A new class of fused imidazoles by intramolecular nucleophilic ipso- substitution in 2-alkylsulfonylimidazoles: Synthesis of 2,3- dihydroimidazo[2,1-b][1,3]oxazoles

Article abstract of DOI:10.1055/s-1999-3571

Starting from readily available thiouronium salts 1 and α-halocarbonyl compounds 2, a simple and efficient synthesis of 2-alkylthioimidazoles 3 was accomplished. Reduction of the carbonyl group, followed by oxidation of the 2-alkylthioether moiety, afforded sulfones 8. Intramolecular nucleophilic ipso-substitution in 2-alkylsulfonylimidazoles 8 efficiently furnished a novel class of fused imidazoxazoles. This finding was extended towards the generation in solution of a small library of 2,3-dihydroimidazo[2,1- b][1,3]oxazoles.

Full text of DOI:10.1055/s-1999-3571

PAPER
1613
A New Class of Fused Imidazoles by Intramolecular Nucleophilic
ipso-Substitution in 2-Alkylsulfonylimidazoles: Synthesis of
2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
Montserrat Heras,a,1 Montserrat Ventura,a Anthony Linden,b José M. Villalgordo*a
a Departament de Química, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, E-17071 Girona, Spain
b Organisch-Chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Fax +34(972)418150; E-mail: dqjvs@xamba.udg.es
Received 24 May 1999
ipso-substitution at the C-2 position have been report-
ed,21,22 and although many efforts have been devoted to
the synthesis of, for instance, imidazo[1,2-a]pyridines,23
there are no literature reports on the synthesis of imida-
Abstract: Starting from readily available thiouronium salts 1 and a-
halocarbonyl compounds 2, a simple and efficient synthesis of 2-
alkylthioimidazoles 3 was accomplished. Reduction of the carbonyl
group, followed by oxidation of the 2-alkylthioether moiety, afford-
ed sulfones 8. Intramolecular nucleophilic ipso-substitution in 2- zo[2,1-b][1,3]oxazoles.
alkylsulfonylimidazoles 8 efficiently furnished a novel class of
Herein, we wish to report our findings on the use for the
fused imidazoxazoles. This finding was extended towards the gen-
eration in solution of a small library of 2,3-dihydroimidazo[2,1-
b][1,3]oxazoles.
first time of alkylsulfonyl substituents in electron-rich im-
idazoles, as effective leaving groups in intramolecular nu-
cleophilic ipso-substitution reactions, and their
application toward the preparation of a novel class of
fused imidazoles. Thus, when thiouronium salts 1, readily
available from the corresponding alkyl halide and thio-
urea in refluxing ethanol, were allowed to react in MeCN
Key words: synthesis, 2-alkylthioimidazoles, alkylsulfonyl groups,
leaving groups, intramolecular nucleophilic ipso-substitution, imi-
dazoles, 2,3-dihydroimidazo[2,1-b][1,3]oxazoles
Heteroaromatic nucleophilic addition-elimination reac-
tions are commonly recognized in many electron-defi-
cient heterocycles.2 However, analogous reactions with
electron-rich heterocycles,3–5 and more accurately, with
electron-rich imidazoles and condensed imidazoles, are
rather uncommon.6–8 On the other hand, alkyl- or aryl-
sulfinyl or -sulfonyl substituents as leaving groups in elec-
tron-deficient heteroaromatic systems have been reported
to have reactivity equivalent to, or greater than, that of a
chloro group, and many examples concerning the reactiv-
ity of electron deficient azines bearing alkylsulfinyl- and
-sulfonyl groups, with simple nucleophiles have been re-
ported.9,10 To the best of our knowledge, however, there is
only one recent literature precedent for the use of sulfinyl
or sulfonyl substituents as leaving groups on imidazoles.11
However, only strongly activated imidazoles bearing
electron-withdrawing groups were reported to undergo ef-
ficient ipso-substitution reactions with a variety of differ-
ent nucleophiles.
During the course of our studies on the development of ef-
ficient methodologies that could be readily adapted for the
combinatorial and/or parallel synthesis in solution or on
solid supports of relevant core structures,12-16 we focused
our attention on the imidazole nucleus. Imidazoles are im-
portant pharmacophores, and many biologically active
compounds incorporate this moiety into their structures.
Particularly interesting, are fused [1,2-a]imidazoles,
which have been reported to have antiulcer, antidepres-
sant, antibacterial and TxA2 synthase inhibitory activi-
ties.17-20 Recently, innovative protocols for the synthesis
of [1,2-a]-fused imidazoles using intramolecular radical
Figure ORTEP plot27 of the molecular structure of 3a with 50%
probability ellipsoids
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1614
M. Heras et al.
PAPER
Table 2 Prepared 2-Alkylthio- and 2-Alkylsulfonylimidazoles 3a–
d, 4 and 5
Producta
R
R1
Yield (%) mp (ºC)
3a
3b
3c
3d
4
PhCH2
C10H21
C10H21
PhCH2
C10H21
PhCH2
Ph
78
57
65
55
53
50
142–143
Me
Ph
colourless oil
67.5–68
Me
Me
Me
74–75
colourless oil
207–208
5
a Satisfactory microanalyses obtained: C 0.28, H 0.30, N 0.27.
poor reactivity of this type of electron rich imidazoles to-
wards nucleophilic ipso-substitution reactions. In most
cases, together with unreacted starting material, only deg-
radation products were obtained from which dealkylated
imidazole, as exemplified by 5, could be isolated and
identified as the main product (Scheme 1 and Tables 2 and
3).
Scheme 1
The generation of 5 as the main product in these reactions
suggested that the presence of the carbonyl group in 4
could negatively interfere in a possible nucleophilic sub-
stitution to afford 6. Therefore, we proceeded further by
reducing 3a–c with NaBH4 in MeOH to the corresponding
alcohols 7a–c. Subsequent oxidation with m-CPBA in
CH2Cl2 led to the corresponding sulfones 8a–c in good
yields. When these sulfones 8 (as exemplified by 8a, R1
= Ph) were treated with MeONa in MeOH at room tem-
perature, a smooth reaction leading to 2,3-dihydroimid-
with 2 equivalents of the corresponding a-halocarbonyl
compound 2 in the presence of a suitable base such as di-
isopropylethylamine (DIPEA), the corresponding 2-alky-
lthioimidazoles 3 were isolated in good yields. The
structural elucidation of compounds 3 was accomplished
by the usual spectroscopic methods, and in addition, 3a
was subjected to an X-ray crystal-structure analysis that
unambiguously confirmed the structure (Figure, Table 1).
Next, as in the model case 3b, we found that oxidation of
the thioether moiety with m-CPBA in CH2Cl2, led to the
corresponding sulfone 4 in 53% yield. When 2-alkylsulfo-
nylimidazole 4 was prompted to react with a wide range
of different nucleophiles (N-, O-, S-, and C-nucleophiles),
even under very forcing conditions, no substitution prod-
ucts 6 were observed. These results confirmed the known
R1
R1
N
N
NaBH4
RS
O
N
RS
HO
N
MeOH/r.t.
(80-95%)
R1
R1
3a-c
7a-c
R1
R1
Table 1 Selected Bond Lengths (Å) and Angles (°) for 3a
N
m-CPBA
CH2Cl2
MeONa
MeOH/r.t.
N
O
S–C(2)
1.751(3)
1.841(3)
1.372(3)
1.364(3)
1.453(3)
1.313(3)
1.381(3)
1.368(4)
RO2S
HO
N
N
(80%, from 8a)
S–C(14)
C(2)–S–C(14)
99.3(1)
106.5(2)
105.5(2)
111.8(2)
109.7(2)
106.6(2)
R1
(60-70%)
R1
N(1)–C(2)
N(1)–C(5)
N(1)–C(6)
N(3)–C(2)
N(3)–C(4)
C(4)–C(5)
C(2)–N(1)–C(5)
C(2)–N(3)–C(4)
N(1)–C(2)–N(3)
N(3)–C(4)–C(5)
N(1)–C(5)–C(4)
9 R1 = Ph
8a-c
R1
N
MeONa/MeOH/∆
MeO
HO
N
10
R1
Scheme 2
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
1615
Table 3 MS, IR and NMR Data of Imidazoles 3, 4 and 5
Prod- MS
IR (KBr)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
uct
m/z (%)
n (cm-1)
3a
386 ([M+2]+, 28), 385 ([M+1]+, 3058, 3052, 2955, 2927,
4.2 (s, 2 H), 5.0 (s, 2 H), 7.15– 40.95, 52 (t, CH2), 118.4,
100), 384 ([M]+, 23), 291 (19),
1697, 1596, 1580, 1490,
7.9 (m, 16 H)
124.88, 126.89, 127.4, 127.9,
264 (17), 263 (82), 262 (12), 145 1451, 1406, 1391, 1347,
(18), 121 (26), 105 (10), 93 (26), 1229, 1204, 1178, 1154,
128.5, 128.6, 128.8, 128.9, (d,
CHarom), 133.7 (s, Carom), 134.2,
137.9, 140.8, 142.7 (s, Carom),
191.4 (s, CO)
92 (16), 91 (19)
1120, 1073, 982, 774, 752,
689
3b
3c
312 ([M+2]+, 20), 311 ([M+1]+, 2955, 2925, 2854, 1739,
0.89 (t, 3 H, J = 6.4), 1.25–
1.35 (m, 14 H), 1.55–1.65 (m, CH2), 26.9 (q, CH3), 28.56,
2 H), 2.2 (s, 3 H), 2.25 (d, 3 H, 29.02, 29.21, 29.41, 29.44,
J = 0.8), 3.0 (t, 2 H, J = 7.4),
4.7 (s, 2 H), 6.65 (d, 1 H,
J = 0.8)
13.8, 14.02 (q, CH3), 22.6 (t,
100), 310 ([M]+, 6), 255 (14),
1560, 1457, 1429, 1377,
1359, 1287, 1168, 1168,
1118, 1044, 998, 978, 800,
716
171 (32), 170 (19)
29.6, 31.8, 35.35, 55.50 (t,
CH2), 118.2 (d, CHarom),
139.17, 140.8, (s, Carom), 201.5
(s, CO)
436 ([M+2]+, 23), 435 ([M+1]+, 2954, 2925, 2853, 1702,
100), 434 ([M]+, 10), 295 (37),
1598, 1455, 1430, 1348,
294 (18), 261 (12), 190 (11), 189 1226, 1208, 1182, 1226,
(31) 1208, 1182, 753, 690
0.91 (t, 3 H, J = 6.4), 1.25–1.4 14.05 (q, CH3), 22.6, 28.6,
(m, 14 H), 1.6–1.7 (m, 2 H),
3.05 (t, 2 H, J = 7.3), 5.42 (s,
2 H), 7.2–8.0 (m, 11 H)
29.0, 29.25, 29.45, 29.5, 29.65,
31.8, 35.8, 55.45 (t, CH2),
118.0, 124.85, 126.8, 128.0,
128.45, 129.0 (d, CHarom.),
133.85 (s, Carom.), 134.2 (d,
CHarom.), 134.35, 142.4 (s,
Carom.), 191.7 (s, CO)
3d
4
262 ([M+2]+, 17), 261 ([M+1]+, 3125, 3083, 3025, 2947,
2.0 (s, 3 H), 2.28 (s, 3 H), 4.12 13.8 (q, CH3), 26.72 (q, CH3),
(s, 2 H), 4.32 (s, 2 H), 6.61 (s, 40.65, 55.10 (t, CH2), 118.70,
100), 260 ([M]+, 15), 171 (11)
2921, 2852, 1718, 1561,
1493, 1428, 1357, 1288,
1170, 1123, 1066, 806, 769,
704
1 H), 7.1–7.3 (m, 5 H)
127.4, 128.65, 128.8 (d, CH),
137.65, 139.2, 139.5 (s, Carom),
201.2 (s, CO)
344 ([M+2]+, 18), 343 ([M+1]+, 3150, 2953, 2921, 2850,
91), 341 ([M]+, 8), 139 (44), 137 1727, 1465, 1406, 1362,
0.93 (t, 3 H), 1.3–1.45 (m, 14 13.5 (q, CH3), 14.0 (q, CH3),
H), 1.65–1.85 (m, 2 H), 2.3 (s, 21.5, 22.6 (t, CH2), 26.9 (q,
(36), 133 (35), 131 (30), 123
(49), 121 (42), 119 (58), 117
(30), 111 (48), 109 (100), 107
(69), 105 (76)
1324, 1303, 1290, 1224,
1175, 1154, 1114, 678
6 H, CH3CO, CH3), 3.3–3.4
(m, 2 H), 5.13 (s, 2 H), 6.65 (s, 29.6, 31.8, 55.2, 56.8 (t, CH2),
1 H)
CH3), 28.15, 28.9, 29.2, 29.4,
122.2 (d, CHarom), 139.2, 140.1
(s, Carom), 200.1 (s, CO)
5
238 ([M+2]+, 14), 237 ([M+1]+, 3043, 2966, 2918, 2853,
2.16 (s, 3 H), 4.68 (s, 2 H),
6.99 (s, 1 Harom), 7.1–7.35 (m, 128.0 (s, Carom), 129.2 (d,
13.5 (q, CH3), 60.3 (t, CH2),
100), 236 ([M]+, 6), 173 (11)
2810, 2723, 1653, 1577,
1495, 1439, 1323, 1282,
1254, 1200, 1147, 1121,
1007, 929, 875, 787, 700
5 Harom
)
CHarom), 128.95 (s, Carom),
129.2, 129.7 (d, CHarom),
140.3, 140.4 (s, Carom
)
azo[2,1-b][1,3]oxazole 9 took place in a very clean and ef-
ficient manner. Although the 2-alkylsulfonyl groups in 8
were readily displaced in these reactions, not even traces
of the corresponding 2-methoxyimidazole derivatives of
type 10 were detected (Scheme 2, Tables 4 and 5).
Table 4 Prepared Imidazoles 7 and 8 and 2,3-Dihydroimidazo[2,1-
b][1,3]oxazole 9
Producta
R
R1
Yield
(%)
mp (ºC)
7a
7b
7c
8a
8b
8c
9
PhCH2
C10H21
C10H21
PhCH2
C10H21
C10H21
–
Ph
Me
Ph
Ph
Me
Ph
Ph
95
82
82
65
60
61
81
116–117
This transformation presumably took place through initial
formation of the corresponding alkoxy derivative 11, fol-
lowed by intramolecular nucleophilic ipso-substitution to
afford 9. These results were confirmed independently
simply by treating a solution of 8a in THF with 1.2 equiv-
alents of NaH at room temperature to give 9 in good iso-
lated yields. However, protection of the hydroxy group as
the methyl ether derivative 12 (from 7a) followed by oxi-
dation to sulfone 13 and subsequent treatment with
NaOMe in MeOH or with other nucleophiles even at high
temperatures resulted in no reaction, and unreacted start-
colourless oil
70.5–72
134–135
colourless oil
80–81
192–193 (dec)
a Satisfactory microanalyses obtained: C ± 0.27, H ± 0.22, N ± 0.30.
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1616
M. Heras et al.
PAPER
Table 5 MS, IR and NMR Data of Imidazoles 7, 8 and Dihydroimidazoxazole 9
Prod-
uct
MS
m/z (%)
IR (KBr)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
n (cm-1)
7a
7b
7c
388 ([M+2]+, 6), 387 ([M+1]+, 3438, 3063, 1600, 1492, 1454, 3.74 (dd, 1 H, J = 14.0, 8.8),
40.85 (t, CH2), 54.5 (t, CH2),
73.0 (d, CH), 118.6, 124.6,
24), 386 ([M]+, 8), 293 (24),
279 (10), 266 (21), 265 (100),
264 (23), 247 (16), 145 (18),
121 (12), 105 (13), 93 (46), 92
(25), 91 (31), 79 (15), 63 (11),
55 (17)
1412, 1190, 1061, 751, 696
3.9 (dd, 1 H, J = 14.0, 3.3),
4.15(s, 2 H), 4.8 (s, 1 H, OH), 125.85, 126.6, 127.3, 127.9,
4.96 (dd, 1 H, J = 8.8, 3.3),
7.1–7.65 (m, 16 H)
128.4, 128.45, 128.5, 128.75,
(d, CHarom), 133.45, 137.7,
140.2, 141.05, 141.6 (s, Carom
)
312 ([M+2]+, 20), 311
3205, 2959, 2924, 2853, 1567, 0.9 (t, 3 H, J = 6.4), 1.25–1.35 13.55 (q, CH3), 14.0 (q, CH3),
1468, 1412 (m, 17 H), 1.5–1.6 (m, 2 H), 20.5(q, CH3), 22.6, 28.6, 29.0,
2.2 (s, 3 H), 2.9–3.0 (m, 2 H), 29.25, 29.45, 29.5, 29.6,
([M+1]+, 100), 310 ([M]+, 6),
255 (14), 171 (32), 170 (19)
3.79 (dd, 1 H, J = 14, 8.4),
4.01 (dd, 1 H, J = 14, 3.4),
4.1–4.15 (m, 1 H), 6.75 (s,
1 H)
31.85, 35.5, 53.9 (t, CH2), 66.9
(d, CH), 118.6 (d, CHarom),
137.9, 140.1 (s, Carom
)
438 ([M+2]+, 24), 437
3150, 3063, 3030, 2954, 2925, 0.91 (t, 3 H, J = 6.4), 1.25–
14.05 (q, CH3), 22.6, 28.55,
([M+1]+, 86), 436 ([M]+, 9),
279 (25), 203 (10), 191 (17),
190 (27), 189 (21), 179 (11),
178 (18), 177 (74), 176 (100),
175 (20), 173 (10)
2853, 1602, 1489, 1455, 1415, 1.45 (m, 14 H), 1.55–1.60 (m, 29.05, 29.25, 29.4, 29.5,
1191, 1063, 747, 698
2 H), 3.0–3.05 (m, 2 H), 4.05
(dd, 1 H, J = 14, 9), 4.23 (dd,
29.65, 31.85, 35.65, 54.8 (t,
CH2), 73.15 (d, CH), 118.25,
1 H, J = 14,0, 5.0 (s, 1 H, OH), 124.55, 125.9, 126.5, 127.95,
5.19 (dd, J = 9, 3), 7.2–7.6 (m, 128.35, 128.6, (d, CHarom),
11 H)
133.5, 141.2, 141.25, 141.7 (s,
Carom
)
8a
420 ([M+2]+, 28), 419
3448, 3149, 3070, 3050, 3030, 2.5 (s, 1 H, OH), 3.73 (dd, 1 H, 54.85 (t, CH2), 62.1 (t, CH2),
2924, 1596, 1496, 1455, 1412, J = 14, 8.8), 4.2 (dd, 1 H, J = 73.25 (d, CH), 121.75, 125.3,
1376, 1329, 1256, 1236, 1152, 14.0, 3), 4.57 (dd, 1 H, J = 8.8, 125.6 (d, CHarom), 127.25 (s,
([M+1]+, 100), 401 (10), 293
(11), 265 (45), 264 (10), 93
(16), 91 (16), 65 (22)
1113, 1089, 1061, 962, 906,
786, 762, 696
3), 4.67, 4.70 (2d, 2 H, J = 14), Carom), 127.8, 128.2, 128.6,
7.15–7.85 (m, 16 H)
128.65, 128.7, 129.05, 131.2
(d, CHarom), 132.4, 138.8,
140.3, 141.75 (s, Carom
)
8b
8c
346([M+2]+, 18), 345
3371, 2954, 2925, 2855, 1559, 0.93 (t, 3 H, J = 6.6), 1.25–1.4 13.45 (q, CH3), 14.0 (q, CH3),
1463, 1422, 1344, 1322, 1217, (m, 17 H), 1.75–1.9 (m, 2 H), 20.7 (q, CH3), 21.8, 22.6, 28.1,
([M+1]+, 100), 344 ([M]+, 8),
141 (58), 140 (12), 139 (68)
1154, 1118, 1012, 937, 841,
780, 711
2.2 (s, 3 H), 2.4 (s, 1 H, OH),
3.4–3.45 (m, 2 H), 4.0–4.15
(m, 2H), 4.4–4.45 (m, 1 H),
6.9 (s, 1 H)
28.9, 29.2, 29.4, 29.6, 31.8,
54.45, 55.4 (t, CH2), 67.65,
122.3 (d, CH), 138.5, 140.3 (s,
Carom
)
470 ([M+2]+, 31), 469
([M+1]+, 100), 468 ([M]+, 4),
279 (12), 277 (11), 266 (15),
265 (68), 264 (17), 263 (52),
261 (11), 245 (24), 193 (20),
191 (49)
3415, 3143, 3063, 3030, 2953, 0.92 (t, 3 H, J = 6.4), 1.2–1.5
2925, 2854, 1715, 1602, 1489, (m, 14 H), 1.8–2.0 (m, 2 H),
1463, 1404, 1377, 1321, 1224, 2.85 (s, 1 H, OH), 3.5–3.55
14.05 (q, CH3), 21.85, 22.6,
28.15, 28.9, 29.2, 29.4, 31.8,
55.1, 55.2 (t, CH2), 73.65, (d,
1150, 1115, 1091, 1062, 760,
701
(m, 2 H), 4.38 (dd, 1 H, J = 14, CH), 121.2, 125.2, 125.8,
8.6), 4.78 (dd, 1 H, J = 14, 127.7, 128.35, 128.6, 128.7 (d,
3.2), 5.2 (dd, 2 H, J = 8.6, 3.2), CHarom), 132.5, 140.35,
7.3–7.8 (m, 11 H) 141.35, 141.55 (s, Carom
)
9
263 ([M+1]+, 13), 262 ([M]+,
3029, 2882, 1604, 1585, 1571, 4.21 (dd, 1 H, J = 10, 8), 4.73 50.25 (d, CH), 86.7 (t, CH2),
65), 171 (29), 128 (12), 116
(23), 105 (11), 104 (100), 103 930, 765, 709, 695
(23), 78 (16), 77 (18)
1494, 1480, 1381, 1286, 976,
(dd, 1 H, J = 10, 8), 6.41 (t,
1 H, J = 8), 7.25–7.8 (m,
11 H)
107.9, 123.8, 126.05, 126.55,
128.5, 128.9, 129.2, (d,
CHarom), 135.0, 137.9, 141.0,
159.1 (s, Carom
)
ing material was recovered almost quantitatively (Scheme tions used to efficiently achieve the transformations to
3).
these novel fused imidazoxazoles of type 9, we decided to
explore further the synthetic applicability of these find-
ings. With the aim of adapting the methodology to the sol-
id support12 in such a way that could afford libraries of
fused imidazoxazoles with increased molecular diversity,
we initially explored in solution an epoxidation reaction
on the carbonyl group in imidazoles of type 3. Epoxide
Obviously, the entropy factor seems to be the driving
force for the formation of fused imidazoxazoles 9, favour-
ing intramolecular versus intermolecular nucleophilic ad-
dition-elimination reactions in electron rich imidazoles.
Therefore, due to the exceptionally mild reaction condi-
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
1617
R1
R1
Ph
Ph
N
N
N
I
N
NaH
Ph
S
N
MeONa
MeOH
+
Me3S O
Ph
S
N
Ph
S
N
O
Ph
Ph
S
N
DMF/50°C
77-80%
O
O
O
O
O
OH
ONa
3a R1 = Me
3b R1 = Ph
16a R1 = Me
16b R1 = Ph
R1
15
R1
Ph
8a
Ph
R1
11
N
15 (2.6 Equiv.)
Ph
S
N
O
N
O
NaH/DMF/90°C
NaH
17 (R1 = Ph)
(81% from 3b)
THF/r.t.
R1
N
9
Ph
Scheme 4
Ph
Ph
N
N
m-CPBA
CH2Cl2
MeI
NaH/THF/r.t.
opening with different nucleophiles should lead to the cor-
responding tertiary alcohols, which, by subsequent oxida-
tion to the corresponding sulfone followed by
intramolecular ipso-substitution reactions with concomi-
tant release of the 2-alkylsulfonyl group, under the above
described conditions, should afford different 2,3-dihy-
droimidazo[2,1-b][1,3]oxazoles.
Ph
S
N
Ph
S
N
MeO
HO
Ph
7a
12
Ph
R1
Ph
N
N
MeONa
MeOH
Thus, when imidazoles 3a,b, were allowed to react under
optimized conditions of 1.1 equivalents of trimethylsulfo-
nium iodide 15 in the presence of 1 equivalent of NaH in
DMF at 50ºC, the epoxides 16a,b were formed exclusive-
ly and isolated in good yields. Other reaction conditions,
such as varying the amount of base, the amount of sulfo-
nium reagent 15, solvents and temperatures, resulted in
the formation of oxetane derivatives 17, together with the
epoxide 16, in different proportions. When the reaction
MeO
MeO
N
Ph
S
N
O
O
OMe
R1
Ph
13
14
Scheme 3
R1
N
N
N
18
Ph
S
N
N
22a R1 = Me
H
OH
22b R1 = Ph
t-BuOK
DMF/60°C
N
N
R1
R1
N
N
N
N
19
H
Ph
S
N
23a R1 = Me
N
R1
OH
t-BuOK
DMF/60°C
23b R1 = Ph
N
N
R1
R1
N
N
N
Ph
S
N
R1
N
O
N
N
20
H
Ph
S
N
N
N
R1
(1:1 ratio)
Ph
S
N
N
OH
+
N
16a R1 = Me
16b R1 = Ph
t-BuOK
DMF/60°C
N
OH
N
N
24 (R1 = Ph)
25 (R1 = Ph)
N
R1
R1
N
N
R1
R1
N
N
N
H
21
Ph
S
N
+
N
Ph
S
N
N
N
t-BuOK
DMF/60°C
OH
(2:1 ratio)
OH
N
N
N
27 (R1 = Ph)
26 (R1 = Ph)
R1
R1
Scheme 5
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1618
M. Heras et al.
PAPER
Table 6 Prepared Epoxides 16 and Oxetane 17
was carried out with 2.5 equivalents of base and 2.6 equiv-
alents of 15 in DMF at 90 ºC, the oxetane derivative 17
was the sole isolated product in 81% yield (from 3b,
Scheme 4 and Tables 6 and 7).
Producta
16a
R1
Yield (%)
mp (ºC).
Me
Ph
Ph
68
80
81
yellowish oil
90.1–91.7
82.4–84.9
With a good procedure in our hands to selectively form
epoxides 16, or oxetanes 17 if desired, we proceeded fur-
ther by studying the epoxide opening reaction with differ-
ent azoles. Thus, when epoxides 16a,b were treated with
2.5 equivalents of 1H-imidazole (18), 1H-1,2,4-triazole
16b
17
a Satisfactory microanalyses obtained: C 0.28, H 0.26, N 0.18.
Table 7 MS, IR and NMR Data of Epoxides 16 and Oxetane 17
Prod- MS
IR (KBr)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
uct
m/z (%)
n (cm-1)
16a
276 ([M+2]+, 19), 275
3056, 3029, 2966, 2927, 2853, 1.13 (s, 3 H), 2.27 (d, 3 H, J = 13.84, 18.4 (q, CH3), 40.45,
1564, 1492, 1446, 1429, 1358, 0.8), 2.52 (dd, 2 H, J = 14.4), 50.6, 51.65 (t, CH2), 55.8 (s,
3.56 (d, 1 H, J = 14.6), 3.85 (d, C), 118.4 (s, Carom), 127.3,
1 H, J = 14.6), 4.2 (s, 2 H), 128.45, 128.75 (d, CHarom),
([M+1]+, 100), 274 ([M]+, 7),
219 (13), 205 (12), 185 (18),
171 (11), 167 (16), 165 (12)
1285, 1170, 1113, 1071, 895,
791, 768, 703
6.75 (d, 1 H, J = 0.8), 7.15–7.3 137.7, 139.25 (s, Carom
)
(m, 5 H)
16b
17
400 ([M+2]+, 29), 399
3142, 3064, 3029, 2924, 1728, 2.71 (dd, 2 H, J = 5), 4.05 (d, 1 40.3, 49.75, 52.8 (t, CH2),
([M+1]+, 100), 398 ([M]+, 13), 1602, 1494, 1455, 1433, 1194, H, J = 15), 4.25, 4.30 (2d, 2 H, 59.44 (s, C), 117.7, 124.75,
177 (18), 176 (35), 123 (30),
121 (32), 119 (41), 109 (61),
107 (47), 105 (82)
756, 697
J = 12.8), 4.43 (d, 1 H, J = 15), 126.0, 126.85, 127.5, 128.35,
7.2–7.45 (m, 14 H), 7.8-7.85
128.5, 128.5, 128.85 (d,
(m, 2 H)
CHarom), 133.75, 136.4, 137.8,
141.1, 142.45 (s, Carom
)
414 ([M+2]+, 19), 413
([M+1]+, 64), 412 ([M]+, 13),
133 (93), 105 (100)
3056, 3031, 2938, 2967, 2873, 2.6–2.7 (m, 2 H), 3.85 (d, 1 H, 30.55, 40.1, 55.3, 65.3 (t,
1602, 1488, 1451, 1422, 1357, J = 14.8), 4.2 (d, 1 H, J = 14.8), CH2), 87.5 (s, C), 118.4,
1342, 1233, 1189, 1114, 1069, 4.2–4.45 (m, 4 H), 7.2–7.55
1027, 979, 958, 868, 776, 747, (m, 14 H), 7.85–7.9 (m, 2 H)
694
124.0, 124.7, 126.75, 127.35,
127.55, 128.4, 128.45, 128.5,
128.8 (d, CHarom), 134.0,
137.75, 141.6, 142.2, 143.5 (s,
Carom
)
(19),1H-tetrazole (20) or benzotriazole (21), in the pres-
ence of t-BuOK in DMF at 60–100 ºC for 5–7 hours, the
corresponding azolyl derivatives 22–27 were obtained in
94–98% yield. When the potassium salts of 1H-imidazole
R1
R1
N
N
m-CPBA
Ph
S
N
Ph
S
N
CH2Cl2
OH
O
O
OH
Nu
Nu
R1
Table 8 Prepared Epoxide Ring Opening Products 22–27
R1
22-27
28-33
Prod- R1
uct
Reaction Reaction
Time (h) Temperature (%)
Yield mp (ºC)
R1
(ºC)
Nu
22a
22b
23a
23b
24
Me
6
6
5
5
7
7
6
6
60
60
92
95
93
88
45
53
56
38
colourless oil
176–177
NaH/THF
r.t.
N
N
O
Ph
Me
Ph
Ph
Ph
Ph
Ph
R1
60
colourless oil
164–165
34-39
R1 = Me, Ph
N
100
60
N
N
N
N
N
N
N
77–78
Nu =
N
N
N
N
N
N
N
N
25
60
158–159
26
60
128–130 (dec.)
183–184 (dec.)
N
N
N
27
60
a Satisfactory microanalyses obtained: C 0.27, H 0.26, N 0.28.
Scheme 6
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
1619
Table 9 MS, IR and NMR Data of Epoxide Ring Opening Products 22–27
Prod-
uct
MS
m/z (%)
IR (KBr)
n (cm-1
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
)
22a
22b
344 ([M+2]+, 21), 343
3147, 3113, 3030, 2978,
2933, 2856, 1566, 1509,
0.97 (s, 3 H), 2.23 (s, 3 H), 3.57, 13.8, 22.4 (q, CH3), 40.75, 53.55,
3.60 (2 d, 2 H, J = 14.2), 3.68 (s, 55.0 (t, CH2), 71.5 (s, C), 119.55,
([M+1]+, 100), 342 ([M]+,
9), 219 (11), 185 (57), 171 1447, 1412, 1378, 1289,
(13), 167 (13), 165 (12)
2 H), 4.14, 4.18 (2 d, 2 H, J =
12.6), 5.68 (s, 1 H, OH), 6.81 (s, 128.65 (d, CHarom), 137.65 (s,
1 H), 6.9–7.6 (m, 8 H) Carom), 138.1 (d, CHarom), 138.7,
139.45 (s, Carom
120.60, 127.4, 127.85, 128.45,
1237, 1140, 1107, 1078,
1035, 913, 818, 740, 701,
663
)
468 ([M+2]+, 32), 467
3280, 3108, 3060, 3028,
2937, 2878, 1649, 1603,
3.76 (d, 1 H, J =14), 4.0, 4.2 (2 d, 40.5, 54.2, 54.4 (t, CH2), 76.4 (s,
2 H, J = 14.4), 4.12 (d, 1 H, J = C), 118.65, 119.7166, 124.75,
14), 4.26, 4.30 (2 d, 2 H, J = 12), 125.7, 126.85, 127.45, 128.0,
([M+1]+, 100), 466 ([M]+,
9), 189 (17), 187 (53), 109 1509, 1494, 1454, 1415,
(41), 107 (42), 105 (61)
1288, 1194, 1132, 1107,
1080, 787, 756, 698
6.19 (s, 1 H), 6.36 (s, 1 H), 6.91
(s, 1 H), 7.15–7.45 (m, 14 H),
7.75–7.8 (m, 2 H)
128.15, 128.5, 128.6, 128.75 (d,
CHarom), 133.85 (s, Carom), 137.9
(d, CHarom), 138.15, 140.4,
141.25, 142.15 (s, Carom
)
23a
23b
345 ([M+2]+, 21), 344
([M+1]+, 100), 343 ([M]+,
18), 185 (21)
3219, 3149, 3030, 2977,
2936, 1657, 1566, 1507,
1445, 1412, 1382, 1276,
1245, 1207, 1168, 1137,
1016, 767, 702, 678
0.95 (s, 3 H), 2.23 (s, 3 H), 3.64, 13.75, 22.9 (q, CH3), 40.6, 52.95,
3.70 (2 d, 2 H, J = 14.4), 3.96, 4.0 56.35 (t, CH2), 71.8 (s, C), 119.4,
(2 d, 2 H, J = 14), 4.15, 4.25 (2 d, 127.4, 128.45, 128.7 (d, CHarom),
2 H, J = 12.6), 4.65 (s, 1 H, OH), 137.6, 138.8, 139.65 (s, Carom),
6.92 (s, 1 H), 7.1–7.3 (m, 5 H),
144.45, 151.45 (d, CHarom)
7.88 (s,1 H), 8.0 (s, 1 H)
469 ([M+2]+, 31), 468
([M+1]+, 100), 467 ([M]+,
25), 190 ( 23), 189 (17),
188 (16), 154 (22), 149
(22), 137 (18), 136 (28),
121 (16), 109 (17), 107
(23), 105 (38)
3425, 3192, 3125, 3058,
3027, 2923, 1657, 1601,
1497, 1445, 1413, 1347,
1272, 1192, 1129, 1069,
1014, 753
3.91 (d, 1 H, J = 14.6), 3.95 (d, 1 40.3, 53.85, 55.3 (t, CH2), 76.65
H, J = 14), 4.17 (d, 1 H, J = 14.6), (s, C), 118.65, 124.75, 124.95,
4.27 (d, 1 H, J = 14), 4.39, 4.42 (2 126.95, 127.55, 128.25, 128.55,
d, 2 H, J = 12.8), 4.82 (s, 1 H,
128.6, 128.7, 128.75, 128.8 (d,
OH), 7.2–7.6 (m, 14 H), 7.81 (s, CHarom), 133.7, 138.1, 139.75,
1 H), 7.8–7.85 (m, 3 H)
141.1, 142.35 (s, Carom), 144.2,
151.8 (d, CHarom
)
24
25
26
27
470 ([M+2]+, 21), 469
([M+1]+, 65), 468 ([M]+,
14), 191 (19), 190 (37),
189 (40), 149 (89), 107
(61), 105 (100)
3291, 3104, 3059, 3029,
2925, 2853, 1651, 1603,
1485, 1450, 1424, 1241,
1171, 1102, 1069, 1028,
952, 911, 756, 696, 658
4.04, 4.10 (2 d, 2 H, J = 14.8),
4.19, 4.22 (2 d, 2 H, J = 12.8),
4.44, 4.52 (2 d, 2 H, J = 14.4),
7.2–7.45 (m, 14 H), 7.7–7.75 (m, 128.75, 128.95 (d, CHarom),
2 H), 8.34 (s, 1 H)
40.5, 53.15, 54.95 (t, CH2), 75.75
(s, C), 118.3, 124.85, 125.0,
127.15, 127.55, 128.6, 128.65,
133.35, 137.75, 138.65, 141.5,
142.45 (s, Carom), 143.6 (d,
CHarom
)
470 ([M+2]+, 32), 469
([M+1]+, 100), 468 ([M]+,
33), 189 (22), 154 (44),
149 (68), 107 ( 58), 105
(75)
3489, 3059, 3030, 2922,
2852, 1603, 1489, 1455,
1362, 1329, 1277, 1195,
1152, 1126, 1073, 1023,
888, 749, 699
3.94 (d, 1 H, J = 14.6), 4.18 (d,
40.4, 53.95, 58.65 (t, CH2), 76.95
1 H, J = 14.6), 4.27 (s, 1 H, OH), (s, C), 118.5, 124.8, 125.1,
4.32, 4.40 (2 , 2 H, J = 12.8), 4.48 126.95, 127.5, 128.45, 128.55,
(d, 1 H, J = 14), 5.21 (d, 1 H, J = 128.60, 128.65, 128.75 (d,
14), 7.15–7.45 (m, 14 H), 7.8–
7.85 (m, 2 H), 8.37 (s, 1 H)
CHarom), 133.65, 137.75, 138.6,
141.35, 142.35 (s, Carom), 152.5
(d, CHarom
)
519 ([M+2]+, 35), 518
([M+1]+, 100), 517 ([M]+,
25), 154 (47), 137 (29),
136 (45), 120 (21), 105
(36)
3178, 3136, 3021, 2968,
2940, 1596, 1486, 1447,
1421, 1381, 1172, 1141,
1106, 1068, 747, 691
4.07 (d, 1 H, J = 14.6), 4.15–4.4 40.45, 53.55, 54.6 (t, CH2), 76.9
(m, 4 H), 4.59 (d, 1 H, J = 14.2), (s, C), 109.5, 118.6, 119.8,
4.88 (d, 1 H, J = 14.2), 7.1–7.4
(m, 17 H), 7.45–7.95 (m, 3 H)
124.05, 124.8, 125.1, 126.9,
127.45, 127.65, 128.25, 128.55,
128.6, 128.7, (d, CHarom), 133.75,
137.75, 139.7, 141.25, 142.4,
145.1 (s, Carom
)
519 ([M+2]+, 36), 518
([M+1]+, 100), 517 ([M]+,
30), 190 (23), 154 (74),
137 (29), 136 (66), 120
(20), 107 (23), 105 (29)
3485, 3061, 3029, 2985,
2947, 1604, 1562, 1492,
1456, 1427, 1412, 1359,
1276, 1200, 1167, 886, 749, OH), 7.15–7.45 (m, 16 H), 7.8–
725, 690 7.85 (m, 4 H)
3.93, 4.0 (2 d, 2 H, J = 14.4), 4.22 40.5, 54.05, 61.7 (t, CH2), 76.35
(s, 2 H), 4.76 (d, 1 H, J = 14), (s, C), 117.85, 118.5, 124.75,
5.22 (d, 1 H, J = 14), 5.49 (s, 1 H, 125.35, 126.8, 126.85, 127.35,
128.1, 128.5, 128.75 (d, CHarom),
133.9, 137.7, 139.45, 141.4,
142.15,143.75 (s, Carom
)
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1620
M. Heras et al.
PAPER
Table 10 Prepared Sulfone Derivatives 28–33
were recorded on Bruker DPX200 Advance at 200 and 50 MHz re-
spectively using TMS as internal standard. IR spectra were recorded
on a Nicolet 205FT-IR. MS spectra were recorded on a VG Quattro
instrument in the positive ionization FAB mode, using 3-NBA or 1-
thioglycerol as matrix. Elemental analyses were performed on a
Carlo Erba 1106 elemental analyser instrument. Analytical TLC
was performed on precoated TLC plates, silica gel SIL G/UV254
from Macheray-Nagel. Flash chromatography purifications were
performed SDS silica gel (230–400 mesh).
Producta
R1
Yield
(%)
mp (ºC)
28a
28b
29a
29b
30
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
62
81
65
81
57
78
67
62
86–87
197–198
72–74
109–110
92–94
2-Alkylthioimidazoles 3a–d; General Procedure
To a mixture of thiouronium salt 1a–b (20 mmol) and the appropri-
ate a-haloketone 2a–b (40mmol) in MeCN (100 mL), was added
DIPEA (10.45 mL, 60 mmol) dropwise and the mixture was stirred
at r.t. for 6–8 h. The solution was evaporated to dryness, and the res-
idue was partitioned between EtOAc (150 mL) and H2O (100 mL).
The organic phase was separated, washed with brine (50 mL), dried
(MgSO4) and the solvent evaporated to give a crude material 3a–d
which was purified by flash chromatography using hexanes/EtOAc
(4:1 to 1:1) as eluent (Tables 2 and 3).
31
165–166
147–148
222–223
32
33
a Satisfactory microanalyses obtained: C 0.28, H 0.26, N 0.30.
Crystal Data for 3a24
C24H20N2OS, Mr = 384.49, orthorhombic, space group P212121,
a = 12.630(2), b = 18.828(2), c = 8.406(3) Å, V = 1998.9(8) Å3,
Z = 4, Dc = 1.278 g cm-3, crystal dimensions: 0.27 × 0.40 × 0.40
mm, T = –83 °C, Rigaku AFC5R diffractometer, Mo Ka radiation,
l = 0.71069 Å, m = 0.178 mm-1, w-2q scans, 2qmax = 55°, 5172
measured reflections of which 4176 were unique. Friedel opposites
were recorded for all unique reflections with 2q < 50°. The intensi-
ties were corrected for Lorentz and polarization effects, but not for
absorption. The structure was solved by direct methods using
SHELXS8625 and refined on F by full-matrix least-squares methods
using teXsan.26 H-atoms were in calculated positions. The refine-
ment of 254 parameters using 3026 observed reflections with I >
2s(I) gave R = 0.0427, wR = 0.0309, S = 1.308, Drmax = 0.25
eÅ-3 and absolute structure parameter = 0.04(10).
(18) or 1H-1,2,4-triazole (19) were employed, only one
type of isomers 22a,b and 23a,b were obtained in near
quantitative yields; however, under identical conditions,
the use of the potassium salts of 1H-tetrazole (20) or ben-
zotriazole (21) afforded two types of isomers 24/25 and
26/27, in 1:1 and 2:1 ratios, respectively, as a result of ep-
oxide ring opening through the N-2 atom in the azole moi-
ety. These isomers, 24/25 and 26/27 could easily be
separated by flash-chromatography (Scheme 5, Tables 8
and 9).
Oxidation of 22–27 to the corresponding alcohol sulfones
29–33 with 2.1 equivalents of m-CPBA followed by in-
tramolecular ipso-substitution by treatment with NaH in
THF at room temperature, efficiently furnished 2-azolyl
imidazoxazoles 34–39 in good overall yields (Scheme 6,
Tables 10,11, 12 and 13).
Alcohol Derivatives 7a–c; General Procedure
To a stirred and cooled (0 ºC) solution of 2-alkylthioimidazoles 3a–
c (12 mmol) in MeOH (60 mL) was added NaBH4 (1.14 g, 30
mmol) in small portions while stirring (vigorous evolution of gas
observed). Stirring was continued for 1 h at 0 ºC and at r.t. over-
night. The solution was evaporated to dryness, and the crude residue
was partitioned between EtOAc (100 mL) and aq satd NH4Cl solu-
tion (200 mL). The organic layer was separated, washed with H2O
(50 mL), dried (MgSO4), and evaporated to give a residue which
was purified by flash chromatography using hexanes/EtOAc (9:1 to
4:1) as eluent (Tables 4 and 5).
In summary, we have shown that the reaction between
thiouronium salts of type 1 and a-halocarbonyl com-
pounds 2 under the described conditions efficiently leads
to 2-alkylthioimidazoles 3 in good yields. These com-
pounds are useful precursors in the preparation of novel
2,3-dihydroimidazo[2,1-b][1,3] oxazoles 9 by intramolec-
ular nucleophilic displacement of the 2-sulfonyl deriva-
tives 8. This is the first time that such intramolecular
nucleophilic ipso-substitution reactions using alkylsulfo-
nyl groups as leaving groups in electron rich imidazoles
have been described. Their synthetic applicability in the
preparation of a series of imidazoxazoles 34–39 has been
demonstrated. Further developments of this strategy, in-
cluding the use of polymer-bound thiouronium salts that
may have widespread synthetic utility, are now in
progress in our laboratory and will be published in due
course.
2-(2-Benzylsulfanyl-1-(2-methoxy-2-phenylethyl)-4-phenyl-1H-
imidazole (12)
To a solution of 7a (4.25 g, 11 mmol) in anhyd THF (35 mL) was
added NaH (60% dispersion in mineral oil, 0.48 g, 12.1 mmol) in
small portions at r.t. After the gas evolution had ceased, MeI (2.05
mL, 33 mmol) was added in one portion. The resulting mixture was
stirred at r.t. under N2, for 6 h. The solvent was evaporated and the
resulting residue was partitioned between EtOAc (150 mL) and (50
mL). The organic phase was separated, washed with brine (50 mL),
separated, dried (MgSO4) and filtered. The solvent was evaporated
and the resulting residue purified by flash chromatography (hex-
anes/EtOAc, 14:1) to afford pure 12 as a colourless oil; yield: 4.05
g (92%).
1H NMR (DMSO-d6): d = 3.18 (s, 3 H, OCH3), 3.93 (d, 2 H, J = 5
Hz), 4.1 (t, 1 H, J = 5 Hz), 4.29, 4.35 (2 d, 2 H, J = 12.8 Hz), 7.2–
7.5 (m, 14 Harom), 7.85–7.9 (m, 2 Harom).
All commercially available chemicals were used without prior puri-
fication, except that THF was dried over Na/benzophenone prior to
use. Melting points (capillary tube) were determined using a Gal-
lenkamp apparatus and are uncorrected. NMR (1H and 13C) spectra
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
1621
Table 11 MS, IR and NMR Data of Sulfone Derivatives 28–33
Prod-
uct
MS
m/z (%)
IR (KBr)
n (cm-1
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
)
28a
28b
29a
29b
376 ([M+2]+, 17), 3366, 3143, 2923, 2853,
0.95 (s, 3H), 2.34 (s, 3 H), 3.51 (d, 1 H, 13.7, 22.23 (q, CH3), 53.65, 54.7,
J = 14.2), 3.6 (s, 1 H, OH), 3.67 (dd, 2 62.3 (t, CH2), 70.95 (s, C), 120.6,
375 ([M+1]+,
100), 221 (19),
219 (23)
1653, 1601, 1510, 1456,
1417, 1322, 1253, 1151,
H, J = 14.2), 3.77 (d, 1 H, J = 14.2),
123.2 (d, CHarom), 127.15 (s, Carom),
1120, 1079, 915, 879, 782, 4.65, 4.70 (2 d, 2 H, J= 13.8), 6.75 (s, 1 127.8, 128.65, 129.2, 131.1, 138.1
747, 699
H), 6.81 (s, 1H), 7.0 (s, 1 H), 7.0–7.15 (d, CHarom), 139.25, 139.3 (s, Carom
(m, 2 H), 7.3–7.35 (m, 4 H)
)
500 ([M+2]+, 33), 3453, 3141, 3063, 3033,
3.5 (d, 1 H, J = 14.2), 3.84 (d, 1 H, J = 53.8, 54.95, 62.0, (t, CH2), 75.7 (s,
499 ([M+1]+,
100), 187 (40),
1713, 1604, 1512, 1451,
1403, 1378, 1321, 1291,
14.4), 4.3 (d, J = 14.2), 4.56 (d, 1 H,
C), 119.7, 121.8, 125.3, 125.65,
J = 14.4), 4.9, 5.0, (2 d, 2H, JJ = 13.8), 126.9, 127.95, 128.35, 128.7,
154 (44), 149 (33), 1251, 1238, 1154, 1110,
137 (33), 136 (49) 1081, 919, 766, 745, 697,
637
6.12 (s, 1 H), 6.41 (s, 1 H), 6.88 (s,
1 H), 7.2–7.6 (m, 14 H), 7.8–7.85 (m,
2 H)
129.25, 131.2, 132.35 (d, CHarom),
138.1 (s, Carom), 138.13 (d, CH),
140.2, 140.5, 142.1 (s, Carom
)
377 ([M+2]+, 16), 3244, 3135, 3034, 2979,
0.91 (s, 3 H), 2.31 (s, 3 H), 3.64 (d, 1 H, 13.6, 22.75 (q, CH3), 53.05, 55.4,
J = 14.2), 3.72, 3.78 (2 d, 2 H, J = 14.4), 65.75, (t, CH2), 71.15 (s, C), 123.25
376 ([M+1]+,
2926, 1627, 1554, 1508,
1454, 1418, 1323, 1277,
1248, 1204, 1134, 1014,
912, 879, 783, 730, 699
100), 375 ([M]+,
6), 222 (27), 221
(12), 220 (53)
4.07 (d, 1 H, J = 14.2), 4.22 (s, 1 H,
OH), 4.64, 4.70, (2 d, 2 H, J = 13.8),
(d, CHarom), 127.0 (s, C), 128.6,
129.15, 131.0 (d, CHarom), 139.2,
7.04 (s, 1 H), 7.1–7.3 (m, 5 H), 7.91 (s, 139.3 (s, Carom), 144.55, 151.8 (d,
1 H), 8.02 (s, 1 H).
CHarom)
501 ([M+2]+, 24), 3423, 3128, 3061, 2956,
500 ([M+1]+, 75), 2924, 2853, 1719, 1508,
154 (61), 149 (41), 1457, 1380, 1322, 1276,
137 (53), 136 (76), 1251, 1200, 1155, 1138,
123 (44), 121 (46), 1116, 1072, 1025, 944,
3.64 (d, 1 H, J = 14), 3.79 (d, 1 H, J =
14.6), 4.57 (d, 1 H, J = 14), 4.65, 4.7
54.25, 54.75, 61.95 (t, CH2), 76.15
(s, C), 122.15, 124.9, 125.3, 127.0,
(2 d, 2 H, J = 13.9), 4.72, 4.76 (2 d, 1 H, 128.0, 128.3, 128.7, 128.75, 129.2
J = 14.6), 5.0 (d, 1 H, J = 13.9), 5.01 (s, (d, CHarom), 131.25, 132.3, 139.55,
1 H, OH), 7.25–7.9 (m, 18 H)
140.45 (s, Carom), 142.25, 151.85 (d,
CHarom
109 (77), 105
(100)
767, 696, 677
)
30
31
32
502 ([M+2]+, 31), 3432, 3140, 3061, 3032,
3.79 (d, 1 H, J = 14.8), 4.17 (d, 1 H, J = 53.95, 54.7, 62.0 (t, CH2), 75.15(s,
14), 4.33 (s, 1 H, OH), 4.42 (d, 1 H, J = C), 121.6, 124.95, 125.3 (d, CHarom),
501 ([M+1]+,
100), 500 ([M]+,
8), 154 (50), 149
(75)
2922, 2853, 1716, 1604,
1486, 1451, 1417, 1381,
1329, 1257, 1155, 1110,
1072, 945, 767, 729, 695
14.8), 4.69, 4.72, (2 d, 2 H, J = 14.2),
125.5 (s, Carom), 126.6, 128.15,
4.85 (d, 1 H, J = 14), 7.5–7.1 (m, 14 H), 128.75, 128.9, 129.1, 129.4, 131.2
7.75–7.8 (m, 2 H), 8.23 (s, 1H)
(d, CHarom), 131.95, 138.3, 140.5,
142.45 (s, Carom), 143.5 (d, CH)
502 ([M+2]+, 4),
3468, 3138, 3031, 2922,
3.86 (d, 1 H, J = 14.8), 4.16 (d, 1 H, J = 54.2, 58.3, 61.7 (t, CH2), 75.6 (s, C),
14), 4.44 (s, 1 H, OH), 4.66 (d, 1 H, J = 121.75, 125.1, 125.3 (d, CHarom),
501 ([M+1]+, 12), 2853, 1491, 1452, 1381,
500 ([M]+, 8), 149 1321, 1287, 1246, 1197,
14.8), 4.69 (d, 2 H, J = 13.8), 4.94 (d,
1 H, J = 13.8), 5.27 (d, 1 H, J = 14),
7.15–7.45 (m, 14 H), 7.8–7.85 (m,
2 H), 8.37 (s, 1H)
126.85 (s, Carom), 128.0, 128.55,
128.7, 128.85, 129.1, 131.2 (d,
CHarom), 132.2, 138.45, 140.6, 142.2
(77), 133 (100),
1150, 1113, 1025, 697
119 (57), 109 (77),
107 (72), 105 (96)
(s, Carom), 152.5 (d, CHarom
)
551 ([M+2]+, 15), 3168, 3128, 3063, 2952,
550 ([M+1]+, 42), 1496, 1449, 1386, 1317,
4.65–4.75 (m, 3 H), 4.85 (d, 1 H, J =
13.2), 5.15, 5.25, (2 d, 2 H, J = 14.4),
6.19 (s, 1 H, OH), 7.2–8.0 (m, 20 H)
54.0, 55.45, 61.2 (t, CH2), 76.05 (s,
C), 111.7, 118.85, 121.95, 123.65,
124.75, 125.95, 126.95 (d, CHarom),
127.25 (s, Carom), 127.65, 127.85,
128.15, 128.35, 128.6, 128.85,
131.35 (d, CHarom), 132.55, 134.2,
140.05, 140.45, 141.3, 144.9 (s,
155 (30), 154
(100)
1259, 1206, 1159, 1115,
755, 694
Carom
)
33
551 ([M+2]+, 2),
550 ([M+1]+, 4),
307 (15), 155 (28), 1318, 1279, 1239, 1190,
154 (100), 136
(81)
3433, 3129, 3021, 2976,
2924, 1486, 1448, 1373,
4.17 (dd, 4 H, J = 13.8), 5.14, 5.20 (2 d, 54.4, 61.6, 63.4 (t, CH2), 75.85 (s,
2 H, J = 14), 6.31 (s, 1 H, OH), 7.1–
C), 118.3, 122.25, 125.05, 126.2 (d,
CHarom), 126.9 (s, Carom), 127.6,
127.9, 128.15, 128.45, 128.7, 129.0,
129.15, 131.65 (d, CHarom), 132.9,
140.25, 140.85, 141.75, 144.1 (s,
7.95 (m, 20 H)
1148, 1107, 786, 752, 692
Carom
)
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1622
M. Heras et al.
PAPER
Table 12 Prepared 2,3-Dihydroimidazo[2,1-b][1,3]oxazole Deriva-
tives 34–39
portions. The mixture was stirred under N2 at r.t. for 5 h. The solvent
was evaporated, and the residue was partitioned between EtOAc (30
mL) and H2O (30 mL). The organic layer was separated, washed
with brine (15 mL) and dried (MgSO4). Elimination of the solvent
and purification of the resulting residue by flash-chromatography
(hexanes/EtOAc, 2:1 as eluent) afforded pure 9 as colourless solid.
0.21g, (81%) (Tables 4 and 5).
Compounda R1
Nu
Yield
(%)
mp (ºC)
34a
34b
35a
35b
36
Me
Ph
88
88
77
87
63
colourless oil
2-Benzylsulfonyl-1-(2-methoxy-2-phenylethyl)-4-phenyl-1H-
imidazole (13)
1H NMR (200 MHz, CDCl3): d = 3.12 (s, 3 H, OCH3), 3.85 (dd, 2
H, CH2, J = 13.4 Hz, J’ = 8.4Hz), 4.1–4.25 (m, 1 H), 4.71, 4.75,
4.78 (2 d, 2 H, J = 13.8 Hz), 7.25–7.85 (m, 14 Harom), 7.85–7.9 (m,
2 Harom).
188–189
Me
Ph
colourless oil
149–150 (dec.)
124–126 (dec.)
13C NMR(50 MHz, CDCl3): d = 53.8 (t, CH2), 56.95 (q, CH3), 61.9
(t, CH2), 82.8 (d, CH), 121.75 (s, C), 125.25, 126.4 (d, CHarom),
127.3, (s, Carom), 127.7, 128.35, 128.65, 128.7, 129, 131.15 (d,
CHarom), 132.65, 137.85, 139.85, 141.55, (s, Carom).
IR (KBr): n = 3139, 3033, 2948, 2920, 1701, 1601, 1493, 1455,
1411, 1380, 1329, 1242, 1155, 1016, 786, 759, 737 cm-1.
MS: m/z (%):434 ([M+2]+, 8), 433 ([M+1]+, 100), 432 (([M]+, 10),
279 (13), 277 (10).
Ph
Anal. Calcd for C25H24N2O3S (432.5): C, 69.42; H, 5.59; N, 6.48.
Found: C, 69.76; H, 5.79; N, 6.79.
37
38
Ph
Ph
62
55
160–161 (dec.)
170–171 (dec.)
2-Benzylsulfanyl-4-methyl-1-(2-methyl-2-oxiranylmethyl)-1H-
imidazole (16a)
A mixture containing trimethylsulfoxonium iodide 15 (2.32 g,
10.56 mmol), and NaH (60% dispersion in mineral oil, 0.38g, 9.6
mmol) in DMF (29 mL) was stirred under N2 at r.t. for 1 h. Then, 3a
(2.5 g, 9.6 mmol) was added in one portion. The mixture was stirred
at r.t. for 1 h. DMF was distilled off, and the resulting residue was
partitioned between EtOAc (100 mL) and H2O (20 mL). The organ-
ic layer was separated, washed with brine (20 mL), dried (MgSO4),
filtered, and the solvent evaporated to give crude 16a which was pu-
rified by flash chromatography (hexanes/EtOAc, 4:1); yellowish oil
(1.79 g, 68%) (Tables 6 and 7).
39
Ph
53
252–254 (dec.)
a Satisfactory microanalyses obtained: C ± 0.23, H ± 0.27, N ± 0.30.
2-Benzylsulfanyl-4-phenyl-1-(2-phenyl-2-oxiranylmethyl)-1H-
imidazole (16b)
13C NMR(CDCl3): d = 40.25 (t, CH2), 52.5 (t, CH2), 56.95 (q, CH3),
82.75 (d, CH), 118.3 (s, C), 124.75, 126.5, 126.65, 127.3, 128.35,
128.5, 128.65, 128.85 (d, CHarom), 134.15, 138.0, 138.25, 140.7,
141.9 (6 s, Carom).
A mixture containing trimethylsulfoxonium iodide 15 (2.9g, 13.2
mmol) and NaH (60% dispersion in mineral oil, 0.48 g, 12 mmol)
in DMF (36 mL) was stirred under N2 at r.t for 1 h. Then, the mix-
ture was heated until 50ºC and 3b (4.61 g, 12 mmol) was added in
one portion and the mixture stirred at 50 ºC for 15 h. DMF was dis-
tilled off and the resulting residue was partitioned between EtOAc
(100 mL) and H2O (50 mL). The organic layer was separated,
washed with brine (20 mL), dried (MgSO4), filtered, and evaporated
to give a residue that was purified by flash chromatography (hex-
anes/EtOAc,14:1) to afford 16b as a colourless solid 3.82 g (80%)
(Tables 6 and 7).
IR (film): n = 3061, 3029, 2932, 1605, 1493, 1455, 1434, 1416,
1399, 1371, 1195, 1181, 1106, 1075, 1027, 747, 698 cm-1.
MS: m/z (%) = 402 ([M+2]+, 24), 401 ([M+1]+, 100), 400 (M+, 9),
279 (20), 267 (11), 266 (19), 233 (25).
Anal. Calcd for C25H24N2OS (400.5): C, 74.97; H, 6.04; N, 6.99.
Found: C, 75.08; H, 6.28; N, 7.26.
Oxidation of 2-Alkylthioimidazoles 3b, 7a–c and 12 to the Cor-
responding Sulfones 4, 8a-c, 13; General Procedure
2-Benzylsulfanyl-4-phenyl-1-(2-phenyl-2-oxetanylmethyl)-1H-
imidazole (17)
To a cooled (0ºC) solution of the different 2-alkylthioimidazoles 3b,
7a–c and 12 (10 mmol) in CH2Cl2 (60 mL) was added m-CPBA
(6.66 g, 22 mmol) in small portions. The mixture was then stirred at
r.t. overnight, then diluted with EtOAc (200 mL) and washed with
aq satd NaHCO3 solution (2 × 50 mL) and brine (50 mL). The sep-
arated organic layer was dried (MgSO4), filtered and evaporated to
give a residue which was purified by flash chromatography using
hexanes/EtOAc (from 9:1 to 1:1) as eluent (Tables 2–5).
A mixture containing trimethylsulfoxonium iodide 15 (2.48g, 11.28
mmol), NaH (60% dispersion in mineral oil, 0.43 g, 10.85 mmol),
and DMF (14 mL) was stirred under N2 at r.t. for 1h. Then, the mix-
ture was heated to 90 ºC and 3b (1.67 g, 4.34 mmol) was added in
one portion and stirred at 90ºC for 15 h. DMF was distilled off, and
the resulting residue was partitioned between EtOAc (100 mL) and
H2O (80 mL). The organic layer was separated, washed with brine
(10 mL), dried (MgSO4), filtered and evaporated to give a residue
that was purified by flash chromatography (hexanes/EtOAc, 14:1)
to afford 17 as a colourless oil, 1.45 g (81%), which solidified on
standing (Tables 6 and 7).
2,3-Dihydro-2,6-diphenylimidazo[2,1-b][1,3]oxazole (9)
To a solution of 8a (0.418g, 1 mmol) in anhyd THF (3 mL) was add-
ed NaH (60% dispersion in mineral oil, 0.06g, 1.5 mmol) in small
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles
1623
Table 13 MS, IR and NMR Data of 2,3-Dihydroimidazo[2,1-b][1,3]oxazole Derivatives 34–39
Prod-
uct
MS
m/z (%)
IR (KBr)
n (cm-1
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
)
34a
34b
219 ([M+1]+, 100),
218 ([M]+, 17), 217
(26), 215 (25), 207
(43), 205 (32), 203
(34), 197 (26), 195
(28)
2922, 2853, 1572, 1510,
1449, 1386, 1313, 1284,
1232, 1161, 1081, 780,
749, 701, 664
1.55 (s, 3 H), 2.11 (s, 3 H), 3.83 (s,
2 H), 4.25 (s, 2 H), 6.21 (s, 1 H), 7.05 (t, CH2), 91.34 (s, C), 106.53 (s,
14.56, 23.44 (q, CH3), 51.49, 53.66
(s, 2Harom), 7.53 (s, 1Harom
)
Carom), 120.25, 129.84, 137.94,
139.41 (d, CHarom), 157.54 (s, Carom
)
343 ([M+1]+, 100),
342 ([M]+, 22), 183
(37), 154 (80), 137
(56), 136 (75)
3428, 3128, 3026, 2976,
1577, 1499, 1441, 1373,
1287, 1229, 1176, 1071,
1018, 743, 696
4.37 (s, 2 H), 4.52, 4.55 (2 d, 2 H,
J = 15), 6.83 (s, 1Harom.), 6.9 (s,
1Harom), 6.95 (s, 1Harom), 7.2-7.4 (m, 126.82, 128.49, 129.14, 129.21,
9 H), 7.65–7.70 (m, 2 H) 129.44 (d, CHarom), 134.07 (s, Carom),
137.91 (d, CHarom), 138.41, 143.11,
157.99 (s, Carom
52.77, 55.3 (t, CH2), 94.56 (s, C),
106.22, 120.31, 124.32, 124.43,
)
35a
35b
220 ([M+1]+, 100),
219 ([M]+, 20), 217
(11), 215 (12)
3117, 2922, 2854, 1654,
1572, 1509, 1446, 1387,
1356, 1307, 1275, 1209,
1138, 1016, 959, 904, 786, 14.6), 6.18 (d, 1 H, J = 1.1), 7.9 (s,
750, 701
1.59 (s, 3 H), 2.08 (d, 3 H, JJ = 1.1), 14.52, 23.64 (q, CH3), 51.50, 55.72
3.82 (d, 1 H, J = 9.6), 4.25 (d, 1 H,
J = 9.6), 4.51, 4.55 (2 d, 2 H, J =
(t, CH2), 90.75 (s, C), 106.54,
139.26 (s, Carom), 144.60, 151.92,
157.39 (d, CHarom)
1Harom), 8.22 (s, 1Harom).
344 ([M+1]+, 100),
343 ([M]+, 32), 185
(21), 184 (47), 136
(30), 105 (38)
3405, 3123, 3061, 1604,
1577, 1505, 1445, 1374,
1328, 1274, 1137, 1024,
1001, 786, 678, 650
4.34 (d, 1 H, J = 9.8), 4.74 (s, 2 H),
4.9 (d, 1 H, J = 9.8), 6.7 (s, 1 H),
7.90–7.20 (m, 10Harom), 7.91 (s,
52.36, 56.94 (t, CH2), 93.74 (s, C),
106.2, 124.32, 124.41, 126.7,
129.06, 129.16, 129.27 (d, CHarom),
134.05, 138.33, 142.86 (s, Carom),
144.8, 151.99 (d, CHarom), 157.79 (s,
1Harom), 8.05 (s, 1Harom
)
Carom
)
36
37
38
345 ([M+1]+, 12),
344 ([M]+, 5), 154
(100), 138 (44), 137
(87), 136 (97), 107
(40), 105 (32)
3047, 2970, 2908, 1582,
1481, 1432, 1311, 1186,
1153, 1103, 996, 831, 748, 1Harom), 7.25–7.60 (m, 10Harom),
4.46, 4.50 (2 d, 2 H, J = 10), 5.32,
5.40 (2 d, 2 H, J = 15), 6.82 (s,
52.72, 55.44 (t, CH2), 93.42 (s, C),
106.4, 124.29, 124.37, 126.98,
128.5, 129.46, 129.71 (d, CHarom),
133.73, 137.21 (s, Carom), 143.14 (d,
711, 693
8.74 (s, 1Harom)
CHarom), 143.65, 157.42 (s, Carom
)
345 ([M+1]+, 100),
344 ([M]+, 69), 275
(34), 155 (37), 154
(97), 137 (84), 136
(98)
3135, 3062, 3006, 2959,
1694, 1653, 1584, 1502,
1450, 1410, 1377, 1326,
1306, 1283, 1126, 1023,
885, 748, 702
4.45 (d, 1 H, J = 10), 5.02 (d, 1 H,
J = 10), 5.25, 5.35 (2 d, 2 H, J = 15), 106.05, 124.99, 125.81, 127.98,
50.90, 53.86 (t, CH2), 93.11 (s, C),
6.81 (s, 1Harom), 7.25–7.65 (m,
10Harom), 8.45 (s, 1Harom
128.43, 129.27, 129.49 (d, CHarom),
134.06, 137.84, 143.02 (s, Carom),
153.05 (d, CHarom), 157.98 (s, Carom
)
)
394 ([M+1]+, 10),
393 ([M]+, 5), 307
(15), 155 (30), 154
(100)
3063, 3029, 2978, 2931,
1682, 1586, 1497, 1448,
1374, 1274, 1173, 1103,
1020, 1003, 886, 738, 701
4.42 (d, 1 H, J = 9.8), 5.02 (d, 1 H,
J = 9.8) 5.28, 5.37 (2 d, 2 H, J = 15.4) 106.17, 110.06, 119.64, 124.28,
6.7 (s, 1Harom), 7.2–8.0 (m, 14Harom
52.32, 55.85 (t, CH2), 94.96 (s, C),
)
124.53, 126.63, 128.34, 129.18,
129.28 (d, CHarom), 133.76, 134.05,
138.63, 142.66, 145.57, 157.7 (s,
Carom).
39
394 ([M+1]+, 6), 275 3073, 3030, 2959,, 1692,
5.75 (s, 2 H), 5.83 (s, 2 H), 7.208.0
(m, 15Harom)
61.60, 64.95 (t, CH2), 93.48 (s, C),
104.24 (d, CHarom), 107.15 (s, Carom),
119.64 (d, CH arom), 119.98 (s, Car-
om), 122.64, 126.34, 128.88, 129.10,
129.23, 129.28 (d, CHarom), 135.11,
(20), 149 (100), 133
(30), 132 (20)
1580, 1502, 1454, 1378,
1330, 1280, 1173, 1123,
1020, 1013, 896, 758, 701,
693
137.36, 143.66, 152.80 (s, Carom
)
Epoxide Ring Opening Reaction; Azolyl Derivatives 22–27;
General Procedure
resulting residue was purified by flash chromatography (hexanes/
EtOAc, 9:1 to 100% EtOAc as eluent) (Tables 8 and 9).
To a mixture of the appropriate epoxide 16a,b (1.13 mmol) and the
different azoles 18–21 (4.52 mmol) in DMF (5.6 mL) was added
KOBu-t (0.32 g, 2.82 mmol) at r.t. The resulting mixture was stirred
under N2 at the temperature and time specified in Table 8. DMF was
distilled off and the residue was partitioned between EtOAc (50
mL) and H2O (50 mL). The organic phase was separated, washed
with brine (15 mL), dried (MgSO4), filtered and concentrated. The
Oxidation of 22–27 to Sulfones 28–33; General Procedure
To a cooled, (0 ºC) solution of the corresponding alcohols 22–27
(0.6 mmol) in CH2Cl2 (6 mL) was added m-CPBA (3.99 g, 1.32
mmol) in small portions. The mixture was stirred overnight as the
temperature was increased from 0 ºC to r.t. and then diluted with
EtOAc (50 mL), washed with aq satd NaHCO3 solution (2 × 10
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York

1624
M. Heras et al.
PAPER
mL) and brine (10 mL). The separated organic layer was dried
(MgSO4), filtered and concentrated. The resulting crude material
was purified by flash chromatography (hexanes/EtOAc, 4:1 to
100% EtOAc as eluent) (Tables 10 and 11).
(12) Obrecht, D.; Villalgordo, J. M. Solid-Supported
Combinatorial and Parallel Synthesis of Small-Molecular-
Weight Compound Libraries; Tetrahedron Organic Chemistry
Series, Pergamon: Oxford, 1998.
(13) Obrecht, D.; Grieder, A.; Abrecht, C.; Villalgordo, J. M. Helv.
Chim. Acta 1997, 80, 65.
(14) Chucholowsky, A.; Masquelin, T.; Obrecht, D.; Stadlwieser,
J.; Villalgordo, J. M. Chimia 1996, 50, 525.
(15) Villalgordo, J. M. Meth. Find. Exp. Clin. Pharmacol 1997, 19
(Suppl. A), 37.
Intramolecular ipso-Substitution; 2-Azolyl-2,3-dihydroimid-
azo[2,1b][1,3]oxazole Derivatives 34–39; General Procedure
To a solution of the appropriate alcohol sulfones 28–33 (0.4 mmol)
in anhyd THF (1.5 mL) was added NaH (60% dispersion in mineral
oil, 17.6 mg, 0.44 mmol) in one portion at r.t. H2 gas evolution be-
gan immediately. The mixture was stirred at r.t. under N2 for the
time specified in Table 12. The solvent was removed in vacuo and
the residue was partitioned between EtOAc (50 mL) and H2O (20
mL). The organic phase was separated, washed with brine (15 mL),
dried (MgSO4), filtered, and the filtrate was concentrated. The re-
sulting residue was purified by flash chromatography (hexanes/
EtOAc, 9:1 to 100% EtOAc as eluent) (Tables 12 and 13).
(16) Villalgordo, J. M.; Obrecht, D.; Chucholowsky, A. Synlett
1998, 1405.
(17) Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Lovey, R. G.;
Elliot, A. J.; Guzik, H.; Solomon, D. M.; Conn, D. J.;
Domalski, M. S.; Wong, S.-C.; Gold, E. H.; Long, J. F.; Chiu,
P. J. S.; Steinberg, M.; McPhail, A. T. J. Med. Chem. 1985, 28,
876.
(18) Fos, E.; Bosca, F.; Mauleon, D.; Garganico, G. J. Heterocycl.
Chem. 1993, 30, 473.
Acknowledgement
(19) Stefancich, G.; Silvestri, R.; Artico, M. J. Heterocycl. Chem
1993, 30, 529.
Generous financial support from Ministerio de Educación y Ciencia
(Spain) through project PB94-0509, Medichem S.A. (Barcelona)
and Roviall Química S.L. (Murcia) is gratefully acknowledged.
Thanks are due to Dr. Llüisa Matas (Servei d´Anàlisi, Universitat de
Girona) for recording the NMR spectra and microanalysis and to
Dr. Dolors Pujol (Facultad de Farmacia, Universidad de Barcelona)
and Dr. M. Maestro and Dr. J. Mahía (Servicios Xerais de Apoio á
Investigación, Universidade da Coruña) for recording the mass
spectra.
(20) Shawcross, A.; Stanforth, S. P. J. Heterocycl. Chem. 1993, 30,
563.
(21) Aldabbagh, F.; Bowman, W. R. Tetrahedron Lett. 1997, 38,
3793.
(22) Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron Lett.
1997, 38, 7937.
(23) Hua, D. H.; Zhang, F.; Chen, J.; Robinson, P. D. J. Org. Chem.
1994, 59, 5084.
(24) Crystallographic data (excluding structure factors) for the
structure of 3a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-121745. Copies of the data can be obtained free of
charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. (fax:+441223-336033; email:
deposit@ccdc.cam.ac.uk).
(25) Sheldrick, G. M. SHELXS86. Acta Crystallogr. Sect. A 1990,
46, 467.
(26) teXsan. Single Crystal Structure Analysis Software, Version
1.8. Molecular Structure Corporation: The Woodlands, Texas,
1997.
References
(1) Part of the planned Ph.D. Thesis of M.H. (Universitat de
Girona).
(2) Shepard, R. G.; Fedrick, J. F. Adv. Heterocycl. Chem. 1965, 4,
145.
(3) Vecchietti, V.; Dredi, E.; Lauria, F. J. Chem. Soc. C 1971,
2554.
(4) Franco, F.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem.
1982, 47, 1682.
(27) Johnson, C. K. ORTEPII. Report ORNL-5138, Oak Ridge
National Laboratory, Oak Ridge, Tennessee, 1976.
(5) Zumbrunn, A. Synthesis 1998, 1357.
(6) Grimmett, M. R. Adv. Heterocycl. Chem. 1970, 12, 103.
(7) Grimmett, M. R. Adv. Heterocycl. Chem. 1980, 27, 241.
(8) Preston, P. N. Chem. Rev. 1974, 74, 279.
(9) Brown, D. J.; Ford, P. W. J. Chem. Soc. C 1967, 568.
(10) Barlin, G. B.; Brown, W. V. J. Chem. Soc. C 1967, 2473.
(11) Jarosinski, M. A.; Anderson, W. K. J. Org. Chem. 1991, 56,
4058.
Article Identifier:
1437-210X,E;1999,0,09,1613,1624,ftx,en;P03399SS.pdf
Synthesis 1999, No. 9, 1613–1624 ISSN 0039-7881 © Thieme Stuttgart · New York