Arylpropanolamines incorporating an antioxidant function as neuroprotective agents

Article abstract of DOI:10.1071/CH03010

A series of arylpropanolamines containing dipyrrolidinylpyrimidines as an antioxidant function have been synthesized and evaluated as dual function neuroprotective agents. Their in vitro efficacy as sodium channel blocking agents and antioxidants has been evaluated and compared with those of the ethanolamine derivative (1), which has been shown to be neuroprotective in a rat model of stroke. The ability of the present compounds to displace ³H-BTX toxin from sodium-ion channels in a rat brain membrane fraction was shown to be largely independent of the substituents on the aryl ring, which suggests that this activity may be mainly associated with the aminopyrimidine moiety. Structure-activity relationships for antioxidant efficacy were less clear, but the unsymmetrical pyrimidines were consistently more active than their symmetrical isomers. A brief theoretical investigation of this observation is reported.

Full text of DOI:10.1071/CH03010

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 597–605
Arylpropanolamines Incorporating an Antioxidant
Function as Neuroprotective Agents
Lida Joubran,A W. Roy Jackson,B,D Eva M. Campi,B Andrea J. Robinson,A Bradley A. Wells,A
Peter D. Godfrey,A Jennifer K. CallawayC and Bevyn JarrottC
A School of Chemistry, Box 23, Monash University, Clayton 3800, Australia.
B Centre for Green Chemistry, Box 23, Monash University, Clayton 3800, Australia.
C Department of Pharmacology, Monash University, Clayton 3800, Australia.
D Author to whom correspondence should be addressed (e-mail: w.r.jackson@sci.monash.edu.au).
A series of arylpropanolamines containing dipyrrolidinylpyrimidines as an antioxidant function have been synthe-
sized and evaluated as dual function neuroprotective agents. Their in vitro efficacy as sodium channel blocking
agents and antioxidants has been evaluated and compared with those of the ethanolamine derivative (1), which has
3
been shown to be neuroprotective in a rat model of stroke. The ability of the present compounds to displace H-
BTX toxin from sodium-ion channels in a rat brain membrane fraction was shown to be largely independent of the
substituents on the aryl ring, which suggests that this activity may be mainly associated with the aminopyrimidine
moiety. Structure–activity relationships for antioxidant efficacy were less clear, but the unsymmetrical pyrimidines
were consistently more active than their symmetrical isomers. A brief theoretical investigation of this observation
is reported.
Manuscript received: 8 January 2003.
Final version: 9 April 2003.
But
OH
Introduction
OH
N
N
N
The ethanolamine derivative (1), which contains some of the
structuralfeaturesofifenprodil(2)[1] andanantioxidantfunc-
tion, has been shown to be neuroprotective in a rat model of
stroke with a desirable therapeutic window of three hours
(Scheme 1).[2,3] The patent application describing this com-
pound also describes the preparation and pharmacological
activity of a wide range of related compounds, many of which
involve a combination of arylethanolamine derivatives and
an antioxidant functionality.[4] The antioxidants incorporated
into the structures were mainly phenolic in nature, i.e. Trolox
or 2,6-di-tert-butylphenols.
OH
But
HO
(1)
Cl
(2)
OH
OH
N
N
N
Br
N
HOOC
N
N
O
Trolox
(3)
N
N
O
N
N
N
In related studies, a series of compounds containing
a different antioxidant moiety, amino-substituted pyrim-
idines, were prepared. The amino-substituted pyrimidine
group is incorporated in the neuroprotective steroid tiri-
lazad (Scheme 1).[5] Some of the compounds containing the
aminopyrimidineantioxidantshowedinterestingactivityboth
as Na+ channel blockers and as antioxidants. For example,
compound (3), whose preparation and antioxidant activity
was reported recently by us,[6] showed comparable Na+ chan-
nel blocking activity to compound (1) but was not quite as
effective an antioxidant, as shown by the biological Sapphire
assay[7,8] and by its oxidation potential (Epolx), which was
measured using cyclic voltammetry.[6]
N
O
Tirilazad
Scheme 1.
compound lamotrigine (Scheme 2), have been shown to block
voltage-gated Na+ channels, and the Na+ channel blocking
activity of compound (3) and its analogues could, therefore,
be due to both the arylethanolamine and aminopyrimidine
functionalities.
It was thus decided to prepare and evaluate a series of
arylpropanolamines (4) and (5) (see Scheme 3) which do
not contain an arylethanolamine group but which retain
the aminopyrimidine antioxidant moiety of (3) and the BW
It is noteworthy that several diamino-substituted pyrimi-
dines,[9] such as BW 1003C87, BW 619C89, and the related
© CSIRO 2003
10.1071/CH03010
0004-9425/03/060597

598
L. Joubran et al.
Cl
Cl
Ph
MeO
Cl
CI
CI
CF3
CI
NH2
NH2
O
N
N
N
N
N
CI
N
N
O
N
OH
CN
N
N
N
H2N
NH2
N
NH2
N
H
N
H
CH3
BW 1003C87
BW 619C89
Scheme 2.
O
Lamotrigine
(12)
(11)
Diagram 1.
O
OH
(8)
Br
CN
LiAlH4
NaCN
NH2
conditions, which shows that the electron-donating power of
the pyrrolidino nitrogen atoms prevents the chlorine atom
from undergoing nucleophilic substitution.
All of these compounds contain one chiral carbon atom
and it was considered important to evaluate the pharma-
cological activity of individual enantiomers. The parent
compound (5a) was converted into the ester (11) (Diagram 1)
with (S)-(–)-Mosher’s acid, but all attempts to separate the
diastereomeric esters either by chromatography or fractional
crystallization failed.
R
R
R
(7)
(6)
(Na) R ϭ H
(Nb) R ϭ 4-Br
(Nc) R ϭ 4-OMe
(Nd) R ϭ 4-OCF3
Cl
N
N
Cl
Cl
Cl
Cl
Cl
N
OH
OH
N
N
N
ϩ
N
N
H
H
R
(9)
R
(10)
Cl
Enzymatic reduction of the cyanoketone (7a)[10] using
yeast gave the (S)-configured isomer of the cyanoalcohol
(12) with an optical rotation value of [α]2D0 −69◦, which com-
pared well with literature. Subsequent reduction of the cyano
function in (12) with LiAlH4 yielded the (S)-aminoalcohol
(S)-(8a). The aminoalcohol was then converted, as described
above, into the symmetrical and unsymmetrical dichloro-
pyrimidines (9a) and (10a), which were separated and reacted
individually with pyrrolidine to give the dipyrrolidinylpyrim-
idines (S)-(4a) and (S)-(5a), respectively.The unsymmetrical
isomer (5a) was converted into its MTPA-ester (S)-(11).
1H and 19F NMR spectroscopy independently showed a 4 : 1
ratio of diastereomers, giving an enantiomeric excess (e.e.)
of 64% for the (S)-enantiomer.
HN
HN
OH
N
N
OH
N
N
N
H
N
ϩ
N
H
N
R
(5)
R
(4)
N
N
Scheme 3.
compounds. The arylethanol functionality was to be retained
but was to be joined to the aminopyrimidine by a simple two-
carbon spacer, thus eliminating the arylethanolamine moiety.
Furthermore, any possible activity of the piperazine ring in
(3) was also eliminated.
Na+ Channel Activity
3
The ability of the compounds (4) and (5) to displace H-
Results and Discussion
batrachotoxin (BTX) from Na+ channels in a rat brain
membrane fraction was measured by a standard procedure[11]
and the results are summarized in Table 1. IC50 (µM) val-
ues and their ranges are listed together with binding data at
concentrations of 1 and 10 µM. Allowing for the uncertainty
in the measurements, all compounds showed very similar
BTX binding affinity at 1 and 10 µM concentrations and
similar IC50 values. The p-bromo compounds (4b) and (5b)
(Entries 3 and 4) gave indications of slightly less activity
than the others (Entries 1, 2, 5–8). The two compounds
with para-trifluoromethoxy substituents (4d) and (5d)
(Entries 7 and 8) marginally showed the best activity.
However, none of these compounds were as active as the
lead compound (1) (Entry 12) or the key compound (3)
(Entry 13), which were themselves comparable in activity
(all having IC50 of ca. 0.3 µM) to dibucaine, a well known
3H-BTX specific inhibitor.[12] No consistent differences were
observed between the symmetrical (4) and unsymmetrical (5)
isomers.
Synthesis of Propanolamine Derivatives (4) and (5)
Arangeofα-bromoacetophenones(6)wereconvertedintothe
acetonitrile derivatives (7) which, in turn, were reduced with
lithium aluminium hydride to the arylpropanolamines (8) in
yields varying from 40 to 90% (Scheme 3). The amines (8)
were treated with 2,4,6-trichloropyrimidine to give a mix-
ture of symmetrical (9) and unsymmetrical (10) dichloro-
pyrimidine derivatives in an approximately equimolar ratio
under conditions described previously for preparation of
the related ethanolamine derivatives.[6] The symmetrical and
unsymmetrical compounds were readily separated and the
pure compounds isolated with combined yields in the range
of 64–89%. Conversion to the dipyrrolidinyl compounds (4)
and (5) again followed the literature procedure[6] and gave
pure compounds in yields varying from 30 to 75%.
Attempted preparation of the unsymmetrical isomer (5a)
by treatment of amine (8a) with preformed 6-chloro-
2,4-dipyrrolidinylpyrimidine failed, even under vigorous

Arylpropanolamines Incorporating an Antioxidant Function as Neuroprotective Agents
599
Table 1. Results of pharmacological assaysA
Entry
Substrate
R
3H-BTX Specific Binding
Sapphire LPO-586 Colourimetric Assay
1 µM
10 µM
IC50 [µM]
IC50 range
IC50 [µM]
IC50 range
Max inhibition [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
(4a)
(5a)
(4b)
(5b)
(4c)
(5c)
(4d)
(5d)
(S)-(4a)B
(S)-(5a)B
dibucaine
(1)
H
H
Br
Br
OMe
OMe
OCF3
OCF3
H
H
–
–
–
27 11
88
78
83
81
87
97
98
100
89
95
3
2.8
2.9
4.3
3.2
2.9
1.9
1.1
1.1
2.0
1.0
0.25
0.28
0.31
0.9–8.4
1.5–5.7
1.3–13.7
1.4–7.2
2.1–4.1
0.7–5.2
0.5–2.0
0.8–1.5
1.5–2.7
0.8–1.3
184
49
>1000
475
722
128
>1000
645
152–224
38–64
–
445–507
601–878
104–157
–
342–1216
–
549–1231
–
81
92
18
76
56
87
4
78
28
57
–
17
16
28
20
37
45
45
44
58
77
69
75
4
5
6
4
4
0
3
4
1
6
3
1
0
1
1
0
3
0
2
0
1
3
1
1
>1000
822
C
97
87
100
0.22–0.28
0.14–0.42
0.24–0.41
–
62
123
46–82
87–180
81
87
(3)
A Replicates, n = 2–4.
B These samples were enriched with the (S)-enantiomer.
C Not tested (no antioxidant properties).
These results suggest that the 3H-BTX specific inhibition
observed in the series of compounds (4) and (5) is mainly
associated with the aminopyrimidine moiety. Thus, the effect
of changing substituents in the remote aryl ring on receptor
binding is likely to be small. The compounds BW 1003C87,
BW 619C89, and lamotrigine (Scheme 2) all have planar
heterocyclic rings with two amino substituents and show
Na+ channel blocking activity. Such activity thus appears
to be associated with a range of amino-substituted nitrogen-
containing heterocycles including compounds (4) and (5).
The greater activity of the aryl β-ethanolamine derivative (3)
suggests that this moiety has Na+ ion channel blocking activ-
ity which is additive to or greater than that facilitated by the
aminopyrimidine moiety.
enantiomerically enriched samples (4a) and (5a) (Entries 9
and 10), which showed a dramatic loss of activity relative to
the racemic compounds (Entries 1 and 2). It should be noted
that the Sapphire assay has previously been demonstrated
to give results which were concordant with other biologi-
cal (TBARS) and chemical (cyclic voltammetry) assays.[6]
However, in this work, the much greater range of results
obtained using this assay means that the results must not be
over-interpreted. Although the results must be treated with
caution, it appears that the least active compounds have a
strong electron-withdrawing substituent in the para-position.
Thus para-bromo and para-trifluoromethoxy substituents,
with Hammett σ values of +0.2 and +0.35 respectively,
show less activity than the unsubstituted and para-methoxy
compounds with σ values of 0.0 and −0.27.
The enantiomerically enriched samples of (4a) and (5a)
(Entries 9 and 10) showed evidence of being more active
than the racemic samples, emphasizing the importance of
assessing single enantiomers where possible.
Only one clear trend was observed, namely, that the
unsymmetrical isomers (5) were more active than the sym-
metrical isomers (4). Previous work by us has shown that it is
necessary to have three amino substituents on the pyrimidine
ring in order for antioxidant activity to be displayed.[6] Thus,
a short theoretical study of the energies of the radical species
obtained on oxidation of model analogues of symmetrical
and unsymmetrical triamino-substituted pyrimidines was
carried out.
Antioxidant Activity
The antioxidant activity was measured using the Sapphire
colorimetric assay with modifications described previously
by us.[6] Lipid peroxidation was stimulated by Fe3+ (100 µM)
and the IC50 (µM) and maximum inhibition are given in
Table 1. The unsymmetrical isomers (5) consistently showed
better antioxidant activity than the symmetrical isomers (4)
in both IC50 and maximum inhibition values. Compound (3)
(Entry 13), which also contains the unsymmetrical pyrro-
lidinylpyrimidine structure, showed a maximum inhibition
value similar to the isomers (5).
Compound (5a) was comparable in antioxidant activity to
compound (1) (Entry 12), which has a di-tert-butylphenol
as the antioxidant moiety. Compound (5c) (Entry 6) was
comparable in antioxidant activity to compound (3) (Entry
13), both of which have the same unsymmetrical pyrimidine
antioxidant moiety.
Theoretical Studies
PM3 semi-empirical calculations for the radical cations (13)
and (14), derived from the N-methyl-bis(dimethylamino)-
pyrimidine analogues of (4) and (5), suggested electron-
spin densities as illustrated in Figure 1. As expected, a
significant portion of unpaired electron density resides on
nitrogen. However, a significant amount of unpaired electron
density also resides on carbon atoms, and the symmetri-
cal (15) and unsymmetrical (16) canonical forms, which
best represent these structures, are shown in Scheme 4. The
symmetrical isomer can be seen to have a cross-conjugated
structure in contrast to the fully conjugated unsymmetri-
cal isomer, and thus could be expected to be of lower
stability.
The large range of values for antioxidant activity obtained
on changing the substituents in the remote aromatic ring is
difficult to explain. Even more puzzling are the results for the

600
L. Joubran et al.
Fig. 1. Electron spin densities of the symmetrical (13), left, and unsymmetrical (14), right, radical cations.
source. Mass spectra (EI) were recorded on a VG TRIO-1 Quadrupole
Mass Spectrometer at 70 eV with a source temperature of 200◦C. Micro-
analyses were performed by Chemical and Microanalytical Services Pty
Ltd, Melbourne. Merck Silica Gel 60 (230–400 mesh, no. 9385) was
used for flash chromatography.
N
N
N
3
N
1
N
2
1
NH
ϩ
ϩ
4
N
N
2
H
H
N
3
N
(15)
(16)
Brominated Acetophenones
The compounds (6b)–(6d) were prepared as described in the
literature.[14,15]
Scheme 4.
This suggestion is consistent with the pKa values of
5.69 for 4-aminopyrimidine itself and 3.45 for the 2-amino
isomer.[13] The greater basicity of the former suggests that the
cation which can be stabilized by linear conjugation is more
stable than the cation from the 2-isomer where stabilization
would involve cross-conjugation.
However, density functional calculations using Gaus-
sian98 do not reveal any significant energy differences
between the radical cations (13) and (14) relative to their
parent molecules, i.e. the N-methyl-bis(dimethylamino)
pyrimidine analogues of (4) and (5).
2-Bromo-4ꢀ-trifluoromethoxyacetophenone (6d)
Prepared in 83% yield as a white solid,[16] mp 52–54◦C (Found:
[M + Na]+•, 304.9399. C9H679BrF3O2 requires [M + Na]+•, 304.9401).
δH (300 MHz) 8.05 (2 H, d, J 8.7, H2ꢀ and H6ꢀ), 7.32 (2 H, d, J 8.7, H3ꢀ
3
and H5ꢀ), 4.41 (2 H, s, H2). δC (75 MHz) 190.0 (C1), 153.3 (q, JCF
1.7, C4ꢀ), 132.2 (C1ꢀ), 131.2 (C2ꢀ and C6ꢀ), 120.7 (q, 4JCF 1.2, C3ꢀ and
C5ꢀ), 120.4 (q, 1JCF 259.4, OCF3), 30.5 (C2).
Propanenitriles (7a)–(7d)
The propanenitriles were prepared as described by Long.[17]
3-Oxo-3-phenylpropanenitrile (7a)
A solution of sodium cyanide (0.74 g, 15.07 mmol) in water (10 mL)
was added slowly to a stirred solution of 2-bromoacetophenone (6a)
(1.00 g, 5.02 mmol) in methanol (15 mL) under nitrogen. The mixture
was allowed to stir at ambient temperature for 3 h and was then con-
centrated under reduced pressure. Water (10 mL) was added followed
by acetic acid (to pH 3) to give a precipitate which was collected by
filtration to give 3-oxo-3-phenylpropanenitrile (7a) as a pale cream,
crystalline solid (1.59 g, 80%), mp 79.6–79.8◦C (lit.[18] 80.5–80.7◦C).
Conclusions
A range of arylpropanolamines with aminopyrimidine sub-
stituents have been prepared and evaluated as dual function
neuroprotective agents. In vitro studies suggest that the
sodium-channel blocking activity, as well as the antioxidant
activity, is mainly associated with the aminopyrimidine moi-
ety.The unsymmetrical aminopyrimidine isomers were found
to be more active antioxidants.
3-(4ꢀ-Bromophenyl)-3-oxopropanenitrile (7b)
2,4ꢀ-Dibromoacetophenone (6b) (1.00 g, 3.59 mmol) gave the nitrile
(7b) as a pale cream, crystalline solid (0.71 g, 88%), mp 159.3–160.3◦C
(lit.[19] 159◦C, 164–165◦C). δH (300 MHz) 7.71 (2 H, d, J 8.6, H2ꢀ and
H6ꢀ), 7.60 (2 H, d, J 8.6, H3ꢀ and H5ꢀ), 3.95 (2 H, s, H2). δC (75 MHz)
186.4 (C3), 133.2 (C1ꢀ), 132.8 (C2ꢀ and C6ꢀ), 130.5 (C4ꢀ), 130.1 (C3ꢀ
and C5ꢀ), 113.6 (CN), 29.5 (C2).
Experimental
Syntheses
Melting points are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer 1600 FT-IR spectrophotometer. 1H, 13C, and 19F NMR
spectra were recorded using Bruker AM-300 and DRX-400 spectro-
meters for solutions in CDCl3 unless otherwise stated. Mass spectra
(ESI) were measured on a Bruker BioApex 47 e− Fourier transform
mass spectrometer with a 4.7 T magnet and an Analytica electrospray
3-Oxo-3-(4ꢀ-methoxyphenyl)propanenitrile (7c)
2-Bromo-4ꢀ-methoxyacetophenone (6c) (4.00 g, 17.46 mmol) gave the
nitrile (7c) as a cream, crystalline solid (2.04 g, 67%), mp 127.4–
127.6◦C (lit.[20] 132–133◦C, lit.[21] 125–127◦C). δH (300 MHz) 7.91

Arylpropanolamines Incorporating an Antioxidant Function as Neuroprotective Agents
601
(2 H, d, J 9.0, H2ꢀ and H6ꢀ), 6.98 (2 H, d, J 9.0, H3ꢀ and H5ꢀ), 4.00
(2 H, s, H2), 3.90 (3 H, s, OCH3). δC (75 MHz) 185.5 (C3), 164.9 (C4ꢀ),
131.1 (C2ꢀ and C6ꢀ), 127.5 (C1ꢀ), 114.5 (C3ꢀ and C5ꢀ), 114.2 (CN), 55.8
(OCH3), 29.1 (C2).
2.78 (3 H, br s, exchangeable OH and NH2), 1.86–1.69 (2 H, m, H2).
δC (75 MHz) 158.8 (C4ꢀ), 137.5 (C1ꢀ), 127.0 (C2ꢀ and C6ꢀ), 113.8 (C3ꢀ
and C5ꢀ), 75.1 (C1), 55.4 (OCH3), 40.7 (C3), 40.2 (C2). Mass spectrum
(EI) m/z 181 (10%, M+•), 164 (32), 163 (100), 137 (45), 135 (62), 133
(78), 109 (28), 94 (48), 91 (46), 78 (18), 77 (95), 66 (22), 65 (45), 63
(47), 55 (15).
3-Oxo-3-(4ꢀ-trifluoromethoxyphenyl)propanenitrile (7d)
2-Bromo-4ꢀ-trifluoromethoxyacetophenone (6d) (1.00 g, 3.71 mmol)
gave the nitrile (7d) as a cream, crystalline solid (0.69 g, 85%), mp 74.0–
75.4◦C (lit.[22] 79–81◦C). δH (300 MHz) 8.00 (2 H, d, J 8.9, H2ꢀ and
H6ꢀ), 7.36 (2 H, d, J 8.9, H3ꢀ and H5ꢀ), 4.07 (2 H, s, H2). δC (75 MHz)
185.9 (C3), 153.9 (q, 3JCF 1.7, C4ꢀ), 132.4 (C1ꢀ), 130.8 (C2ꢀ and C6ꢀ),
120.9 (q, 4JCF 1.2, C3ꢀ and C5ꢀ), 120.3 (q, 1JCF 259.8, OCF3), 113.6
(CN), 29.6 (C2).
3-Amino-1-(4ꢀ-trifluoromethoxyphenyl)propanol (8d)
Inasimilarmanner, 3-oxo-3-(4ꢀ-trifluoromethoxyphenyl)propanenitrile
(7d) (0.50 g, 2.18 mmol) gave a yellow oil (0.41 g) which was puri-
fied by acid–base extraction. The crude mixture was poured into 2M
HCl (20 mL), CH2Cl2 (20 mL) was added, and the organic layer was
separated. The aqueous layer was basified to pH 14 by addition of
NaOH pellets and extracted with CH2Cl2 (3 × 50 mL). The extracts
were dried and the solvent removed under vacuum to give the amino
alcohol (8d) as a clear oil (0.21 g, 41%) (Found: C, 51.0; H, 4.5; N,
5.9%; [M + H]+•, 236.0892. C10H12F3NO2 requires C, 51.1; H, 5.1;
N, 6.0%; [M + H]+•, 236.0898). νmax (neat)/cm−1 3360bm, 2936bm,
2874bm, 1595m, 1510m, 1268bs, 1161bs, 1070bm, 1018m, 922m. δH
(400 MHz) 7.31 (2 H, d, J 8.5, H2ꢀ and H6ꢀ), 7.08 (2 H, d, J 8.5, H3ꢀ and
H5ꢀ), 4.88 (1 H, dd, J 8.8, 2.9, H1), 3.06–3.01 (1 H, m, H3), 2.91–2.85
(1 H, m, H3), 2.70–2.20 (3 H, br s, exchangeable OH and NH2), 1.76
(1 H, m, H2), 1.61 (1 H, m, H2). δC (100 MHz) 148.4 (q, 3JCF 1.5, C4ꢀ),
Preparation of Propanolamines (8a)–(8d)
3-Amino-1-phenylpropanol (8a)
A solution of 3-oxo-3-phenylpropanenitrile (7a) (1.00 g, 6.89 mmol) in
THF (20 mL) was added dropwise to a stirred suspension of LiAlH4
(2.61 g, 6.90 mmol) in THF (20 mL) at 0◦C. The mixture was warmed
to ambient temperature and stirred for 15 min at which point TLC anal-
ysis indicated the absence of any starting material. The mixture was
cooled, Na2SO4·10H2O (10 g) was added portionwise until the effer-
vescence ceased, and the mixture was allowed to stir for a further 15 min.
The suspension was filtered and the filter cake was washed with ether
(20 mL). The filtrate was reduced under vacuum to yield a yellow oil
(0.68 g). Kugelrohr distillation gave the amine (8a) as a colourless liquid
that solidified to a colourless solid (0.67 g, 64%), bp 150◦C/0.1 mmHg
(lit.[23] 107–110◦C/0.5 mmHg), mp 57.4–58.2◦C (lit.[23] 63–64◦C). δH
(300 MHz) 7.40–7.22 (5 H, m, ArH), 4.96 (1 H, dd, J 8.5, 3.2, H1),
3.08 (1 H, m, H3), 2.95 (1 H, m, H3), 2.78 (3 H, br s, exchangeable OH
and NH2), 1.91–1.69 (2 H, m, H2). δC (75 MHz) 145.3 (C1ꢀ), 128.4
(C3ꢀ and C5ꢀ), 127.2 (C4ꢀ), 125.8 (C2ꢀ and C6ꢀ), 75.8 (C1), 41.0 (C3),
40.2 (C2).
4
144.2 (C1ꢀ), 127.2 (C2ꢀ and C6ꢀ), 121.0 (q, JCF 0.40, C3ꢀ and C5ꢀ),
1
120.8 (q, JCF 256.7, OCF3), 75.8 (C1), 41.0 (C3), 39.7 (C2). Mass
•
spectrum (ESI) m/z 236 [M + H]+
.
Arylpropanolamino Dichloropyrimidines (9a)–(9d) and (10a)–(10d)
A solution of 2,4,6-trichloropyrimidine (4 mmol) in dry 1,4-dioxane
(10 mL) was added dropwise at ambient temperature to a stirred solution
of the amino alcohol (8a)–(8d) (4 mmol) in dry 1,4-dioxane (20 mL).
Once addition was complete, NaHCO3 (24 mmol) was added and
the resulting mixture was heated at reflux for 2–6 h. The mixture
was cooled to ambient temperature, quenched with water (20 mL),
and basified to pH 12 by addition of 2M NaOH. The mixture was
extracted with CH2Cl2 (3 × 40 mL), dried, filtered, and concentrated.
In all cases, the 1H NMR spectrum indicated that the compounds (9)
and (10) were present in ca. 1 : 1 ratio. Flash chromatography (SiO2,
50% ether/light petroleum) gave the symmetrical isomer (9) followed
by the unsymmetrical isomer (10).
3-Amino-1-(4ꢀ-bromophenyl)propanol (8b)
Reaction of 3-(4ꢀ-bromophenyl)-3-oxopropanenitrile (7b) (0.70 g,
3.14 mmol) with LiAlH4 (0.72 g, 18.84 mmol) gave a yellow oil (0.47 g).
Spectroscopic data (1H NMR) showed a mixture of (8b) and the
debrominated compound, 3-amino-1-phenylpropanol (8a) in a ratio of
3 : 1. Kugelrohr distillation gave the amino alcohol (8b) as a colour-
•
less oil (0.35 g, 49%), bp 180–200◦C/0.2 mmHg (Found: [M + H]+
,
4,6-Dichloro-2-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)pyrimidine (9a)
and 2,4-Dichloro-6-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)
pyrimidine (10a)
229.0094; 231.0073. C9H1279BrNO requires [M + H]+•, 229.0103;
C9H1281BrNO requires [M + H]+•, 231.0082). νmax (neat)/cm−1
3360bs, 2937s, 2870s, 1673m, 1590s, 1401s, 1338m, 1199m, 1176m,
1071s, 1010s, 996m, 824s, 702s, 467s. δH (300 MHz) 7.46 (2 H, d, J
8.4, H3ꢀ and H5ꢀ), 7.30 (2 H, d, J 8.3, H2ꢀ and H6ꢀ), 4.92 (1 H, dd,
J 8.6, 3.0, H1), 2.89 (1 H, ddd, J 12.4, 5.7, 3.9, H3), 2.75 (1 H, ddd, J
12.4, 9.4, 3.6, H3), 1.67–1.59 (1 H, m, H2), 1.54–1.42 (1 H, m, H2). δC
(75 MHz) 144.4 (C1ꢀ), 131.4 (C3ꢀ and C5ꢀ), 127.6 (C2ꢀ and C6ꢀ), 120.3
(C4ꢀ), 75.3 (C1), 40.8 (C3), 39.6 (C2). Mass spectrum (ESI) m/z 232
(92%, [M(81Br) + H]+), 230 (100, [M(79Br) + H]+•).
Reaction of 2-amino-1-phenylpropanol (8a) (0.60 g, 3.97 mmol) after
reflux for 2 h gave a yellow gum (0.95 g).
Compound (9a). Isolated as a white solid (0.40 g, 34%), mp 120.9–
121◦C (Found: C, 52.3; H, 4.4; N, 14.0%. C13H13Cl2N3O requires C,
52.4; H, 4.4; N, 14.1%). νmax (KBr)/cm−1 3376bs, 3269bs, 3116m,
2363m, 2345m, 1654m, 1637m, 1599bs, 1582bs, 1519s, 1455s, 1426m,
1238m, 1122m, 1093s, 1067m, 1012m, 816m, 794m, 766m, 702m,
538m. δH (300 MHz) 7.36–7.26 (5 H, m, ArH), 6.59 (1 H, s, H5),
5.85 (1 H, br s, exchangeable OH or NH), 4.78 (1 H, m, H3ꢀ), 3.74
(1 H, m, H1ꢀ), 3.47 (1 H, m, H1ꢀ), 2.84 (1 H, d, J 3.3, exchange-
able OH or NH), 2.00–1.94 (2 H, m, H2ꢀ). δC (75 MHz) 162.05 (C2),
162.0 (C4 and C6), 144.1 (C1ꢀꢀ), 128.8 (C3ꢀꢀ and C5ꢀꢀ), 127.9 (C4ꢀꢀ),
125.9 (C2ꢀꢀ and C6ꢀꢀ), 109.3 (C5), 72.5 (C3ꢀ), 39.4 (C1ꢀ), 39.2 (C2ꢀ).
Mass spectrum (ESI) m/z 322 (67%, [M(35Cl)(37Cl) + Na]+•), 320
Reactions using a lesser excess of LiAlH4 (substrate (7b)/LiAlH4
ratio 1 : 2) or for a shorter time (5 min) were attempted but in all cases
the debromination compound (8a) still formed.
3-Amino-1-(4ꢀ-methoxyphenyl)propanol (8c)
Reaction of 3-oxo-3-(4ꢀ-methoxyphenyl)propanenitrile (7c) (2.00 g,
11.4 mmol) with LiAlH4 gave a cream solid (1.82 g) which was tri-
turated with ether to give the amino alcohol (8c) as a white solid (1.78 g,
86%), mp 102–104◦C (lit.[24] 123–125◦C, but with incorrect elemen-
tal analysis) (Found: C, 66.1; H, 8.4; N, 7.6%; [M + H]+•, 181.1103.
C10H15NO2 requires C, 66.2; H, 8.4; N, 7.7%; [M + H]+•, 181.1102).
νmax (KBr)/cm−1 3354s, 2854bs, 1610s, 1509s, 1459m, 1299m, 1248s,
1169s, 1081s, 1029s, 977m, 919m, 829m. δH (300 MHz) 7.29 (2 H, d, J
8.4, H2ꢀꢀ and H6ꢀꢀ), 6.87 (2 H, d, J 8.4, H3ꢀꢀ and H5ꢀꢀ), 4.88 (1 H, dd, J
8.1, 3.5, H1), 3.79 (3 H, s, OCH3), 3.04 (1 H, m, H3), 2.92 (1 H, m, H3),
•
(100, [M(35Cl)2 + Na]+ ), 300 (52, [M(35Cl)(37Cl) + H]+•), 298 (72,
[M(35Cl)2 + H]+•).
Compound (10a). Isolated as a white solid (0.47 g, 40%), mp 98.1–
98.6◦C (Found: C, 52.3; H, 4.4; N, 14.1%. C13H13Cl2N3O requires
C, 52.4; H, 4.4; N, 14.1%). νmax (KBr)/cm−1 3630m, 3395bs, 3320bs,
3200m, 2872m, 1592bs, 1528m, 1508m, 1499m, 1458m, 826m, 701m.
δH (300 MHz) 7.32–7.19 (5 H, m, ArH), 6.18 (1 H, s, H5), 5.85 (1 H,
br s, exchangeable OH or NH), 4.78 (1 H, m, [4.84 (t, J 6.3 on D2O
exchange)], H3ꢀ), 3.72 (1 H, br s, H1ꢀ), 3.42 (1 H, br s, H1ꢀ), 2.62 (1 H,

602
L. Joubran et al.
br s, exchangeable OH or NH), 1.96–1.93 (2 H, m, H2ꢀ). δC (75 MHz)
178.0 (C6), 164.3 (C2 and C4), 143.8 (C1ꢀꢀ), 128.9 (C3ꢀꢀ and C5 ꢀꢀ),
128.3 (C4ꢀꢀ), 125.8 (C2ꢀꢀ and C6ꢀꢀ), 100.6 (C5), 73.5 (C3ꢀ), 39.7 (C1ꢀ),
38.0 (C2ꢀ). Mass spectrum (ESI) m/z 302 (12%, [M(37Cl)2 + H]+•),
and C6ꢀꢀ), 113.5 (C3ꢀꢀ and C5ꢀꢀ), 102.7 (C5), 71.3 (C3ꢀ), 55.1 (OCH3),
38.6 (C1ꢀ), 38.1 (C2ꢀ), C6 not observed. Mass spectrum (ESI) m/z 330
•
(55%, [M(35Cl)(37Cl) + H]+ ), 328 (100, [M(35Cl)2 + H]+•).
•
300 (54, [M(35Cl)(37Cl) + H]+ ), 298 (84, [M(35Cl)2 + H]+•).
4,6-Dichloro-2-[3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)
propylamino]pyrimidine (9d) and
2-[3ꢀ-(4ꢀꢀ-Bromophenyl)-3ꢀ-hydroxypropylamino]-
4,6-dichloropyrimidine (9b) and
2,4-Dichloro-6-[3ꢀ-hydroxy-
3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)propylamino]pyrimidine (10d)
6-[3ꢀ-(4ꢀꢀ-Bromophenyl)-3ꢀ-hydroxypropylamino]-
2,4-dichloropyrimidine (10b)
Reaction of 3-amino-1-(4ꢀ-trifluoromethoxyphenyl)propanol (8d)
(0.48 g, 2.04 mmol) after reflux for 3 h gave an orange gum (0.75 g).
Reaction of 3-amino-1-(4ꢀ-bromophenyl)propanol (8b) (0.50 g,
2.17 mmol) after reflux for 6 h gave an orange oil (0.81 g).
Compound (9d). Isolated as a white solid (0.37 g, 47%), mp
•
112.9–114.9◦C (Found: C, 44.0; H, 3.1; N, 11.0%; [M + H]+
,
Compound (9b). Isolated as a white solid (0.26 g, 32%), mp 115.4–
115.6◦C (Found: C, 41.6; H, 3.0; N, 11.2%. C13H12 BrCl2N3O requires
C, 41.6; H, 3.2; N, 11.1%). νmax (KBr)/cm−1 3752s, 3413bm, 2365m,
1654s, 1610s, 1560m, 1523s, 1491m, 1458m, 1256m, 1094m, 1010s,
817m, 786m. δH (300 MHz) 7.47 (2 H, d, J 8.4, H3ꢀꢀ and H5ꢀꢀ), 7.24 (2 H,
d, J 8.4, H2ꢀꢀ and H6ꢀꢀ), 6.62 (1 H, s, H5), 5.80 (1 H, br s, exchangeable
OH or NH), 4.74 (1 H, m, H3ꢀ), 3.84–3.74 (1 H, m, H1ꢀ), 3.72–3.36
(1 H, m, H1ꢀ), 3.13 (1 H, br d, J 3.5, exchangeable OH or NH), 1.97–1.90
(2 H, m, H2ꢀ). δC (75 MHz) 162.0 (C4 and C6), 161.9 (C2), 143.1 (C1ꢀꢀ),
131.8 (C3ꢀꢀ and C5ꢀꢀ), 127.5 (C2ꢀꢀ and C6ꢀꢀ), 121.5 (C4ꢀꢀ), 109.3 (C5),
71.4 (C3ꢀ), 39.2 (C1ꢀ), 38.8 (C2ꢀ). Mass spectrum (ESI) m/z 378 (56%,
382.0326. C14H12Cl2F3N3O2 requires C, 44.1; H, 3.1; N, 11.0%;
[M(35Cl2) + H]+•, 382.0337). νmax (KBr)/cm−1 3282bm, 1604m,
1560m, 1523m, 1454m, 1278s, 1164m, 789m. δH (300 MHz) 7.40 (2 H,
d, J 8.8, H2ꢀꢀ and H6ꢀꢀ), 7.22 (2 H, d, J 8.8, H3ꢀꢀ and H5ꢀꢀ), 6.63 (1 H,
s, H5), 5.88 (1 H, br s, exchangeable OH or NH), 4.78 (1 H, m, H3ꢀ),
3.79 (1 H, m, H1ꢀ), 3.48 (1 H, m, H1ꢀ), 3.30 (1 H, d, J 3.6, exchangeable
OH or NH), 2.03–1.87 (2 H, m, H2ꢀ). δC (75 MHz) 162.2 (C2), 162.1
(C4 and C6), 148.7 (q, JCF 1.9, C4ꢀꢀ), 142.8 (C1ꢀꢀ), 127.2 (C2ꢀꢀ and
3
C6ꢀꢀ), 121.4 (q, 4JCF 1.1, C3ꢀꢀ and C5ꢀꢀ), 120.6 (q, 1JCF 256.9, OCF3),
71.2 (C3ꢀ), 39.3 (C1ꢀ),•38.9 (C2ꢀ). Mass spectrum (ESI) m/z 384 (52%,
[M(37Cl)(35Cl) + H]+ ), 382 (92, [M(35Cl)2 + H]+•).
•
[M(81Br)(37Cl)(35Cl) − H]− ), 376 (100, [M(81Br)(35Cl)2 − H]−•), 374
Compound (10d). Isolated as a white solid (0.31 g, 40%), mp
78–80◦C (Found: [M + H]+•, 382.0327. C14H1235Cl2F3N3O2 requires
[M + H]+•, 382.0337). νmax (KBr)/cm−1 3412bs, 3284m, 1638m,
1618s, 1560m, 1508m, 1236bm, 1213m, 1157m, 1198m, 1075m. δH
(300 MHz) 7.40 (2 H, d, J 8.1, H2ꢀꢀ and H6ꢀꢀ), 7.22 (2 H, d, J 8.1, H3ꢀꢀ
and H5ꢀꢀ), 6.28 (1 H, s, H5), 5.99–5.21 (1 H, br s, exchangeable OH or
NH), 4.86 (1 H, s, H3ꢀ), 3.63 (1 H, m, H1ꢀ), 3.47 (1 H, m, H1ꢀ), 3.01 (1 H,
br s, exchangeable OH or NH), 1.96–1.94 (2 H, m, H2ꢀ). δC (75 MHz)
(68, [M (79Br)(35Cl)2 − H]−•).
mp 54.3–54.7◦C (Found: C, 41.0; H, 3.0; N, 10.8%; [M + H]+
Compound (10b). Isolated as
a
white solid (0.26 g, 32%•),
,
375.9607. C13H12Cl2BrN3 requires C, 41.0; H, 3.2; N, 11.1%;
[M(79Br35Cl2) + H]+•, 375.9641). νmax (KBr)/cm−1 3413bs, 2346m,
1594bs, 1528m, 1480m, 1490m, 1448m, 1364m, 1278m, 1208m,
1121m, 1072m, 1010m, 975m. δH (300 MHz) 7.50 (2 H, d, J 8.4, H3ꢀꢀ
and H5ꢀꢀ), 7.22 (2 H, d, J 8.4, H2ꢀꢀ and H6ꢀꢀ), 6.27 (1 H, s, H5), 6.18–
5.59 (1 H, br s, exchangeable OH or NH), 4.80 (1 H, m, H3ꢀ), 3.67
(1 H, m, H1ꢀ), 3.46 (1 H, m, H1ꢀ), 2.97 (1 H, br s, exchangeable OH
or NH), 2.16–1.94 (2 H, m, H2ꢀ). δC (75 MHz) 165.0 (C4), 164.0 (C2),
142.7 (C1ꢀꢀ), 131.7 (C3ꢀꢀ and C5ꢀꢀ), 127.33 (C2ꢀꢀ and C6ꢀꢀ), 121.5 (C4ꢀꢀ),
102.9 (C5), 72.1 (C3ꢀ), 39.2 (C1ꢀ), 38.5 (C2ꢀ), C6 not detected. Mass
spectrum (ESI) m/z 378•(52%, [M(81Br)(37Cl)(35Cl) − H]−•), 376 (100,
[M(81Br)(35Cl)2 − H]− ), 374 (60, [M(79Br)(35Cl)2 − H]−•).
174.3 (C6), 164.3 (C4), 160.1 (C2), 148.9 (q, JCF 1.5, C4ꢀꢀ), 142.5
3
(C1ꢀꢀ), 127.2 (C2ꢀꢀ and C6ꢀꢀ), 121.3 (C3ꢀꢀ and C5ꢀꢀ), 120.6 (q, 1JCF 257.2,
OCF3), 102.8 (C5), 72.2•(C3ꢀ), 39.3 (C1ꢀ), 38.2 (C2ꢀ). Mass spectrum
(ESI) m/z 382 [M + H]+
.
Arylpropanolamino Dipyrrolidinylpyrimidines (4a)–(4d)
and (5a)–(5d)
A stirred mixture of the arylpropanolamino dichloropyrimidines (9a)–
(9d) or (10a)–(10d) (ca. 1 mmol) and pyrrolidine (20 mL) was heated
under reflux for 10 h.The excess pyrrolidine was removed under vacuum
and the resulting yellow oil was dissolved in CH2Cl2 (20 mL), washed
with saturated aqueous NaHCO3 solution (2 × 20 mL), dried, filtered,
and concentrated to yield the product as a crude solid. In all cases, the
1H NMR spectrum of the crude material indicated mainly the desired
product. Recrystallization from ethyl acetate or chromatography gave
the dipyrrolidinylpyrimidine compounds.
4,6-Dichloro-2-[3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-methoxyphenyl)
propylamino] pyrimidine (9c)
and 2,4-Dichloro-6-[3ꢀ-hydroxy-
3ꢀ-(4ꢀꢀ-methoxyphenyl)propylamino]pyrimidine (10c)
Reaction of 3-amino-1-(4ꢀ-methoxyphenyl)propanol (8c) (1.00 g,
5.52 mmol) after reflux for 4 h gave a yellow gum (1.80 g).
Compound (9c). Isolated as a white solid (0.58 g, 32%), mp 87.0–
87.2◦C (Found: C, 51.3; H, 4.6; N, 12.8%. C14H15Cl2N3O2 requires
C, 51.4; H, 4.6; N, 12.8%). νmax (KBr)/cm−1 3425bs, 3281bs, 1604s,
1560s, 1523s, 1257s, 1094m, 819m, 787m. δH (300 MHz) 7.28 (2 H,
d, J 8.7, H2ꢀꢀ and H6ꢀꢀ), 6.89 (2 H, d, J 8.7, H3ꢀꢀ and H5ꢀꢀ), 6.60
(1 H, s, H5), 5.82 (1 H, br s, exchangeable OH or NH), 4.75 (1 H, m,
H3ꢀ), 3.80 (3 H, s, OCH3), 3.70 (1 H, m, H1ꢀ), 3.50 (1 H, m, H1ꢀ), 2.63
(1 H, d, J 3.3, exchangeable OH or NH), 2.01–1.91 (2 H, m, H2ꢀ). δC
(75 MHz) 162.0 (C2), 161.9 (C4 and C6), 159.4 (C4ꢀꢀ), 136.3 (C1ꢀꢀ),
127.1 (C2ꢀꢀ and C6ꢀꢀ), 114.1 (C3ꢀꢀ and C5ꢀꢀ), 109.1 (C5), 72.2 (C3ꢀ),
55.5 (OCH3), 39.2 (C1ꢀ), 38.7 (C2ꢀ). Mass spectrum (ESI) m/z 352
6-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-2,4-di(pyrrolidin-
1-yl)pyrimidine (5a)
Reaction of 2,4-dichloro-6-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)pyrimi-
dine (10a) (0.40 g, 1.34 mmol) and pyrrolidine gave a crude solid
(0.52 g). Recrystallization from ethyl acetate gave the pyrimidine (5a)
as a white, crystalline solid (0.27 g, 55%), mp 126◦C (dec.) (Found:
C, 68.6; H, 8.0; N, 19.0%; [M + H]+•, 368.2441. C21H29N5O requires
C, 68.6; H, 8.0; N, 19.0%; [M + H]+•, 368.2450). νmax (KBr)/cm−1
3347bs, 3172bm, 2958bs, 2853bs, 1570bs, 1506bs, 1439bs, 1345bs,
1250m, 1172m, 975m, 788s, 764s, 701s. δH (400 MHz; [D6]DMSO)
7.24–7.09 (5 H, m, ArH), 6.01 (1 H, br s, exchangeable OH or NH),
5.27 (1 H, br s, exchangeable OH or NH), 4.61 (1 H, s, H5), 4.50 (1 H,
m, H3ꢀ), 3.29–3.00 (10 H, m, H1ꢀ and NCH2CH2), 1.77–1.67 (10 H,
m, H2ꢀ and NCH2CH2). δC (100 MHz; [D6]DMSO) 163.3 (C6), 161.0
(C4), 159.7 (C2), 146.0 (C1ꢀꢀ), 127.9 (C3ꢀꢀ and C5ꢀꢀ), 126.5 (C4ꢀꢀ), 125.7
(C2ꢀꢀ and C6ꢀꢀ), 72.2 (C5), 70.1 (C3ꢀ), 45.8, 45.5 (NCH2CH2), 40.0
(C1ꢀ), 37.3 (C•2ꢀ); 25.0, 24.7 (NCH2CH2). Mass spectrum (ESI) m/z
•
(70%, [M(35Cl)(37Cl) + Na]+ ), 350 (100, [M(35Cl)2 + Na]+•).
Compound (10c). Isolated as a white solid (0.65 g, 36%), mp 88.6–
90.6◦C (Found: C, 52.0; H, 5.0; N, 13.1%; [M + H]+•, 328.0618.
•
C14H15Cl2N3O2 requires C, 51.4; H, 4.6; N, 12.8%; [M(35Cl2) + H]+
,
328.0619). νmax (KBr)/cm−1 3414bs, 2980m, 1594s, 1512s, 1442m,
1248m, 1176m, 1121m, 1033m, 828m. δH (300 MHz) 7.16 (2 H, d, J
8.6, H2ꢀꢀ and H6ꢀꢀ), 6.75 (2 H, d, J 8.7, H3ꢀꢀ and H5ꢀꢀ), 6.24 (1 H, s,
H5), 5.95–5.89 (1 H, br s, exchangeable OH or NH), 4.80 (1 H, m, H3ꢀ),
3.80 (3 H, s, OCH3), 3.72 (1 H, m, H1ꢀ), 3.50 (1 H, br s, H1ꢀ), 2.31
(1 H, br s, exchangeable OH or NH), 2.01–1.97 (2 H, br m, H2ꢀ). δC
(75 MHz) 166.6 (C4), 164.2 (C2), 158.5 (C4ꢀꢀ), 136.6 (C1ꢀꢀ), 126.7 (C2ꢀꢀ
368 [M + H]+
.

Arylpropanolamines Incorporating an Antioxidant Function as Neuroprotective Agents
603
6-[3ꢀ-(4ꢀꢀ-Bromophenyl)-3ꢀ-hydroxypropylamino]-
2,4-di(pyrrolidin-1-yl)pyrimidine (5b)
acetate/methanol, 4 : 4 : 1) gave the pyrimidine (4a) as a white, crys-
talline solid (0.34 g, 70%), mp 112.7–112.9◦C (Found: C, 68.5; H, 7.8;
N, 19.0%; [M + H]+•, 368.2428. C21H29N5O requires C, 68.6; H, 8.0;
N, 19.0%; [M + H]+•, 368.2450). νmax (KBr)/cm−1 3415bs, 2966bm,
2867bm, 1594bs, 1559s, 1509s, 1456s, 1352m, 1318m. δH (300 MHz)
7.39–7.17 (5 H, m, ArH), 6.41 (1 H, br s, exchangeable OH and NH),
4.91 (1 H, br s, exchangeable OH and NH), 4.78 (1 H, dd, J 13.7, 3.2,
H3ꢀ), 4.64 (1 H, s, H5), 4.20–4.07 (1 H, m, H1ꢀ), 3.51–3.41 (8 H, m,
NCH2CH2), 3.29–3.22 (1 H, m, H1ꢀ), 2.04–1.68 (10 H, m, H2ꢀ and
NCH2CH2). δC (75 MHz) 162.5 (C4 and C6), 161.4 (C2), 144.9 (C1ꢀꢀ),
128.4 (C3ꢀꢀ and C5ꢀꢀ), 127.0 (C4ꢀꢀ), 126.1 (C2ꢀꢀ and C6ꢀꢀ), 73.5 (C5), 70.0
(C3ꢀ), 46.7(NCH2CH2), 42.2(C1ꢀ)•, 37.6(C2ꢀ), 25.7(NCH2CH2). Mass
Reaction of 6-[3ꢀ-(4ꢀꢀ-bromophenyl)-3ꢀ-hydroxypropylamino]-2,4-
dichloropyrimidine (10 b) (0.30 g, 0.80 mmol) and pyrrolidine gave a
crude solid (0.32 g). Recrystallization from ethyl acetate gave the pyrim-
idine (5b) as a cream, crystalline solid (0.12 g, 32%), mp 136◦C (dec.)
(Found: C, 52.4; H, 6.1; N, 14.6%. C21H29N5OBrCl requires C, 52.4;
H, 6.0; N, 14.4%). νmax (KBr)/cm−1 3413bm, 2966bm, 1572s, 1508m,
1474m, 1438m, 1346m. δH (300 MHz) 7.41 (2 H, d, J 8.4, H3ꢀꢀ and
H5ꢀꢀ), 7.24 (2 H, d, J 8.4, H2ꢀꢀ and H6ꢀꢀ), 6.26 (1 H, br s, exchangeable
OH or NH), 4.73 (1 H, s, H5), 4.65 (1 H, dd, J 10.0, 3.7, H3ꢀ), 4.31
(1 H, br s, exchangeable OH or NH), 4.21–4.08 (1 H, m, H1ꢀ), 3.67–
3.40 (8 H, br m, NCH2CH2), 3.24–3.15 (1 H, m, H1ꢀ), 1.96–1.66 (10 H,
m, H2ꢀ and NCH2CH2). δC (75 MHz) 163.7 (C6), 161.4 (C4), 159.8
(C2), 143.8 (C1ꢀꢀ), 131.3 (C3ꢀꢀ and C5ꢀꢀ), 127.7 (C2ꢀꢀ and C6ꢀꢀ), 120.5
(C4ꢀꢀ), 72.7 (C5), 68.6 (C3ꢀ), 46.6, 46.2 (NCH2CH2), 41.7 (C1ꢀ), 37.1
(C2ꢀ), 25.7, 25.6 (NCH2CH2). Mass spectrum (ESI) m/z 448 (100%,
spectrum (ESI) m/z 368 [M + H]+
.
2-[3ꢀ-(4ꢀꢀ-Bromophenyl)-3ꢀ-hydroxypropylamino]-
4,6-di(pyrrolidin-1-yl)-pyrimidine (4b)
Reaction of 2-[3ꢀ-(4ꢀꢀ-bromophenyl)-3-hydroxypropylamino]-4,6-
dichloropyrimidine (9b) (0.25 g, 0.66 mmol) gave a crude solid (0.32 g).
Recrystallization from ethyl acetate gave the pyrimidine (4b) as a cream,
crystalline solid (0.16 g, 54%), mp 211.2◦C (dec.) (Found: C, 52.4; H,
6.1; N, 14.6%. C21H29N5OBrCl requires C, 52.4; H, 6.1; N, 14.3%).
νmax (KBr)/cm−1 3316bs, 2971bs, 2363m, 2350m, 1726m, 1638s,
1586m, 1557m, 1509s, 1477s, 1459s, 1350m, 1316m. δH (300 MHz)
7.42 (2 H, d, J 8.3, H3ꢀꢀ and H5ꢀꢀ), 7.25 (2 H, d, J 8.3, H2ꢀꢀ and H6ꢀꢀ),
6.33 (1 H, br s, exchangeable OH or NH), 5.78 (1 H, br s, exchangeable
OH or NH), 4.74 (1 H, dd, J 10.8, 2.9, H3ꢀ), 4.63 (1 H, s, H5), 4.16–4.02
(1 H, m, H1ꢀ), 3.67–3.41 (8 H, m, NCH2CH2), 3.32–3.23 (1 H, m, H1ꢀ),
2.00–1.65 (10 H, m, H2ꢀ and NCH2CH2). δC (75 MHz) 171.3 (C4 and
C6), 167.5 (C2), 143.9 (C1ꢀꢀ), 131.4 (C3ꢀꢀ and C5ꢀꢀ), 127.5 (C2ꢀꢀ and
C6ꢀꢀ), 120.6 (C4ꢀꢀ), 73.2 (C5), 68.9 (C3ꢀ), 41.5 (NCH2CH2), 37.3 (C1ꢀ),
29.8 (C2ꢀ), 25.4 (NCH2CH2). Mass spectrum (ESI) m/z 448 (98%,
•
[M(81Br) + H]+ ), 446 (96, [M(79Br) + H]+•).
6-[3ꢀ-Hydroxy-3ꢀ-(4ꢀꢀ-methoxyphenyl)propylamino]-
2,4-di(pyrrolidin-1-yl)pyrimidine (5c)
Reactionof2,4-dichloro-6-[-3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-methoxyphenyl)propyl-
amino]pyrimidine (10c) (0.40 g, 1.22 mmol) gave a crude, cream
solid (0.50 g). Recrystallization from ethyl acetate gave the pyrimi-
dine (5c) as a cream, crystalline solid (0.36 g, 75%), mp 134.7◦C
(dec.) (Found: C, 60.9; H, 7.3; N, 16.0%; [M + H]+•, 398.2547.
•
C22H32N5O2Cl requires C, 60.9; H, 7.4; N, 16.2%; [M + H]+
,
398.2556). νmax (KBr)/cm−1 3344bs, 2968bs, 2855bs, 1578s, 1500bs,
1344s, 1315s, 1303s, 1245s, 1172s, 1102m, 1071m, 1032s, 978s, 820s,
788s, 704m. δH (300 MHz) 7.28 (2 H, d, J 8.6, H2ꢀꢀ and H6ꢀꢀ), 6.84 (2 H,
d, J 8.7, H3ꢀꢀ and H5ꢀꢀ), 5.69 (1 H, br s, exchangeable OH or NH), 4.73
(1 H, s, H5), 4.67 (1 H, dd, J 8.7, 3.9, H3ꢀ), 4.37 (1 H, br s, exchangeable
OH or NH), 4.15–4.01 (1 H, m, H1ꢀ), 3.76 (3 H, s, OCH3), 3.62–3.23
(8 H, br m, NCH2CH2), 3.22–3.14 (1 H, m, H1ꢀ), 1.94–1.73 (10 H, m,
H2ꢀ and NCH2CH2). δC (75 MHz) 164.0 (C4), 161.7 (C2), 158.8 (C4ꢀꢀ),
137.0 (C1ꢀꢀ), 127.2 (C2ꢀꢀ and C6ꢀꢀ), 113.8 (C3ꢀꢀ and C5ꢀꢀ), 72.6 (C5), 69.2
(C3ꢀ), 55.4 (OCH3), 46.5, 46.1 (NCH2CH2), 41.3 (C1ꢀ), 37.3 (C2ꢀ),
25.7, 25.5•(NCH2CH2), C6 not detected. Mass spectrum (ESI) m/z 398
•
[M(81Br) + H]+ ), 446 (100, [M(79Br) + H]+•).
2-[3ꢀ-Hydroxy-3ꢀ-(4ꢀꢀ-methoxyphenyl)propylamino]-
4,6-di(pyrrolidin-1-yl)pyrimidine (4c)
Reaction of 4,6-dichloro-2-[3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-methoxyphenyl)propyl-
amino]pyrimidine (9c) (0.50 g, 1.52 mmol) gave
a crude solid
(0.37 g). Purification by flash chromatography (SiO2, CH2Cl2/ethyl
acetate/methanol, 4 : 4 : 1) gave the pyrimidine (4c) as a cream, crys-
talline solid (0.35 g, 58%), mp (HCl salt) 201.9–202.9◦C (Found: C,
66.5; H, 7.9; N, 17.6%. C22H32ClN5O2 (HCl salt) requires C, 66.5; H,
7.9; N, 17.6%). νmax (KBr)/cm−1 3414bm, 2966bm, 2868bm, 1583s,
1560s, 1510s, 1459s, 1352s, 1318m, 1246m, 1172m, 1129m, 1074m,
1034m, 829m, 788m. δH (300 MHz) 7.29 (2 H, d, J 8.7, H2ꢀꢀ and H6ꢀꢀ),
6.83 (2 H, d, J 8.7, H3ꢀꢀ and H5ꢀꢀ), 6.49 (1 H, br s, exchangeable OH or
NH), 4.74–4.70 (2 H, br m, H3ꢀ and exchangeable OH or NH [4.75–4.70
(1H, dd, J 9.1, 4.1, H3ꢀ) on D2O exchange]), 4.62 (1 H, s, H5), 4.17–4.07
(1 H, m, H1ꢀ), 3.76 (3 H, s, OCH3), 3.66–3.38 (8 H, br m, NCH2CH2),
3.27–3.21 (1 H, m, H1ꢀ), 2.04–1.70 (10 H, m, H2ꢀ and NCH2CH2). δC
(75 MHz) 177.3 (C4 and C6), 161.6 (C2), 158.7 (C4ꢀꢀ), 137.1 (C1ꢀꢀ),
127.2 (C2ꢀꢀ and C6ꢀꢀ), 113.8 (C3ꢀꢀ and C5ꢀꢀ), 68.6 (C5), 66.0 (C3ꢀ), 55.4
[M + H]+
.
6-[3ꢀ-Hydroxy-3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)propylamino]-
2,4-di(pyrrolidin-1-yl)pyrimidine (5d)
Reactionof2,4-dichloro-6-[3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)
propylamino]pyrimidine (10d) (0.20 g, 0.52 mmol) and pyrrolidine
(15 mL) gave a brown solid (0.21 g). Recrystallization from ethyl acetate
gave the pyrimidine (5d) as a cream, crystalline solid (0.08 g, 34%), mp
175.8–176.9◦C (dec.) (Found: [M + H]+•, 452.2266. C22H28F3N5O2
requires[M + H]+•, 452.2273). νmax (KBr)/cm−1 3327s, 3184m, 2966s,
2856s, 1745m, 1576s, 1506s, 1474s, 1438s, 1372m, 1347s, 1305m,
1260s, 1166s, 1079s, 1019m, 975m, 789s, 692m. δH (400 MHz) 7.40
(2 H, d, J 8.4, H2ꢀꢀ and H6ꢀꢀ), 7.14 (2 H, d, J 8.4, H3ꢀꢀ and H5ꢀꢀ), 6.40
(1 H, br s, exchangeable OH or NH), 4.75 (1 H, s, H5), 4.70 (1 H, dd, J
10.1, 3.6, H3ꢀ), 4.33–4.26 (1 H, br s, exchangeable OH or NH), 4.23–
4.10 (1 H, m, H1ꢀ), 3.60–3.28 (8 H, br m, NCH2CH2), 3.27–3.15 (1 H,
m, H1ꢀ), 1.99–1.75 (10 H, m, H2ꢀ and NCH2CH2). δC (100 MHz) 164.4
(OCH3), 46.3 (NCH2CH2), 41.9 (C1ꢀ), 37.4 (C2ꢀ), 25.4 (NCH2CH2).
•
Mass spectrum (ESI) m/z 398 [M + H]+
.
2-[3ꢀ-Hydroxy-3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)propylamino]-
4,6-di(pyrrolidin-1-yl)pyrimidine (4d)
Reactionof4,6-dichloro-2-[3ꢀ-hydroxy-3ꢀ-(4ꢀꢀ-trifluoromethoxyphenyl)
propylamino]pyrimidine (9d) (0.20 g, 0.52 mmol) gave a crude solid
(0.20 g). Purification by flash chromatography (SiO2, CH2Cl2/ethyl
3
(C6), 161.7 (C4), 160.2 (C2), 148.2 (q, JCF 1.8, C4ꢀꢀ), 143.6 (C1ꢀꢀ),
4
127.4 (C2ꢀꢀ and C6ꢀꢀ), 120.9 (q, JCF 0.9, C3ꢀꢀ and C5ꢀꢀ), 120.7 (q,
1JCF 256.6, OCF3), 72.8 (C5), 68.6 (C3ꢀ), 46.5, 46.1 (NCH2CH2), 41.8
(C1ꢀ), 37.0 (C•2ꢀ), 25.7, 25.5 (NCH2CH2). Mass spectrum (ESI) m/z
acetate/methanol, 4 : 4 : 1) gave the pyrimidine (4d) as a cream, crys-
452 [M + H]+
.
•
talline solid (0.07 g, 30%), mp 122.4–124.3◦C (Found: [M + H]+
,
•
452.2266. C22H28F3N5O2 requires [M + H]+
, 452.2273). νmax
2-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-
4,6-di(pyrrolidin-1-yl)pyrimidine (4a)
A stirred mixture of 4,6-dichloro-2-[(3ꢀ-hydroxy-3ꢀ-phenyl)propyl-
amino]pyrimidine (9a) (0.40 g, 1.34 mmol) and pyrrolidine (20 mL) was
heated at reflux for 10 h. Workup as described above gave the crude solid
(0.49 g). Purification by flash chromatography (SiO2, CH2Cl2/ethyl
(KBr)/cm−1 3416bm, 2971bm, 1584s, 1508s, 1460s, 1353s, 1264s,
1160m. δH (300 MHz) 7.32 (2 H, d, J 8.4, H2ꢀꢀ and H6ꢀꢀ), 7.06 (2 H,
d, J 8.4, H3ꢀꢀ and H5ꢀꢀ), 6.55 (1 H, br s, exchangeable OH or NH), 4.92
(1 H, br s, exchangeable OH or NH), 4.70 (1 H, dd, J 10.8, 2.6, H3ꢀ), 4.57
(1 H, s, H5), 4.11–4.02 (1 H, m, H1ꢀ), 3.37–3.33 (8 H, m, NCH2CH2),
3.22–3.16 (1 H, m, H1ꢀ), 2.08–1.60 (10 H, m, H2ꢀ and NCH2CH2). δC

604
L. Joubran et al.
3
(100 MHz) 162.2 (C4 and C6), 161.3 (C2), 148.1 (q, JCF 1.8, C4ꢀꢀ),
143.7 (C1ꢀꢀ), 127.2 (C2ꢀꢀ and C6ꢀꢀ), 120.8 (q, 4JCF 0.6, C3ꢀꢀ and C5ꢀꢀ),
120.7 (q, 1JCF 256.5, OCF3), 73.4 (C5), 68.4 (C3ꢀ), 46.3 (NCH2CH2),
41.8 (C1ꢀ)•, 37.3 (C2ꢀ), 25.6 (NCH2CH2). Mass spectrum (ESI) m/z 452
(C4ꢀ), 125.8 (C2ꢀ and C6ꢀ), 117.5 (CN), 70.3 (C2), 28.1 (C1). The 1H
NMR data were consistent with literature data.[26,28]
(S)-3-Amino-1-phenylpropanol (S)-(8a)
[M + H]+
.
A solution of (S)-3-hydroxy-3-phenylpropanenitrile (12) (0.20 g,
1.36 mmol) in dry THF (10 mL) was added dropwise to a suspension of
LiAlH4 (0.26 g, 6.80 mmol) in dryTHF (5 mL) at 0◦C. The reaction was
worked up as described in the preparation of 3-amino-1-phenylpropanol
(8a) to give the alcohol (S)-(8a) as a cream solid (0.18 g, 88%), [α]D20
−34◦ (c 0.2 in MeOH) (lit.[27] for (S)-(8a) −43.65◦ (c 1.0 in MeOH),
lit.[25] [α]2D5 −46.3◦ (c 1.46 in MeOH), 98% e.e.). The amino alcohol
was predominantly (S), based on the literature[26,28] [α]D values. The
spectral data was consistent with the data for 3-amino-1-phenylpropanol
(8a) and for literature data for the (S)-isomer.[26,28]
Attempted Preparation of the Di(pyrrolidinyl)pyrimidine (5a) Using
6-Chloro-2,4-di(pyrrolidin-1-yl)pyrimidine
A solution of 2-amino-1-phenylpropanol (8a) (0.10 g, 0.40 mmol),
6-chloro-2,4-di(pyrrolidin-1-yl)pyrimidine[25] (0.07 g, 0.40 mmol), and
pyridine (10 mL) was heated at 100◦C for 4 days followed by reaction
at room temperature for 4 days. The mixture was concentrated, satu-
rated NaHCO3 (50 mL) was added, and the mixture was extracted with
CH2Cl2 (2 × 50 mL). The combined organic extracts were dried, fil-
tered, and reduced under vacuum to yield a brown solid (0.12 g). The
1H NMR spectrum of this solid indicated only recovered 6-chloro-2,4-
di(pyrrolidin-1-yl)pyrimidine and the alcohol (8a).
(S)-4,6-Dichloro-2-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)pyrimidine
(S)-(9a) and (S)-2,4-Dichloro-6-(3ꢀ-hydroxy-
3ꢀ-phenylpropylamino)pyrimidine (S)-(10a)
Mosher’s Esters of 6-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-
2,4-di(pyrrolidin-1-yl)pyrimidine (11)
(S)-3-Amino-1-phenylpropanol (S)-(8a) (0.57 g, 3.77 mmol) was cou-
pled with 2,4,6-trichloropyrimidine (0.44 mL, 3.77 mmol) in dioxane
(20 mL) and NaHCO3 (1.90 g, 22.62 mmol), and the isomers formed
were separated as described above for the synthesis of the racemic
dichloro compounds (9a) and (10a). The symmetrical compound (S)-
(9a) (0.36 g, 32%) and the unsymmetrical compound (S)-(10a) (0.34 g,
30%) had spectral data consistent with those of the racemic symmetrical
(9a) and unsymmetrical (10a) isomers.
A solution of 1,3-dicyclohexylcarbodiimide (0.41 g, 1.98 mmol) in dry
CH2Cl2 (5 mL) and 4-dimethylaminopyridine (0.05 g, 0.40 mmol) was
added to a stirred solution of 6-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)-2,4-
di(pyrrolidin-1-yl)pyrimidine (5a) (0.48 g, 1.31 mmol) and (S)-(−)-α-
methoxy-α-(trifluoromethyl)phenylacetic acid [(−)-MTPA] (0.36 mL,
1.98 mmol) in dry CH2Cl2 (5 mL). The reaction was stirred under nitro-
gen at room temperature for 1 h.The mixture was filtered and the filtrate
was diluted with ethyl acetate (20 mL), washed with water (20 mL × 2),
saturated aqueous NaCl (20 mL), dried, filtered, and concentrated to
yield a crude solid (0.71 g). 1H and 19F NMR spectra of this crude mate-
rial showed the diastereomeric esters (11) in a ca. 1 : 1 ratio. Column
chromatography (SiO2, 25% ethyl acetate/ether) gave a ca. 1 : 1 mix-
(S)-6-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-
2,4-di(pyrrolidin-1-yl)pyrimidine (S)-(5a)
(S)-2,6-Dichloro-6-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)pyrimidine(S)-
(10a) (0.30 g, 1.01 mmol) was reacted with pyrrolidine (20 mL) and
purified as described in the preparation of the racemic pyrimidine
(5a). This gave the expected, predominantly (S)-(5a) as a cream solid
(0.30 g, 81%). Spectral data was consistent with the data for the racemic
compound (5a).
ture of both isomers of the ester (11) as a cream solid (0.30 g, 40%)
•
(Found: [M + H]+•, 584.2837. C31H35F3N5O3 requires [M + H]+
,
584.2848). νmax (KBr)/cm−1 3630s, 3422bs, 2949m, 1751m, 1654m,
1560s, 1499m, 1450s, 1346m, 1247m, 1169m, 1121m, 1016m, 916m.
δH (300 MHz) (for both isomers) 7.34–7.09 (20 H, m, ArH), 6.00 (1 H,
m, H3ꢀ), 5.94 (1 H, m, H3ꢀ), 4.54 (1 H, s, H5), 4.51 (1 H, s, H5), 3.44–
3.21 (26 H, m, H2ꢀ, OCH3 and NCH2CH2), 2.33–2.14 (4 H, m, H1ꢀ),
2.11–1.79 (16 H, m, NCH2CH2). δC (75 MHz) 166.1 (C6 and CO),
163.4 (C4), 162.0 (C2), 138.9, 138.8, 132.4, 132.2, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 127.5, 127.0, 126.7 (ArCH), 123.6 (q, 1JCF 288.5,
CF3), 76.9(C5ꢀ), 71.8(C3ꢀ), 55.7, 55.5(OCH3), 46.3, 46.1(NCH2CH2),
38.1, 37.9 (C1ꢀ), 36.2, 36.0 (C2ꢀ), 25.6, 25.4 (NCH2CH2), COCH3
(S)-2-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-
4,6-di(pyrrolidin-1-yl)pyrimidine (S)-(4a)
Similarly, (S)-4,6-dichloro-2-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino) pyri-
midine (S)-(9a) (0.30 g, 1.01 mmol) was reacted with pyrrolidine
(20 mL) and purified as described in the preparation of the racemic
pyrimidine (4a). This gave the predominantly (S)-(4a) as a white solid
(0.32 g, 86%). Spectral data was consistent with the data of the racemic
compound (4a).
not detected. δF (282.4 MHz) −71.67 (s, CF3), −72.10 (s, CF3). Mass
•
spectrum (ESI) m/z 584 [M + H]+
.
Attempts to separate the two isomers by fractional recrystallization
(S)-6-(3ꢀ-Hydroxy-3ꢀ-phenylpropylamino)-
also failed.
2,4-di(pyrrolidin-1-yl)pyrimidine-(−)-MTPA Ester (S)-(11)
A solution of 1,3-dicyclohexylcarbodiimide (0.013 g, 0.06 mmol)
and a few crystals of 4-dimethylaminopyridine in dry CH2Cl2
Preparation of Enantiomerically Enriched 6-(3ꢀ-Hydroxy-
3ꢀ-phenylpropylamino)-2,4-di(pyrrolidin-1-yl)pyrimidine (5a)
(5 mL) was reacted with
a stirred solution of the predom-
(S)-3-Hydroxy-3-phenylpropanenitrile (12)
inantly (S)-6-(3ꢀ-hydroxy-3ꢀ-phenylpropylamino)-2,4-(dipyrrolidin-1-
yl)pyrimidine (S)-(5a) (0.015 g, 0.04 mmol) and (S)-(−)-α-methoxy-α-
(trifluoromethyl)phenylacetic acid [(−)-MTPA] (0.011 mL, 0.06 mmol)
in dry CH2Cl2 (5 mL) as described above for the synthesis
of the Mosher’s esters (11) to give crude (S)-6-(3ꢀ-hydroxy-3ꢀ-
phenylpropylamino-2,4-di(pyrrolidin-1-yl)pyrimidine-(−)-MTPAester
(11) as a solid (0.02 g). Partial spectral data∗ δH (500 MHz) 4.55
(s, H5, (R)-isomer), 4.50 (s, H5, (S)-isomer), 6.05 (dd, J 9.0, 4.7, H3ꢀ,
(S)-isomer), 6.00 (dd, J 8.1, 5.7, H3ꢀ, (R)-isomer). ∗ δF (282.4 MHz)
−71.40 (s, CF3, (R)-isomer), −72.00 (s, CF3, (S)-isomer).The ratios of
corresponding pairs of peaks in the 1H and 19F NMR spectra showed two
diastereisomers in the ratio of ca. 4 : 1, giving an enantiomeric excess
of ca. 64% for the (S)-enantiomer (S)-(11).
Using the method described by Smallridge et al.,[10] 3-oxo-3-
phenylpropanenitrile (7a) (3.00 g, 20.67 mmol) was added to a pre-
cooled (4◦C) suspension of baker’s yeast (414 g) in water (1860 mL)
and the mixture stirred at 4◦C for 7 days. The mixture was filtered,
the filtrate extracted with ethyl acetate (7 × 150 mL), and the combined
extracts were dried and evaporated. Flash-pad chromatography (SiO2,
50% ether/light petroleum) of the crude product gave the (S)-alcohol
(12) as a colourless oil (1.00 g, 33%), [α]2D0 −69◦ (c 0.4 in EtOH) [lit.[10]
−57◦ (c 1.1 in EtOH), lit.[26] −52.5◦ (c 2.6 in EtOH), lit.[27] −57.7◦
(c 2.6 in EtOH) > 96% e.e. (S)]. δH (300 MHz) 7.40–7.31 (5 H, m,
ArH), 5.01 (1 H, t, J 6.2, H1), 2.74 (2 H, d, J 6.3, H2), 2.66 (1 H, br s,
exchangeable OH). δC (75 MHz) 141.3 (C1ꢀ), 129.1 (C3ꢀ and C5ꢀ), 129.0
∗ (R) and (S) isomers were assigned on the basis that the major diastereoisomer expected was the (S,S) compound since the pyrimidine (5a) was derived from
the predominantly (S)-alcohol (12).

Arylpropanolamines Incorporating an Antioxidant Function as Neuroprotective Agents
605
3H-BTX Specific Binding
[4] (a) B. Jarrott, P. M. Beart, W. R. Jackson, V. B. Kenche,
A. D. Robertson, M. P. Collis, Int. Patent WO9743259 1997;
Chem. Abstr. 1998, 128, 34 784. (b) B. Jarrott, J. K. Callaway,
W. R. Jackson, P. M. Beart, Drug Dev. Res. 1999, 46, 261.
[5] D. E. Epps, J. M. McCall, Handbook of Synthetic Antioxidants
1997 (Marcel Dekker: New York, NY).
[6] A. Papanikos, J. Eklund, W. R. Jackson, V. B. Kenche,
E. M. Campi, A. D. Robertson, B. Jarrott, P. M. Beart,
F. E. Munro, J. K. Callaway, Aust. J. Chem. 2002, 55, 205.
[7] J. K. Callaway, P. M. Beart, B. Jarrott, J. Pharmacol. Toxicol.
Methods 1998, 39, 155.
This Na+ channel binding assay involves the use of a steroidal alkaloid,
BTX, as a specific tritiated radioligand for the Na+ channel neurotoxin
binding site 2 in the rat brain homogenate.[29] The competitive ability
of the compounds to displace the toxin at this site was measured.[30]
The results are summarized in Table 1. Table 1 gives IC50 values (i.e.
the amount of compound that leads to 50% inhibition of 3H-BTX in the
rat brain homogenate) and their ranges. The IC50 values were obtained
from concentration response curves constructed using concentrations
in the range of 0.1–100 µM using GraphPad Prism software (n = 2–4).
Table 1 also displays the results for binding data at two specific concen-
trations (1 and 10 µM) and their confidence intervals. The binding data
for dibucaine, the lead compound (1), and its pyrrolidinylpyrimidine
analogue (3) are also included for comparison.
[8] Sapphire assay, in Bioxytech LPO-586 kit (Oxis: Portland, OR).
[9] J. Urenjak, T. P. Obrenovitch, Pharmacol. Rev. 1996, 48, 21.
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with the modifications described previously.[6]
Theoretical Calculations
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The semi-empirical calculations were carried out using the PM3 method
as implemented in the commercial Titan[31] software package. The
N-methyl-bis(dimethylamino)pyrimidine radicals (13) and (14) first
underwent a full geometry optimization at the PM3 level before the wave
function for each was determined. The spin density was then calculated
using the methods internal to this software.
The density functional calculations were carried out using the
Gaussian98[32] software package. Calculations were performed
using the B3LYP/6-311+G(d,p) method as implemented by
this program. Calculations were performed on the N-methyl-
bis(dimethylamino)pyrimidine radicals (13) and (14), as well as their
closed shell counterparts. All structures were first fully optimized at
the B3LYP/6-311+G(d,p) level before the final wave function was
calculated.
Acknowledgments
This project has been supported by Amrad Operations Pty
Ltd, which includes the provision of a post-graduate scholar-
ship (to L.J.). We thank the Australian Research Council for
the provision of Australian postgraduate awards (to L.J.
and B.A.W.) and the National Health and Medical Research
Council of Australia for providing a Senior Research Offi-
cer appointment (to J.C.). We also thank Elena V. Krstew,
Feng Chen, and Jing QingYu for their assistance in the phar-
macological testing. We appreciate the helpful comments
and suggestions of Dr Dave Winkler (CSIRO, Clayton) and
Dr Les Deady (La Trobe University).
[31] W. J. Hehre et al., Titan 1.0.5 2000 (Wavefunction Inc.: Irvine,
CA).
[32] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A.
Montgomery, Jr, R. E. Stratmann, J. C. Burant, S. Dapprich,
J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain,
O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi,
B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski,
G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, N. Rega,
P. Salvador, J. J. Dannenberg, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,
A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L. Andres,
C. Gonzalez, M. Head-Gordon, E. S. Replogle, J.A. Pople, Gaus-
sian 98, Revision A.11.3 2002 (Gaussian Inc.: Pittsburgh, PA).
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