A fast and efficient one-pot microwave assisted synthesis of variously di-substituted 1,2,4-oxadiazoles

Article abstract of DOI:10.1039/c1ob06055d

A one-pot two-step microwave assisted synthesis of variously disubstituted 1,2,4-oxadiazoles from carboxylic acids and amidoximes is reported. This methodology is characterized by short reaction times, is versatile, robust and high-yielding and allows for

Full text of DOI:10.1039/c1ob06055d

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PAPER
A fast and efficient one-pot microwave assisted synthesis of variously
di-substituted 1,2,4-oxadiazoles†
Andrea Porcheddu, Roberta Cadoni and Lidia De Luca*
Received 30th June 2011, Accepted 10th August 2011
DOI: 10.1039/c1ob06055d
A one-pot two-step microwave assisted synthesis of variously disubstituted 1,2,4-oxadiazoles from
carboxylic acids and amidoximes is reported. This methodology is characterized by short reaction
times, is versatile, robust and high-yielding and allows for the preparation of heterocycles with a
stereocenter with 100% enantiomeric purity.
Introduction
The 1,2,4-oxadiazole ring system is an important scaffold con-
tained in many pharmaceutical compounds with a large spectrum
of biological activities.1 1,2,4-Oxadiazoles have been utilized as
Scheme 1 Classical route to 1,2,4-oxadiazoles.
isosteres of amides and esters due to the increased hydrolytic
and metabolic stability of the ring.2 Various 1,2,4,-oxadiazoles
containing chiral a-amino acids were used in peptide mimetics,
as amino acid-Gly dipeptidomimetics3 and Phe-Gly mimetics,4
signal transduction inhibitors,5 and cell adhesion inhibitors.6 1,2,4-
Oxadiazoles variously substituted in the 3,5 positions with aryl or
alkyl groups have been incorporated into efficacious muscarinic
agonists,7 antirhinovirals,8 brain-penetrant metabotropic gluta-
mate subtype 5 (mGlu5) receptor antagonists,9 and serotoninergic
(5-HT3) antagonists.10 The most promising application of 1,2,4-
oxadiazole framework is as potent sphingosine-1-phosphate-1
(S1P1) receptor agonists11 in the treatment of autoimmune and
inflammatory disorders, multiple sclerosis, tumor metastasis and
transplant rejection.
methodologies afford variable yields and do not allow access to
1,2,4-oxadiazoles with both alkyl, aryl and a-amino acids in the
3,5 positions. Besides, the majority of procedures described utilize
only aryl amidoximes due to their higher reactivity compared to
alkyl amidoximes.13 Our goal was to develop a versatile, robust,
high-yielding and speedy protocol for the synthesis of 1,2,4-
oxadiazoles with a significant range of steric substitution patterns
in 3,5 positions. Following our interest in the use of 1,3,5-triazine
derivatives for the synthesis of heterocyclic compounds,15 we
have tested the possibility of using 2-chloro-4,6-dimethoxy-1,3,5-
triazine (CDMT) as an activator of carboxylic acids to prepare
1,2,4-oxadiazoles.
Results and discussion
1,2,4-Oxadiazoles are generally prepared by two step procedures
consisting in a condensation using amidoximes with carboxylic
acid derivatives followed by an intramolecular cyclodehydra-
tion (Scheme 1).12 The cyclization step has been carried out
by the use of additives such as 1-[3-(dimethylamino)propyl]-
3-ethycarbodiimide (EDC), dicyclohexylcarbodiimide (DCC),
1,1¢-carbonyldiimidazole (CDI), o-benzotriazol-1-yl)-N,N,N¢N¢-
tetramethyluronium tetrafluoroborate (TBTU) and the Burgess
reagent, employing intensive reflux conditions in DMF or
pyridine.13
Initially our studies started with the reaction between 3-
phenylpropionic acid (0.15 g, 1 mmol) 1, CDMT (0.19 g, 1.1 mmol)
2 and N-methylmorpholine (NMM) (0.33 mL, 3 mmol) in THF to
form quantitatively the corresponding activated ester 3 in 30 min
(monitored by TLC). To this white suspension, containing the
activated ester, was added phenylamidoxime (0.14 g, 1 mmol) 4
and toluene, and was heated to 120 C for 1 h under microwave
irradiation16 (Scheme 2) to obtain the desired 5-benzyl-3-phenyl-
1,2,4-oxadiazole 5 in good yield (73%).
◦
Unfortunately these approaches require very long reaction times
(from 12 to 24 h) and in some cases the yields are not very
high. In an effort to improve on these procedures, microwave-
assisted methods have been reported.14 Regrettably, all reported
Dipartimento di Chimica, Universita` degli Studi di Sassari, Via Vienna
2, 07100, Sassari, Italy. E-mail: ldeluca@uniss.it; Fax: +3907922212069;
Tel: +39079213529
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06055d
Scheme 2 Synthesis of 1,2,4-oxadiazole under microwave heating.
In order to find the optimum conditions for this synthesis var-
ious parameters, of the second step, such as solvent, temperature
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Table 1 Synthesis of 1,2,4-oxadiazoles: optimization of the reaction
conditions
Table 2 Carboxylic acids and amidoximes diversity
Entry R1
1
R2
Product
Yield (%)
93
Entrya
solvent
T/◦C
Time
Yieldb (%)
1
2
3
4
5
6
7
8
DMF
THF
120
120
120
120
120
150
160
170
120
160
160
60 min
60 min
60 min
60 min
60 min
15 min
5 min
5 min
60 min
5 min
20
40
38
15
72
82
93
92
10c
18d
73e
dioxane
acetonitrile
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2
89
91
75
9
10
11
3
4
n-Bu
48 h
a Reaction conditions: 3-phenylpropinic acid (1.0 mmol), CDMT
(1.1 mmol), and N-methylmorpholine (NMM) (3.0 mmol) THF (3 mL) for
30 min at r.t. Then were added phenylamidoxime (1.0 mmol) and solvent
(2 mL), and heated under microwave irradiation. b Yield was referred
to isolated product after column chromatography. c Reaction performed
under conventional heating in a preheated oil bath at 120 ◦C, isolated
yield after 60 min. d Reaction performed under conventional heating in
a preheated oil bath at 160 ◦C, isolated yield after 5 min. e Reaction
performed under conventional heating in a preheated oil bath at 160 ◦C,
isolated yield after 48 h.
n-Bu
5
6
73
82
and time of microwave irradiation17 were tested. Some of the
most representative results are reported in Table 1. We observed
very poor results when solvents such as DMF, THF, dioxane
and acetonitrile were used (Table 1, entries 1–4), the best results
were obtained with toluene (Table 1, entries 5–8). Temperature
significantly affected the reaction, in fact the best yield was
obtained irradiating the reaction mixture at 160 ◦C for 5 min
(Table 1, entry 7), whereas at higher temperatures no appreciable
increase in yield was observed (Table 1, entry 8). A comparison
between conventional eating (oil bath) and microwave irradiation
was carried out demonstrating a drastically better performance of
the MW-assisted process (Table 1, entries 9–10).
7
8
78
82
undecyl
undecyl
After the optimized reaction conditions were found, we tested
the methodology with an array of commercially available car-
boxylic acids and various substituted amidoximes18 and the yields
were satisfactory in all cases (Table 2).
9
79
87
The nature of side chain did not play a significant role in terms
of conversion to desired product. In the same way the procedure
worked well with both aromatic and aliphatic carboxylic acids,
sterically congested too (Table 2, entries 2 and 5). We should
like to extend the applicability of the methodology to a-amino
acids for obtaining chiral enantiomerically pure a-alkyl-5-1,2,4-
oxadiazolmethanamine. Therefore the reaction was carried out
with both N-Boc and N-Cbz protected a-aminoacids and we were
very pleased to observe that the desired products were obtained
in good yields (Table 2, entries 12, 17–23, 29, 30). It is noteworthy
that the MW conditions employed are compatible with the Boc
protecting group. In contrast the same reaction conducted by
conventional eating (120 ◦C for 60 min or 160 ◦C for 5 min) led to
the cleavage of the Boc group. Using this methodology it was also
possible to prepare 1,2,4-oxadiazole-linked N,N¢-orthogonally
10
11
68
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Table 2 (Contd.)
Table 2 (Contd.)
Entry R1
12
R2
Product
Yield (%)
72
Entry R1
22
R2
Product
Yield (%)
70
13
14
87
93
23
76
24
25
26
84
90
58
15
16
95
89
27
28
62
67
17
18
86
69
29
30
71
74
19
20
72
83
31
65
21
92
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protected dipeptidomimetic reacting N-Boc alanine with
N-Cbz alanine-derived amidoxime (Table 2, entry 31). All of N-
protected a-amino acid-derived 1,2,4-oxadiazoles were optically
active. Significant racemization of the chiral center of the a-amino
acids did not occur under the experimental conditions applied.
(S)-tert-butyl 1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-3-
methylbutylcarbamate 5(XXI) was deprotected with TFA in
DCM (Scheme 3) to the corresponding a-alkyl 5-1,2,4-
oxadiazolemethanamine 6 (Scheme 3) which was then reacted with
(S)-(+)-a-methoxy-a-trifluoromethylphenylacetyl chloride (MP-
TACl). The enantiomeric purity of the Mosher’s amide derived 7
(Scheme 3) was determined by the 19F NMR and 1N NMR spectra
which showed it consisted of only one diastereomeric amide.
282 MHz using CDCl3 solutions and TMS as an internal standard.
Chemical shifts are reported in parts per million (ppm, d) relative
to tetramethylsilane (TMS, d 0.00) or relative to residual solvent
signals (CDCl3, d 7.27 ppm d 2.54). Coupling constants (J values)
are given in Hz, and peak multiplicities are denoted by s (singlet),
bs (broad singlet), d (doublet), dd (doublet of doublets), pd
(pseudo doublet), m (multiplet), q (quartet), and t (triplet). Optical
rotations were measured at ambient temperature in a 10 cm cell,
and c is expressed in g/100 mL. Melting points were determined
in open capillary tubes and are uncorrected.
General procedure for the preparation of 1,2,4-oxadiazoles
3,5-disubstitued (5(I–XXXI)).
To a stirred solution, placed in a tube (10 mL pressure-rated
reaction vial), of a 3-phenylprpionic acid (0.15 g, 1 mmol) in
dry THF (3 mL) was added, at room temperature, 2-chloro-
4,6-dimethoxy-1,3,5-triazine (0.19 g, 1.1 mmol) followed by N-
methylmorpholine (0.33 mL, 3 mmol). The mixture was stirred
(30–60 min) until carboxylic was consumed (monitored by TLC).
Then were added phenylamidoxime (0.14 g, 1 mmol) and toluene
◦
(2 mL) and irradiated to 160 C for 5 min in a self-tuning single
mode irradiating synthesizer. The mixture was cooled rapidly
to room temperature by passing compressed air through the
microwave cavity for 5 min. After cooling to room temperature
the mixture of reaction was concentrated in vacuo, the residue
was solubilized in EtOAc and washed with water and brine. The
organic layer was dried over anhydrous Na2SO4. The solvent was
removed in vacuo and the crude product was easily purified by
column chromatography with hexane/EtOAc to afford 5-benzyl-
3-phenyl-1,2,4-oxadiazole 5(I) as pale yellow oil in good yield
(0.23 g, 93%). Rf 0.37 (hexane/EtOAc: 90/10). (Found: C, 76.76;
H, 5.76; N, 11.07. Calc for C16H14N2O: C, 76.78; H, 5.64; N,
11.19).). nmax/cm-1 3063, 3028, 2924, 2849, 1727, 1593, 1570, 1528,
Scheme 3 Synthesis of Mosher’s amide derivative.
Conclusions
It is worth remarking that by using this methodology it is possible
to prepare variously disubstituted 1,2,4-oxadiazoles in a one-pot
two step procedure directly from commercially available carboxylic
acids and amidoximes. This method is characterized by short
reaction times, is versatile, robust and high-yielding and it is also
possible to prepare heterocycles with a chiral stereocenter with
good chemical yields and 100% optical yield.
1
1446. H NMR (300 MHz, CDCl3) d (ppm): 8.07 (m, 2H); 7.48
(m, 3H); 7.27 (m, 5H); 3.23 (m, 4H).13C NMR (75 MHz, CDCl3) d
(ppm): 178.9; 168.3; 139.4; 131.1; 128.8; 128.7; 128.2; 127.4; 126.7;
114.0; 32.6; 28.5. MS m/z 251 (M+H).
Experimental
General methods
3-Phenyl-5-(1-phenylethyl)-1,2,4-oxadiazole 5(II)
All reagents and solvents were as obtained by commercial source.
The N-Boc and N-Cbz derivatives of the a-amino acids were
prepared according standard methods.1
Yield (0.22 g, 89%). Pale yellow oil. Rf 0.35 (hexane/EtOAc:
90/10). (Found: C, 76.74; H, 5.71; N, 11.10. Calc. for C16H14N2O:
C, 76.78; H, 5.64; N, 11.19). nmax/cm-1 3067, 3035, 2923, 2847,
All conventional reactions were run under dry nitrogen using
standard techniques unless otherwise stated. All solvents were
dried by usual methods and distilled under argon. Thin-layer chro-
matography (TLC) analysis was performed with Merck Kieselgel
60 F254 plates and visualized using UV light at 254 nm, FeCl3
(5% FeCl3 in H2O), and KMnO4 staining. Microwave reactions
were conducted using CEM Discover Synthesis Unit (CEM Corp.,
Matthews, NC). The instrument consists of a continuous focused
microwave power delivery system with operator selectable power
output from 0 to 300W. Reactions were performed in a heavy-
walled glass tubes sealed with a septum. The temperature of the
content of the vessel was monitored using a calibrated infrared
temperature control mounted under the reaction vessel. After
complete irradiation, the reaction tube was cooled with high-
1
1732, 1597, 1572, 1530. H NMR (300 MHz, CDCl3) d (ppm):
8.08 (m, 2H); 7.32 (m, 8H); 7.27 (q, J = 7.2 Hz, 1H); 1.79 (d, J =
7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d (ppm): 178.9; 168.3;
139.4; 131.1; 128.8; 128.7; 128.2; 127.4; 126.7; 114.0; 32.6; 28.5.
MS m/z 251 (M+H).
5-butyl-3-phenyl-1,2,4-oxadiazole 5(III)
Yield (0.18 g, 91%). Pale yellow oil. Rf 0.79 (hexane/EtOAc:
90/10). (Found: C, 71.24; H, 6.95; N, 13.93. Calc. for C12H14N2O:
C, 71.26; H, 6.98; N, 13.85).). nmax/cm-1 3071, 3036, 2960 2934,
2873, 1594, 1570, 1446.1H NMR (300 MHz, CDCl3) d (ppm): 8.08
(m, 2H); 7.49 (m, 3H); 2.95 (t, J = 7.7 Hz, 2H); 1.86 (m, 2H); 1.46
(m, 2H); 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 179.9; 168.1; 130.8; 128.6; 127.4; 126.9; 28.5; 26.1; 22.0;
13.4. MS m/z 203 (M+H).
◦
1
pressure air until the temperature had fallen below 35 C. H
NMR, 13C NMR and 19F NMR were recorded at 300, 75.4 and
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5-butyl-3-o-tolyl-1,2,4-oxadiazole 5(IV)
1H NMR (300 MHz, CDCl3) d (ppm): 7.86 (m, 2H); 7.34 (m, 2H);
4.19 (q, J = 7.1 Hz, 2H); 4.12 (q, J = 7.1 Hz, 1H); 2.40 (s, 3H); 2.28
(t, J = 7.5 Hz, 1H); 2.17 (s, 1H); 1.64 (m, 2H); 1.40 (t, J = 8.1 Hz,
4H); 1.25 (m, 10H); 0.88 (t, J = 7.1 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d (ppm): 166.4; 137.7; 133.2; 129.8; 127.9; 126.4; 124.9;
119.5; 60.5; 31.7; 29.3; 29.1; 28.5; 28.4; 25.1; 22.4; 21.0; 16.8; 14.0;
13.8. MS m/z 315 (M+H).
Yield (0.16 g, 75%). Pale yellow oil. Rf 0.62 (hexane/EtOAc: 95/5).
(Found: C, 72.21; H, 7.48; N, 12.91. Calc. for C13H16N2O: C, 72.19;
H, 7.46; N, 12.95).). nmax/cm-1 3064, 2960, 2932, 2873, 1591, 1569.
1H NMR (300 MHz, CDCl3) d (ppm): 7.97 (m, 1H); 7.34 (m, 3H);
2.95(t, J = 7.5 Hz, 2H); 2.62 (s, 3H), 1.84(m, 2H); 1.45 (m, 2H);
0.97 (t, J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) d (ppm):
178.9; 168.7; 138.1; 131.2; 130.3; 129.9; 126.2; 125.8; 28.6; 26.1;
22.1; 22.0; 13.5. MS m/z 217 (M+H).
5-(4-chlorophenyl)-3-cyclohexyl-1,2,4-oxadiazole 5(X)
Yield (0.23 g, 87%). Yellow solid. mp 107-110 ◦C. Rf 0.61
(hexane/Et2O: 95/5). (Found: C, 63.89; H, 5.76; N, 10.67. Calc
for C14H15ClN2O: C, 64.00; H, 5.75; N, 10.66). nmax/cm-1 3032,
2926, 2857, 1608, 1583, 1509, 1479. 1H NMR (300 MHz, CDCl3)
d (ppm): 8.06 (d, J = 8.5 Hz, 2H); 7.49 (d, 8.5 Hz, 2H); 2.86 (m,
5-neopentyl-3-o-tolyl-1,2,4-oxadiazole 5(V)
Yield (0.18 g, 73%). Pale yellow oil. Rf 0.65 (hexane/EtOAc: 95/5).
(Found: C, 72.98; H, 7.89; N, 12.13. Calc. for C14H18N2O: C, 73.01;
H, 7.88; N, 12.16).). nmax/cm-1 3063, 2961, 2869, 1590, 1568.1H
NMR (300 MHz, CDCl3) d (ppm): 7.99 (d, J = 8.8 Hz, 1H); 7.33
(m, 3H); 2.86 (s, 2H); 2.63 (s, 3H); 1.10 (s, 9H). 13C NMR (75
MHz, CDCl3) d (ppm): 177.4; 168.7; 138.1; 131.3; 130.4; 130.0;
125.9; 114.0; 40.1; 31.9; 29.4; 22.1. MS m/z 231 (M+H).
1H); 2.06 (m, 2H); 1.88 (m, 2H); 1.64 (m, 2H); 1.37 (m, 4H). 13
C
NMR (75 MHz, CDCl3) d (ppm): 175.1; 174.4; 139.1; 129.6; 129.5;
123.2; 36.2; 30.9; 26.0; 25.9. MS m/z 263 (M+H).
3,5-dibenzyl-1,2,4-oxadiazole 5(XI)
Yield (0.17 g, 68%). Pale yellow oil. Rf 0.31 (hexane/Et2O: 78/0.2).
(Found: C, 76.75; H, 5.66; N, 11.16. Calc for C16H14N2O: C, 76.78;
H, 5.64; N, 11.19). nmax/cm-1 3088, 3064, 3031, 2927, 1676, 1576,
1496. 1H NMR (300 MHz, CDCl3) d (ppm): 7.30 (m, 10H); 4.17
(s, 2H); 4.04 (s, 2H). 13C NMR (75 MHz, CDCl3) d (ppm): 177.9;
169.5; 135.4; 133.4; 129.0; 128.9; 128.8; 128.6; 127.5; 127.0; 32.9;
32.3. MS m/z 251 (M+H).
5-(phenoxymethyl)-3-o-tolyl-1,2,4-oxadiazole 5(VI)
Yield (0.22 g, 82%). Pale yellow oil. Rf 0.31 (hexane/EtOAc: 95/5).
(Found: C, 72.11; H, 5.32; N, 10.48. Calc for C16H14N2O2: C, 72.16;
H, 5.30; N, 10.52). nmax/cm-1 3060, 2960, 2926, 2855, 1723, 1589,
1495.1H NMR (300 MHz, CDCl3) d (ppm): 8.00 (d, J = 7.2 Hz,
1H); 7.33 (m, 5H); 7.04 (m, 3H); 5.36 (s, 2H); 2.63 (s, 3H). 13C NMR
(75 MHz, CDCl3) d (ppm): 173.7; 157.6; 138.3; 131.4; 130.7; 130.2;
129.7; 126.0; 122.3; 114.9; 112.4; 107.5; 61.1; 22.1. MS m/z 267
(M+H).
(S)-benzyl 1-(3-benzyl-1,2,4-oxadiazol-5-yl)ethylcarbamate 5(XII)
Yield (0.17 g, 72%). Pale yellow oil. [a]2D0 -36.7 (c 0.30 in DCM). Rf
0.60 (hexane/EtOAc: 60/40). (Found: C, 67.61; H, 5.63; N, 12.16.
Calc for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46). nmax/cm-1 3323,
3088, 3064, 3032, 2986, 2952, 1722 (C O), 1578, 1525, 1455. 1H
NMR (300 MHz, CDCl3) d (ppm): 7.32 (m, 10H); 5.52 (m, 1H);
5.10 (m, 2H); 4.04 (s, 2H); 1.54 (d, J = 7.0 Hz, 3H). 13C NMR (75
MHz, CDCl3) d (ppm): 179.5; 169.3; 159.3; 135.1; 128.9; 128.6;
128.5; 128.2; 128.1; 127.1; 126.9; 67.2; 44.6; 32.2; 19.9. MS m/z
238 (M+H).
5-(2-iodophenyl)-3-o-tolyl-1,2,4-oxadiazole 5(VII)
Yield (0.28 g, 78%). Yellow solid. mp 63-53 ◦C. Rf 0.51 (hex-
ane/EtOAc: 95/5). (Found: C, 49.78; H, 3.03; N, 7.59. Calc for
C15H11IN2O: C, 49.75; H, 3.06; N, 7.73). nmax/cm-1 2923, 2851,
1
1725, 1596, 1567, 1455. H NMR (300 MHz, CDCl3) d (ppm):
8.12 (d, J = 6.4 Hz, 2H); 8.02 (d, J = 7.9 Hz, 1H); 7.53 (t, J = 7.5
Hz, 1H); 7.37 (m, 3H); 7.26 (m, 1H); 2.73 (s, 3H). 13C NMR (75
MHz, CDCl3) d (ppm): 174.4; 169.2; 161.3; 141.7; 138.4; 132.9;
131.6; 131.4; 130.7; 130.2; 129.4; 128.3; 126.0; 94.6; 22.3. MS m/z
363 (M+H).
3-(4-bromobenzyl)-5-(3-methylbenzyl)-1,2,4-oxadiazole 5(XIII)
Yield (0.30 g, 87%). Pale yellow oil. Rf 0.58 (hexane/EtOAc:
90/10). (Found: C, 59.51; H, 4.44; N, 8.12. Calc for C17H15BrN2O:
C, 59.49; H, 4.41; N, 8.16). nmax/cm-1 3027, 2920, 1578, 1488. 1H
NMR (300 MHz, CDCl3) d (ppm): 7.44 (m, 2H); 7.17 (m, 6H);
4.14 (s, 2H); 3.99 (s, 2H); 2.33 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 178.3; 169.0; 138.6; 134.3; 133.1; 131.7; 130.7; 129.6;
128.8; 128.3; 125.8; 121.1; 32.9; 31.7; 21.3. MS m/z 343 (M+H).
5-(3-phenylpropyl)-3-undecyl-1,2,4-oxadiazole 5(VIII)
Yield (0.28 g, 82%). Pale yellow oil. Rf 0.73 (hexane/EtOAc:
90/10). (Found: C, 77.16; H, 9.96; N, 8.13. Calc for C22H34N2O: C,
77.14; H, 10.01; N, 8.18). nmax/cm-1 3063, 3027, 2926, 2855, 1603,
1584, 1496, 1454. 1H NMR (300 MHz, CDCl3) d (ppm): 7.20 (m,
5H); 4.10 (q, J = 8.4 Hz, 2H); 2.63 (t, J = 7.7 Hz, 2H); 2.28 (q,
J = 7.5 Hz, 4H); 1.94 (m, 2H); 1.51 (m, 3H); 1.25 (m, 14H); 0.88
(t, J = 7.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) d (ppm): 173.1;
141.2; 128.2; 128.1; 125.7; 119.5; 59.9; 34.9; 33.3; 31.7; 29.3; 29.2;
29.1; 28.5; 28.4; 26.3; 25.1; 22.4; 16.8; 13.9. MS m/z 343 (M+H).
3-(4-bromobenzyl)-5-(4-methylbenzyl)-1,2,4-oxadiazole 5(XIV)
Yield (0.32 g, 93%). Pale yellow solid. mp 71–74 ◦C. Rf 0.71
(hexane/EtOAc: 80/20). (Found: C, 59.47; H, 4.46; N, 8.14. Calc
for C17H15BrN2O: C, 59.49; H, 4.41; N, 8.16). nmax/cm-1 3024, 2917,
1587, 1513, 1489.1H NMR (300 MHz, CDCl3) d (ppm): 7.43 (d,
J = 8.4 Hz, 2H); 7.16 (m, 6H); 4.13 (s, 2H); 3.98 (s, 2H); 2.32 (s,
3H). 13C NMR (75 MHz, CDCl3) d (ppm): 178.4; 169.0; 137.3;
134.3; 131.7; 130.7; 130.2; 129.5; 128.7; 121.1; 32.5; 31.7; 21.0. MS
m/z 343 (M+H).
5-m-tolyl-3-undecyl-1,2,4-oxadiazole 5(IX)
Yield (0.25 g, 79%). Pale yellow oil. Rf 0.74 (hexane/EtOAc:
90/10). (Found: C, 76.41; H, 9.93; N, 8.88. Calc for C20H30N2O: C,
76.39; H, 9.62; N, 8.91). nmax/cm-1 3056, 2924, 2854, 1568, 1456.
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3-(4-bromobenzyl)-5-(3-phenylpropyl)-1,2,4-oxadiazole 5(XV)
(ppm): 180.0; 169.5; 158.6; 129.9; 127.2; 114.0; 112.3; 60.3; 55.1;
31.3; 28.1; 19.8; 14.1. MS m/z 334 (M+H).
Yield (0.34 g, 95%). Pale yellow oil. Rf 0.29 (hexane/EtOAc:
90/10). (Found: C, 60.49; H, 4.76; N, 7.85. Calc for C18H17BrN2O:
C, 60.52; H, 4.80; N, 7.84). nmax/cm-1 3084, 3061, 3026, 2927, 2858,
1579, 1489.1H NMR (300 MHz, CDCl3) d (ppm): 7.43 (d, J = 8.3
Hz, 2H); 7.21 (m, 7H); 3.98 (s, 2H); 2.83 (t, J = 7.2 Hz, 2H); 2.68
(t, J = 7.5 Hz, 2H); 2.1 (m, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm): 179.8; 168.8; 140.5; 135.1; 134.4; 131.7; 130.6; 128.4; 126.1;
121.1; 34.8; 31.7; 27.9; 25.8. MS m/z 357 (M+H).
(S)-tert-butyl 1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
phenylcarbamate 5(XX)
Yield (0.33 g, 83%). Pale yellow oil. Rf 0.57 (hexane/EtOAc:
80/20). (Found: C, 66.85; H, 6.39; N, 10.66. Calc for C22H25N3O4:
C, 66.82; H 6.37; N, 10.63). nmax/cm-1 3033, 2977, 2932, 1716
(C O), 1612, 1578, 1513. 1H NMR (300 MHz, CDCl3) d (ppm):
7.34 (s, 5H); 7.22 (d, J = 8.4 Hz, 2H); 6.84 (d, J = 8.5 Hz, 2H);
6.09 (s, 1H); 5.65 (s, 1H); 4.01 (s, 2H); 3.78 (s, 3H); 1.44 (s, 9H).
13C NMR (75 MHz, CDCl3) d (ppm): 178.5; 169.9; 158.9; 130.2;
129.4; 129.1; 128.8; 127.4; 127.3; 114.3; 109.4; 60.6; 55.5; 31.6;
28.4; 14.4. MS m/z 396 (M+H).
3-(4-bromobenzyl)-5-phenyl-1,2,4-oxadiazole 5(XVI)
Yield (0.28 g, 89%). Pale yellow solid. mp 76–78 ◦C. Rf 0.30
(hexane/Et2O: 95/5). (Found: C, 57.08; H, 3.54; N, 8.85. Calc for
C15H11BrN2O: C, 57.16; H, 3.52; N, 8.89). nmax/cm-1 2930, 1721,
1607, 1560, 1486. 1H NMR (300 MHz, CDCl3) d (ppm): 8.09 (d,
J = 6.9 Hz, 2H); 7.51 (m, 5H); 7.26 (d, J = 8.3 Hz, 2H); 4.09 (s,
2H). 13C NMR (75 MHz, CDCl3) d (ppm): 175.79; 169.5; 134.4;
132.7; 131.7; 130.7; 128.9; 128.0; 124.0; 121.0; 31.8. MS m/z 315
(M+H).
(S)-tert-butyl 1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-3-
methylbutylcarbamate 5(XXI)
Yield (0.34 g, 92%). Pale yellow oil. [a]2D0 -35.8 (c 1.37 in DCM). Rf
0.53 (hexane/EtOAc: 60/40). nmax/cm-1 3037, 2960, 2934, 2871,
1716 (C O), 1613, 1513, 1465. (Found: C, 63.97; H, 7.80; N,
11.16. Calc for C20H29N3O4: C, 63.98; H 7.79; N, 11.19). 1H NMR
(300 MHz, CDCl3) d (ppm): 7.23 (m, 2H); 6.84 (m, 2H); 5.04 (s,
1H); 4.40 (s, 2H); 3.77 (s, 3H); 3.72 (s, 1H); 1.69 (s, 2H); 1.44 (s,
9H); 0.95 (s, 7H). 13C NMR (75 MHz, CDCl3) d (ppm): 180.3;
169.8; 158.9; 130.2; 129.3; 127.5; 114.3; 60.6; 55.4; 52.3; 46.9; 31.6;
28.4; 24.8; 22.8. MS m/z 376 (M+H).
(S)-benzyl 1-(3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)-2-methyl-
propylcarbamate 5(XVII)
◦
Yield (0.38, 86%). Pale yellow solid. mp 69–71 C. [a]2D0 -61.3 (c
0.42 in DCM). Rf 0.23 (hexane/EtOAc: 90/10). (Found: C, 56.80;
H, 4.97; N, 9.45. Calc for C21H22BrN3O3: C, 56.77; H, 4.99; N,
9.46). nmax/cm-1 3423, 3324, 3033, 2965, 1719 (C O), 1577, 1465.
1H NMR (300 MHz, CDCl3) d (ppm): 7.34 (d, J = 8.3 Hz, 2H);
7.25 (m, 5H); 7.07 (d, J = 8.3 Hz, 2H); 5.41 (d, J = 9.3 Hz, 1H);
5.02 (d, J = 8.4 Hz, 2H); 4.89 (m, 1H); 3.91 (s, 2H); 2.12 (m, 1H);
0.83 (d, J = 6.8 Hz, 6H).13C NMR (75 MHz, CDCl3) d (ppm):
178.8; 168.7; 155.8; 135.8; 134.1; 131.7; 130.5; 128.5; 128.2; 128.1;
121.1; 67.2; 54.0; 32.5; 31.5; 18.5; 17.7. MS m/z 444 (M+H).
(S)-benzyl 1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-2-
methylpropylcarbamate 5(XXII)
Yield (0.27 g, 70%). Pale yellow oil. [a]2D0 -32.2 (c 0.89 in DCM). Rf
0.45 (hexane/EtOAc: 80/20). (Found: C, 66.80; H, 6.34; N, 10.59.
Calc for C22H25N3O4: C, 66.82; H 6.37; N, 10.63). nmax/cm-1 3034,
2965, 2876, 2836, 1717 (C O), 1612, 1575, 1455. 1H NMR (300
MHz, CDCl3) d (ppm): 7.32 (s, 5H); 7.19 (m, 2H); 6.84 (m, 2H);
5.62 (m, 1H); 5.01 (s, 2H); 4.96 (m, 1H); 3.98 (s, 2H); 3.75 (s, 3H);
2.19 (m, 1H); 0.91 (s, 6H). 13C NMR (75 MHz, CDCl3) d (ppm):
178.5; 169.4; 158.5; 155.8; 135.9; 129.8; 128.4; 128.1; 128.0; 127.1;
112.9; 67.1; 55.1; 53.9; 32.5; 31.2; 18.4; 17.6. MS m/z 396 (M+H).
(S)-benzyl-1 (3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)benzylcar-
bamate 5(XVIII)
Yield (0.34, 69%). Pale orange oil. [a]2D0 -9.7 (c 2.14 in DCM). Rf
0.23 (hexane/EtOAc: 70/30). (Found: C, 60.93; H, 4.48; N, 8.50.
Calc for C25H22BrN3O3: C, 60.98; H, 4.50; N, 8.53). nmax/cm-1 3543,
(S)-benzyl 2-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)pyrroli-
dine-1-carboxylate 5(XXIII)
1
3342 2987, 2956, 1732 (C O), 1565, 1545, 1463. H NMR (300
MHz, CDCl3) d (ppm): 7.39 (d, J = 8.3 Hz, 2H); 7.31 (m, 5H);
7.19 (m, 3H); 7.08 (d, J = 8.3 Hz, 2H); 6.93 (m, 2H); 5.45 (m, 1H);
5.37 (m, 1H); 5.07 (s, 2H); 3.95 (s, 2H); 3.19 (d, J = 4.4 Hz, 2H).
13C NMR (75 MHz, CDCl3) d (ppm): 178.4; 168.7; 155.3; 135.8;
134.5; 134.1; 131.7; 130.5; 129.1; 129.0; 128.6; 128.2; 128.0; 127.3;
121.0; 67.2; 49.7; 39.6; 31.4. MS m/z 492 (M+H).
Yield (0.29 g, 76%). Pale yellow oil. [a]2D0 -69.8 (c 0.45 in DCM).
Rf 0.36 (hexane/EtOAc: 60/40). (Found: C, 67.13; H, 5.87; N,
10.71. Calc for C22H23N3O4: C, 67.16; H 5.89; N, 10.68). nmax/cm-1
3063, 3033, 2956, 1705 (C O), 1583, 1513, 1455.1H NMR (300
MHz, CDCl3) d (ppm): 7.18 (m, 7H); 6.78 (m, 2 H); 5.06 (m, 3H);
3.91 (m, 2H); 3.66 (m, 3H); 3.4 8(m, 2H); 2.21 (m, 2H); 1.91 (m,
2H). 13C NMR (75 MHz, CDCl3) d (ppm): 179.5; 169.4; 158.9;
158.3; 135.8; 129.6; 129.5; 128.7; 128.1; 128.0; 113.7; 59.9; 54.9;
54.8; 46.5; 31.9;31.0; 20.6. MS m/z 394 (M+H).
(S)-tert-butyl 1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)ethyl-
carbamate 5(XIX)
Yield (0.24 g, 72%). Pale yellow oil. [a]2D0 -34.2 (c 1.08 in DCM). Rf
0.29 (hexane/EtOAc: 90/10). (Found: C, 61.27; H, 6.93; N, 12.58.
Calc for C17H23N3O4: C, 61.25; H 6.95; N, 12.60). nmax/cm-1 3434,
3344, 3054, 2982, 2934, 2838, 1715 (C O), 1513, 1455. 1H NMR
(300 MHz, CDCl3) d (ppm): 7.22 (d, J = 8.5 Hz, 2H); 6.82 (d, J =
8.6 Hz, 2H); 5.24 (s, 1H); 5.03 (m, 1H); 3.97 (s, 2H); 3.74 (s, 3H);
1.51 (d, J = 7.1 3H); 1.40 (s, 9H). 13C NMR (75 MHz, CDCl3) d
5-benzyl-3-(4-methoxybenzyl)-1,2,4-oxadiazole 5(XXIV)
Yield (0.23 g, 84%). Pale yiellow oil. Rf 0.38 (hexane/EtOAc:
90/10). (Found: C, 72.81; H, 5.73; N, 9.96. Calc for C17H16N2O2:
C, 72.84; H 5.75; N, 9.99). nmax/cm-1 3054, 3004, 2958, 2936, 1612,
1577, 1513. 1H NMR (300 MHz, CDCl3) d (ppm): 7.29 (m, 5H);
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7.23 (d, J = 8.7 Hz, 2H); 6.52 (d, J = 8.5 Hz, 2H); 4.16 (s, 2H); 3.98
(s, 2H); 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3) d (ppm): 177.9;
169.8; 158.6; 133.4; 129.9; 129.0; 128.8; 127.5; 127.3; 114.0; 55.1;
32.9; 31.4. MS m/z 281 (M+H).
168.1; 155.5; 52.9; 52.1; 39.4; 28.5; 28.1; 25.3; 15.7; 15.4; 11.6. MS
m/z 316 (M+H).
(S)-tert-butyl 1-(3-(methylthiomethyl)-1,2,4-oxadiazol-5-yl)-2-
phenylethylcarbamate 5(XXX)
5-phenyl-3-(4-methoxybenzyl)-1,2,4-oxadiazole 5(XXV)
Yield (0.25 g, 74%). Pale yellow oil. [a]2D0 -9.26 (c 0.46 in DCM). Rf
0.71(hexane/EtOAc: 80/20). (Found: C, 58.41; H 6.60; N, 11.99.
Calc for C17H23N3O3S: C, 58.43; H 6.63; N, 12.02). nmax/cm-1 3063,
3029, 2977, 2921, 1716 (C O), 1575, 1506, 1455, 1367. 1H NMR
(300 MHz, CDCl3) d (ppm): 7.25 (m, 3H); 7.04 (m, 2H); 5.32 (m,
1H); 5.16 (d, J = 8.5 Hz, 1H); 3.68 (s, 2H); 3.24 (m, 2H); 2.09 (s,
3H); 1.41 (s, 9H). 13C NMR (75 MHz, CDCl3) d (ppm): 179.1;
167.9; 134.9; 129.2; 128.7; 127.3; 49.3; 44.3; 39.9; 28.2; 27.8; 15.4.
MS m/z 350 (M+H).
Yield (0.24 g, 90%). Pale yellow solid. mp 86–88 ◦C. Rf 0.41
(hexane/EtOAc: 90/10). (Found: C, 72.18; H, 5.28; N, 10.50. Calc
for C16H14N2O2: C, 72.16; H 5.30; N, 10.52). nmax/cm-1 3071, 3034,
1
3008, 2965, 2928, 2832, 1609, 1560, 1510, 1477. H NMR (300
MHz, CDCl3) d (ppm): 8.09 (d, J = 6.8 Hz, 2H); 7.50 (m, 3H);
7.30 (d, J = 8.6 Hz, 2H); 6.87 (d, J = 8.7 Hz, 2H); 4.08 (s, 2H); 3.77
(s, 3H).13C NMR (75 MHz, CDCl3) d (ppm): 175.9; 170.6; 158.9;
132.8; 130.3; 129.2; 128.3; 127.8; 124.5; 114.4; 55.5; 31.8. MS m/z
267 (M+H).
(S)-tert-butyl 1-(3-((R)-tert-butyl ethylcarbamate)-1,2,4-oxadia-
zol-5-yl)ethylcarbamate 5(XXXI)
5-(3-methylbenzyl)-3-(methylthiomethyl)-1,2,4-oxadiazole
5(XXVI)
Yield (0.25 g, 65%). Pale yellow oil. [a]2D0 -59.2 (c 0.78 in DCM). Rf
0.55 (hexane/EtOAc: 70/30). (Found: C, 58.44; H, 6.68; N, 14.33.
Calc for C19H26N4O5: C, 58.45; H, 6.71; N, 14.35). nmax/cm-1 3955,
Yield (0.14 g, 58%). Pale yellow oil. Rf 0.51 (hexane/EtOAc:
90/10). (Found: C, 61.49; H, 5.59; N, 11.54. Calc for C12H14N2OS:
C, 61.51; H 6.02; N, 11.96). nmax/cm-1 3024, 2918, 2863, 1576,
1424, 1362. 1H NMR (300 MHz, CDCl3) d (ppm): 7.17 (m, 4H);
4.18 (s, 2H); 3.68 (s, 2H); 2.34 (s, 3H); 2.13 (s, 3H). 13C NMR
(75 MHz, CDCl3) d (ppm): 178.49; 168.14; 138.61; 133.1; 129.6;
128.7; 128.3; 125.9; 32.88; 27.9; 21.3; 15.6. MS m/z 235 (M+H).
1
2981, 1718 (C O), 1506, 1456. H NMR (300 MHz, CDCl3) d
(ppm): 7.25 (s, 5H); 5.60 (d, J = 7.9 Hz, 1H); 5.33 (d, J = 8.1 Hz,
1H); 5.02 (m, 4H); 1.44 (m, 6H); 1.36 (s, 9H). 13C NMR (75 MHz,
CDCl3) d (ppm): 178180.5; 171.1; 155.3; 154.6; 136.1; 128.4; 128.0;
109.1; 80.3; 66.9; 60.2; 43.9; 29.5; 28.1; 20.2. MS m/z 391 (M+H).
Preparation of (S)-1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
3-methylbutan-1-amine 6
5-(benzyl)-3-(methylthiomethyl)-1,2,4-oxadiazole 5(XXVII)
Yield (0.14 g, 62%). Pale yellow oil. Rf 0.37 (hexane/EtOAc:
90/10). (Found: C, 59.99; H, 5.48; N, 12.73. Calc for C11H12N2OS:
C, 59.97; H 5.49; N, 12.72). nmax/cm-1 3051, 2982, 2919, 1576,
Trifluoro acetic acid (0.63 mL, 8.2 mmol) was added to a solution
of 5(XXI) (0.31 g, 0.82 mmol) in DCM (10 mL) at room tempera-
ture. After 2.5 h the TLC analysis showed the complete absence of
the starting material and the reaction mixture was extracted with
5% HCl aqueous solution. The HCl aqueous solution was then
1
1496. H NMR (300 MHz, CDCl3) d (ppm): 7.33 (m, 5H); 4.23
(s, 2H); 3.68 (s, 2H); 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) d
(ppm): 178.4; 168.2; 133.2; 128.9; 128.8; 127.6; 33.0; 27.9; 15.6.
MS m/z 221 (M+H).
◦
added with a saturated solution of NaHCO3 until pH 8 at 0 C.
The aqueous solution was extracted with DCM. The organic phase
was dried over anhydrous Na2SO4. The solvent was evaporated in
vacuo to give the (S)-1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-
yl)-3-methylbutan-1-amine 6 in good yield (0.26 g, 95%) as a pale
yellow oil. [a]2D0 -7.50 (c 0.88 in DCM). Rf 0.66 (hexane/EtOAc:
60/40). (Found: C, 65.41; H, 7.65; N, 15.29. Calc for C15H21N3O2:
C, 65.43; H, 7.69; N, 15.26). nmax/cm-1 3379, 3368, 3036, 3001,
5-(ethyl-phenylyl)-3-(methylthiomethyl)-1,2,4-oxadiazole
5(XXVIII)
Yield (0.16 g, 67%). Pale yellow oil. Rf 0.53 (hexane/EtOAc:
90/10). (Found: C, 61.49; H 5.98; N, 11.95. Calc for C12H14N2OS:
C, 61.51; H 6.02; N, 11.96). nmax/cm-1 3084, 3061, 3025, 2918, 2859,
1578, 1496, 1453, 1362. 1H NMR (300 MHz, CDCl3) d (ppm): 7.23
(m, 5H); 3.69 (s, 2H); 2.89 (t, J = 7.6 Hz, 2H); 2.73 (t, J = 7.6 Hz,
2H); 2.15 (m, 3H). 13C NMR (75 MHz, CDCl3) d (ppm): 180.1;
168.0; 140.5; 128.5; 128.4; 126.2; 34.9; 27.9; 25.9; 15.6. MS m/z:
235 (M+H).
1
2958, 28702837, 1613, 1574, 1513, 1465. H NMR (300 MHz,
CDCl3) d (ppm): 7.21 (m, 2H); 6.86 (m, 2H); 4.14 (m, 1H); 3.98
(s, 2H); 3.76 (m, 3H); 1.67 (m, 3H); 0.92 (t, J = 6.2 Hz, 6H).
13C NMR (75 MHz, CDCl3) d (ppm): 183.3; 169.7; 158.8; 130.2;
129.2; 127.6; 122.0; 60.5; 55.3; 47.6; 31.6; 24.8; 22.0. MS m/z 276
(M+H).
tert-butyl (1S)-2-methyl-1-(3-(methylthiomethyl)-1,2,4-oxadiazol-
5-yl)butylcarbamate 5(XXIX)
Preparation of (S)-1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
3-methyl-N-((R)-2,2,2(trifluoro-1-methoxy-1-phenylethyl) butan-
1-amine 7
Yield (0.22 g, 71%). Yellow oil. [a]2D0 -25.0 (c 0.22 in DCM). Rf
0.80 (hexane/EtOAc: 80/20). (Found: C, 53.29; H 7.98; N, 13.29.
Calc for C14H25N3O3S: C, 53.31; H 7.99; N, 13.32). nmax/cm-1 3061,
2968, 2933, 2878, 1718 (C O), 1576, 1508, 157, 1367. 1H NMR
(300 MHz, CDCl3) d (ppm): 5.23 (d, J = 8.9 Hz, 1H); 4.98 (m,
1H); 3.69 (s, 2H); 2.11 (s, 3H); 1.96 (m, 1H); 1.43 (s, 9H); 1.20 (m,
2H); 1.00(m, 6H). 13C NMR (75 MHz, CDCl3) d (ppm): 179.7;
A sample of compound 6 (0.9 g, 0.34 mmol) and (S)-
(+)-a-methoxy-a-trifluoromethylphenylacetyl chloride (MPTACl)
(73 mL,0.39 mmol) were mixed with dry pyridine (0.28 mL)
and DCM (0.28 mL) and allowed to stand for 6 h. The
mixture of reaction was added with water and extracted
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three times with Et2O. The organic phase was washed with
a saturated solution of Na2CO3, H2O and dried over anhy-
drous Na2SO4. The solvent was evaporated in vacuo and the
residual crude (S)-1-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
3-methyl-N-((R)-2,2,2(trifluoro-1-methoxy-1-phenylethyl) butan-
1-amine 7 in good yield (0.47 g, 96%) was characterized. [a]D20
-34.9315 (c 0.0032 in DCM). Rf 0.53 (hexane/EtOAc: 60/40).
(Found: C, 61.05; H, 5.72; N, 8.56. Calc for C25H28F3N3O4: C,
61.09; H, 5.74; N, 8.55). nmax/cm-1 3054, 2921, 2872, 1694(C O),
1662, 1578, 1513, 1465. 1H NMR (300 MHz, CDCl3) d (ppm): 7.40
(m, 5H); 7.21 (d, J = 8.8 Hz, 2H); 6.85 (d, J = 8.8 Hz, 2H); 5.41
(q, J = 8.7 Hz, 1H); 4.00 (s, 2H); 3.79 (s, 3H); 3.28 (s, 3H); 1.83 (t,
J = 7.0 Hz, 2H); 1.67 (m, 1H); 0.97 (m, 6H). 13C NMR (75 MHz,
CDCl3) d (ppm): 179.0; 169.6; 158.6; 150.9; 131.4; 129.9; 129.5;
129.0; 128.5; 127.9; 127.1; 114.0; 109.1; 55.2; 54.8; 45.2; 42.2; 33.4;
24.6; 22.6; 21.4. 19F NMR (282 MHz, CDCl3) d (ppm): -70.387.
MS m/z 492 (M+H).
7 L. J. Street, R. Baker, T. Book, C. O. Kneen, A. M. MacLeod, K. J.
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9 J. Roppe, N. D. Smith, D. Huang, L. Tehrani, B. Wang, J. Ander-
son, J. Brodkin, J. Chung, X. Jiang, C. King, B. Munoz, M. A.
Varney, P. Prasit and N. D. P. Cosford, J. Med. Chem., 2004, 47,
4645.
10 C. J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E. M. Seward,
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Acknowledgements
This work was financially supported by Regione Autonoma della
Sardegna (“Sintesi e caratterizzazione delle proprieta` chimiche e
degli effetti neuromodulatori sul SNC di una libreria di donatori
di nitrossido derivati dell’acido di Piloty”)
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7546 | Org. Biomol. Chem., 2011, 9, 7539–7546
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