH3CH), 3.94 (s, 3H, CH3O), 6.78 (apparent
t, J = 7.7 Hz, 1H, Ar HC-4), 7.31 (d, J = 7.1 Hz, 1H, Ar
HC-5), 7.67–7.70 (m, 1H, Ar HC-3), 11.0 (s, 1H, OH);
MS (70 eV) m/z (%) 166 (M+, 62), 134 (100).
4.19. (RS)-Methyl 2-{2-[(tert-butoxycarbonyl)amino]-
propoxy}-3-methylbenzoate (RS)-10
(NH, OH), 1705 (C@O) cmꢀ1 1H NMR: d 1.34 (d,
;
To a stirred solution of N-t-Boc-DL-alaninol (2.40 g,
J = 6.6 Hz, 3H, CH3CH), 1.46 (s, 9H, t-Bu), 1.67 (br s,
1H, OH), 2.28 (s, 3H, CH3Ar), 3.77–3.90 (m, 2H, CH2CH),
4.01 (br s, 1H, CH), 4.65 (d, J = 12.4 Hz, 1H, AB system,
CHHOH), 4.71 (d, J = 12.4 Hz, 1H, AB system,
CHHOH), 4.95 (br d, J = 8.0 Hz, 1H, NH), 7.02 (apparent
t, J = 7.4 Hz, 1H, Ar HC-4), 7.12 (d, J = 6.6 Hz, 1H, Ar
HC-5), 7.18 (d, J = 7.4 Hz, 1H, Ar HC-3); 13C NMR: d
16.3 (1 C), 18.0 (1C), 28.6 (3C), 47.0 (1C), 61.4 (1C), 75.8
(1C), 79.8 (1C), 124.5 (1C), 127.5 (1C), 131.3 (1C), 131.4
(1C), 134.0 (1C), 155.3 (1C), 155.8 (1C); MS (70 eV) m/z
(%) 295 (M+, <1), 120 (100). Anal. Calcd for
(C16H25NO4): C, 65.06; H, 8.53; N, 4.74. Found: C,
65.39; H, 8.51; N, 4.88.
13.7 mmol), methyl 3-methylsalicylate
9
(3.41 g,
20.6 mmol), and triphenylphosphine (5.40 g, 20.6 mmol)
in dry THF (120 mL), under an N2 atmosphere, a solution
of DIAD (4.16 g, 20.6 mmol) in dry THF (60 mL) was
added dropwise. The mixture was stirred at room temper-
ature for 24 h. The solvent was then evaporated under re-
duced pressure, Et2O was added and the precipitate
formed was filtered off. The filtrate was evaporated in vacuo
and the residue was purified by flash chromatography using
silica gel (eluent EtOAc/petroleum ether 1:9) to give 3.32 g
of a yellow oil (75%): IR (neat): 3382 (NH), 1713 (C@O)
cmꢀ1 1H NMR: d 1.35 (d, J = 6.7 Hz, 3H, CH3CH),
;
1.46 (s, 9H, t-Bu), 2.30 (s, 3H, CH3Ar), 3.84–3.92 (m over-
lapping s at 3.90, 3H, CH2 + CH), 3.90 (s overlapping m at
3.84–3.92, 3H, CH3O), 5.44 (br s, 1H, NH), 7.06 (apparent
t, J = 7.7 Hz, 1H, Ar HC-4), 7.34 (dd, J = 7.5, 1.1 Hz, 1H,
Ar HC-5), 7.65 (dd, J = 7.6, 1.6 Hz, 1H, Ar HC-3); 13C
NMR: d 16.4 (1C), 18.0 (1C), 28.6 (3C), 47.0 (1C), 52.4
(1C), 76.4 (1C), 79.3 (1C), 124.0 (1C), 124.6 (1C), 129.6
(1C), 133.0 (1C), 135.6 (1C), 155.8 (1C), 156.8 (1C), 167.0
(1C); MS (70 eV) m/z (%) 323 (M+, <1), 134 (100).
4.23. (+)-(R)-tert-Butyl {2-[2-(hydroxymethyl)-6-methyl-
phenoxy]-1-methylethyl}carbamate (+)-(R)-11
Prepared via the above reaction starting from (+)-(R)-
methyl
2-{2-[(tert-butoxycarbonyl)amino]propoxy}-3-
methylbenzoate [(+)-(R)-10]. Yield: 46%: mp 71–72 °C
20
(EtOAc/petroleum ether); ½aꢁD ¼ þ25:6 (c 2, CHCl3).
Anal. Calcd for (C16H25NO4): C, 65.06; H, 8.53; N, 4.74.
Found: C, 65.07; H, 8.49; N, 4.97. Spectroscopic and spec-
trometric data were in agreement with those of the
racemate.
4.20. (+)-(R)-Methyl 2-{2-[(tert-butoxycarbonyl)amino]-
propoxy}-3-methylbenzoate (+)-(R)-10
Prepared via the above reaction starting from the commer-
4.24. (ꢀ)-(S)-tert-Butyl {2-[2-(hydroxymethyl)-6-methyl-
phenoxy]-1-methylethyl}carbamate (ꢀ)-(S)-11
20
cial N-t-Boc-D-alaninol. Yield: 63%; ½aꢁD ¼ þ15:0 (c 2,
CHCl3). Spectroscopic and spectrometric data were in
agreement with those of the racemate.
Prepared via the above reaction starting from (ꢀ)-(S)-
methyl
2-{2-[(tert-butoxycarbonyl)amino]propoxy}-3-
4.21. (ꢀ)-(S)-Methyl 2-{2-[(tert-butoxycarbonyl)amino]-
propoxy}-3-methylbenzoate (ꢀ)-(S)-10
methylbenzoate (ꢀ)-(S)-10. Yield: 65%: mp 67–68 °C
20
(EtOAc/petroleum ether); ½aꢁD ¼ ꢀ26:7 (c 2, CHCl3); IR
1
(CHCl3): 3446 (NH, OH), 1705 (C@O) cmꢀ1; H NMR:
Prepared via the above reaction starting from the commer-
d 1.34 (d, J = 6.9 Hz, 3H, CH3CH), 1.46 (s, 9H, t-Bu),
2.28 (s, 3H, CH3Ar), 2.52 (br s, 1H, OH), 3.76–3.87 (m,
2H, CH2CH), 3.92–4.06 (br m, 1H, CH), 4.65 (d,
J = 12.4 Hz, 1H, AB system, CHHOH), 4.70 (d,
J = 12.4 Hz, 1H, AB system, CHHOH), 4.95 (br d,
J = 7.1 Hz, 1H, NH), 7.01 (apparent t, J = 7.4 Hz, 1H,
Ar HC-4), 7.12 (d, J = 7.1 Hz, 1H, Ar HC-5), 7.18 (d,
J = 7.4 Hz, 1H, Ar HC-3). Anal. Calcd for (C16H25NO4):
C, 65.06; H, 8.53; N, 4.74. Found: C, 64.93; H, 8.50; N,
20
cial N-t-Boc-L-alaninol. Yield: 75%; ½aꢁD ¼ ꢀ15:0 (c 2,
1
CHCl3); H NMR: d 1.35 (d, J = 6.7 Hz, 3H, CH3CH),
1.46 (s, 9H, t-Bu), 2.31 (s, 3H, CH3Ar), 3.84–3.90 (m,
2H, CH2), 3.90 (s overlapping m at 3.90–4.0, 3H, CH3O),
3.90–4.0 (m overlapping s at 3.90, 1H, CH), 5.44 (br s,
1H, NH), 7.05 (apparent t, J = 7.5 Hz, 1H, Ar HC-4),
7.33 (dd, J = 7.5, 1.1 Hz, 1H, Ar HC-5), 7.65 (dd,
J = 7.8, 1.2 Hz, 1H, Ar HC-3). Other spectroscopic and

2416
M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
4.96. Other spectroscopic and spectrometric data were in
agreement with those of the racemate.
Anal. Calcd for (C11H15NOÆHClÆ0.50H2O): C, 59.32; H,
7.69; N, 6.29. Found: C, 59.09; H, 7.32; N, 5.93.
4.25. (RS)-3,9-Dimethyl-2,3,4,5-tetrahydro-1,4-benz-
oxazepine hydrochloride (RS)-13ÆHCl
4.27. (+)-(R)-3,9-Dimethyl-2,3,4,5-tetrahydro-1,4-benz-
oxazepine hydrobromide (+)-(R)-13ÆHBr
To a suspension of LiAlH4 (0.24 g, 6.28 mmol) in anhy-
drous THF (20 mL), (RS)-3,9-dimethyl-3,4-dihydro-1,4-
benzoxazepin-5(2H)-one (RS)-14 (0.60 g, 3.14 mmol) was
added. The reaction mixture was stirred at room tempera-
ture for 6 h, then at 85 °C for 2 h, and then again at room
temperature overnight. The reaction mixture was quenched
by the careful addition of cold water until the end of gas
evolution. The residue was removed by filtration and the
filtrate additioned with H2O. The aqueous phase was
washed with Et2O, then made alkaline with 2 M NaOH,
and extracted several times with Et2O. The combined ex-
tracts were dried over Na2SO4 and the filtrate was concen-
trated under vacuum to give 0.19 g of (RS)-13 as a yellow
oil (34%). The free amine was treated with a few drops of
hydrochloric aqueous solution. Removal of water by azeo-
tropic distillation (abs EtOH/toluene) afforded (RS)-
13ÆHCl as a white solid, which was recrystallized from
(R)-13 (0.20 g, 1.13 mmol), obtained by extraction from the
corresponding hydrochloride salt, was dissolved in EtOAc
(3 mL) and treated with 48% HBr (1 mL). Water was re-
moved azeotropically to give 0.25 g of a slightly yellowish
solid, which was recrystallized from EtOAc (52%): mp
20
>250 °C; ½aꢁD ¼ þ91:0 (c 0.15, CHCl3); 98% ee (capillary
electrophoresis, injection: 15 psi/s; BGE: phosphate buffer
0.035 M at pH 2.9; chiral selector: hydroxypropyl-b-cyclo-
dextrin 60 mg/mL; voltage: 10 kV). Spectroscopic and
spectrometric data were in agreement with those found
for (R)-13ÆHCl. Anal. Calcd for (C11H15NOÆHBr): C,
51.18; H, 6.25; N, 5.43. Found: C, 51.13; H, 6.25; N, 5.44.
4.28. (ꢀ)-(S)-3,9-Dimethyl-2,3,4,5-tetrahydro-1,4-benz-
oxazepine hydrobromide (ꢀ)-(S)-13ÆHBr
MeOH/Et2O to give 0.11 g of white crystals (48%): mp
Prepared as above starting from (S)-13. Yield: 48%; White
20
þ
230–231 °C; IR (KBr): 2937–2881 NH2
;
1H NMR
solid: mp >250 °C (EtOAc); ½aꢁD ¼ ꢀ82:0 (c 0.4, CHCl3);
(CD3OD): d 1.33 (d, J = 6.6 Hz, 3H, CH3CH), 2.27 (s,
3H, CH3Ar), 3.68 (dd, J = 13.5, 9.3 Hz, 1H, CHHCH),
3.77–3.91 (m, 1H, CH), 4.30 (d, J = 14.3 Hz, 1H, AB sys-
tem, CHHNH), 4.38 (d overlapping dd at 4.45,
J = 14.3 Hz, 1H, AB system, CHHNH), 4.45 (dd overlap-
ping d at 4.38, J = 13.5, 2.7 Hz, 1H, CHHCH), 7.06
(apparent t, J = 7.6 Hz, 1H, Ar HC-7), 7.22 (d overlapping
d at 7.28, J = 7.1 Hz, 1H, Ar HC-8), 7.28 (d overlapping d
at 7.22, J = 8.2 Hz, 1H, Ar HC-6); Anal. Calcd for
(C11H15NOÆHClÆ0.20H2O): C, 60.80; H, 7.61; N, 6.45.
Found: C, 61.17; H, 7.50; N, 6.65.
97% ee (capillary electrophoresis, injection: 15 psi/s;
BGE: phosphate buffer 0.035 M at pH 2.9; chiral selector:
hydroxypropyl-b-cyclodextrin 60 mg/mL; voltage: 10 kV).
Spectroscopic and spectrometric data were in agreement
with those found for (R)-13ÆHCl. Anal. Calcd for
(C11H15NOÆHBr): C, 51.18; H, 6.25; N, 5.43. Found: C,
51.34; H, 6.24; N, 5.40.
4.29. (RS)-3,9-Dimethyl-3,4-dihydro-1,4-benzoxazepin-
5(2H)-one (RS)-14
A solution of (RS)-10 (0.27 g, 0.83 mmol) in 98% HCOOH
(10 mL) was stirred at 0 °C for 2 h. The solvent was re-
moved under vacuum; the residue was taken up with
EtOAc and washed with a NaHCO3 saturated solution.
The organic layer was dried over Na2SO4 and concentrated
under vacuum to give 0.08 g (51%) of a slightly yellowish
solid: mp 118–119 °C; IR (CHCl3): 3408 (NH), 1644
4.26. (+)-(R)-3,9-Dimethyl-2,3,4,5-tetrahydro-1,4-benz-
oxazepine hydrochloride (+)-(R)-13ÆHCl
(R)-7 (0.61 g, 3.13 mmol) was treated with a few drops of
2 M HCl and water was removed azeotropically. After
48 h in EtOH/Et2O solution at 0 °C, the solvent was re-
(C=O) cmꢀ1
;
1H NMR: d 1.25 (d, J = 6.6 Hz, 3H,
moved to give a 0.30 g of a slightly yellowish solid (70%):
20
mp >250 °C (EtOAc); ½aꢁD ¼ þ71:0 (c 0.4, CHCl3); 98%
CH3CH), 2.27 (s, 3H, CH3Ar), 3.63–3.79 (m, 1H, CH),
4.10 (apparent t, J = 9.9 Hz, 1H, CHH), 4.22 (dd,
J = 11.0, 3.6 Hz, 1H, CHH), 6.54 (br s, 1H, NH), 7.04
(apparent t, J = 7.5 Hz, 1H, Ar HC-7), 7.30 (d,
J = 7.4 Hz, 1H, Ar HC-8), 7.71 (d, J = 7.4 Hz, 1H, Ar
HC-6); MS (70 eV) m/z (%) 191 (M+, 65), 119 (100).
ee (capillary electrophoresis, injection: 15 psi/s; BGE:
phosphate buffer 0.035 M at pH 2.9; chiral selector:
hydroxypropyl-b-cyclodextrin 60 mg/mL; voltage: 10 kV);
1
IR (KBr): 2918–2449 NH2þ; H NMR (CD3OD, COSY):
d 1.33 (d, J = 6.6 Hz, 3H, CH3CH), 2.27 (s, 3H, CH3Ar),
3.68 (dd, J = 13.5, 9.3 Hz, 1H, CHHCH), 3.77–3.91 (m,
1H, CH), 4.31 (d, J = 14.3 Hz, 1H, AB system, CHHNH),
4.38 (d overlapping dd at 4.45, J = 14.3 Hz, 1H, AB sys-
tem, CHHNH), 4.45 (dd overlapping d at 4.38, J = 13.4,
2.6 Hz, 1H, CHHCH),7.06 (apparent t, J = 7.4 Hz, 1H,
Ar HC-7), 7.22 (d overlapping d at 7.28, J = 7.4 Hz, 1H,
Ar HC-8), 7.28 (d overlapping d at 7.22, J = 7.7 Hz, 1H,
Ar HC-6); 13C NMR (CD3OD, d 47.8): d 13.3 (1C), 14.7
(1C), 48.1 (1C), 57.1 (1C), 72.8 (1C), 124.3 (1C), 125.2
(1C), 128.6 (1C), 130.5 (1C), 132.4 (1C), 158.4 (1 C);
ESI+/MS m/z 178.2 (MH+); ESI+/MS/MS m/z 161 (100);
Acknowledgments
This work was accomplished, thanks to 0the financial sup-
0
´
port of the Ministero dell Istruzione, dell Universita e della
Ricerca (MIUR 2003033405). The Authors are indebted to
Dr. G. Fracchiolla who kindly donated suitable quantities
of (ꢀ)-(R)-(2-naphthyloxy)phenylacetic acid, used herein
as CSA.

M. M. Cavalluzzi et al. / Tetrahedron: Asymmetry 18 (2007) 2409–2417
2417
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