New synthesis of 1,4-benzothiazepin-5-ones

Article abstract of DOI:10.1023/B:RUCB.0000042278.14695.b3

A new convenient method for the synthesis of 1,4-benzothiazepin-5-ones by a one-pot procedure including condensation of thiosalicylic acid with chloroacetone and the reaction of the resulting 2-(acetoxythio)benzoic acid without isolation with primary amin

Full text of DOI:10.1023/B:RUCB.0000042278.14695.b3

1232
Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1232—1236, June, 2004
New synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀones ✾
M. A. Mironov,ꢀ M. N. Ivantsova, M. I. Tokareva, V. S. Mokrushin
Urals State Technical University,
1
9 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343) 375 41 35. Eꢀmail: mir@htf.ustu.ru
A new convenient method for the synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀones by a oneꢀpot
procedure including condensation of thiosalicylic acid with chloroacetone and the reaction of
the resulting 2ꢀ(acetoxythio)benzoic acid without isolation with primary amines and isocyanides
is proposed. This method can be used for the combinatorial search of compounds with biologiꢀ
cal activities in the 1,4ꢀbenzothiazepine series.
Key words: Ugi reaction, isocyanides, 1,4ꢀbenzothiazepines, combinatorial synthesis.
In recent years, the number of publications devoted to
Results and Discussion
the preparation of heterocyclic compounds by multicomꢀ
1
ponent reactions has sharply increased. This is due to
There are two basically different approaches to the
synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀones using the Ugi reꢀ
action (Scheme 1).
obvious advantages of oneꢀpot synthetic strategy, which
completely eliminates the losses during isolation and puꢀ
rification of intermediate products. In addition, this apꢀ
proach allows one to vary simultaneously several side subꢀ
stituents, which opens up prospects for highly efficient
screening. The greatest diversity of structures is provided
by a combination of a multicomponent reaction and inꢀ
tramolecular cyclization.2 A combination of intramoꢀ
lecular reactions with the fourꢀcomponent Ugi condenꢀ
sation proved to be especially fruitful. We first used this
approach to synthesize 1,4ꢀbenzothiazepinꢀ5ꢀone derivaꢀ
tives. Benzothiazepines exhibit a broad spectrum of bioꢀ
logical activities (for example, they act as calcium chanꢀ
Path A implies intramolecular arylation of the
mercapto group; therefore mercapto ketone, αꢀhaloꢀ
benzoic acid, amine, and isocyanide should be the comꢀ
ponents of the Ugi reaction. In the other case (path B),
the target heterocycle is formed upon intramolecular alkyꢀ
lation, and a different set of components can be used,
namely, haloketone, thiosalicylic acid, amine, and isoꢀ
cyanide. Most important was the possibility of conductꢀ
ing this synthesis in one step by direct mixing of the initial
components. Due to the absence of any published data, it
was necessary to find out whether reagents with unproꢀ
tected mecrapto groups can be used in the Ugi reaction.
Two control experiments were carried out under condiꢀ
tions standard for the Ugi reaction (equimolar ratio of all
reactants, concentrated methanolic solution, room temꢀ
perature); the reactants were selected in such a way as to
exclude intramolecular cyclization (Scheme 2).
3
4
5
6
nelꢀblocking agents and inhibitors of some enzymes );
this has stimulated studies dealing with the combinatorial
synthesis of these compounds based on a solidꢀstate
strategy.7 The purpose of this work was to develop a comꢀ
binatorial liquidꢀphase synthesis of 1,4ꢀbenzothiazepinꢀ
,8
5
ꢀone derivatives that would be free from the drawbacks
inherent in solidꢀstate methods (large excess of the reꢀ
agents, the use of expensive polymeric materials).9
It was found that with mercaptoketone 1 as the comꢀ
ponent, the Ugi reaction proceeds with lower selectivity
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1183—1187, June, 2004.
066ꢀ5285/04/5306ꢀ1232 © 2004 Plenum Publishing Corporation
1

Synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1233
Scheme 2
Scheme 3
t
t
i. H N—Bn, CN—Bu , PhCOOH; ii. H N—Bn, CN—Bu , Me CO.
2
2
2
1
2
and gives a complex mixture of products. Apparently, in
this case, the competing Asinger condensation predomiꢀ
nates.3 When thiosalicylic acid 2 is condensed with
acetone, tertꢀbutyl isocyanide, and benzylamine, no byꢀ
products are detected (see Scheme 2). The structure of
i.
, K2CO3. ii. R —NC, R —NH2.
4
R1
R2
a
b
c
d
e
f
4ꢀMe NC H
Bn
Furfuryl
2
6
4
4
4
4ꢀMe NC H
2
6
4ꢀMe NC H
4ꢀMeOC H CH
2
6
6
4
2
1
2,4ꢀMeOC H3
PyCH2
compound 3 was proved by H NMR spectroscopy, all
6
2,4ꢀMeOC H3
Furfuryl
1
0
6
signals being assigned by analogy with published data.
2,4,6ꢀMeC H2
4ꢀCF C H CH
6
3
6
4
2
The spectrum exhibited a signal for the free mercapto
group (3.83 ppm), while signals for the dimer of comꢀ
pound 3 were absent. Thus, for the synthesis of target
g
h
i
j
k
l
2,4,6ꢀMeC H2
Cyclopropyl
PyCH2
Cyclopropyl
Bn
6
Ad
Ad
4ꢀMorpholinylꢀC H4
6
1
,4ꢀbenzothiazepinꢀ5ꢀones, we chose path B. However,
4ꢀMorpholinylꢀC H4
4ꢀCF C H CH
6
3
6
4
2
the replacement of acetone by chloroacetone did not reꢀ
sult in the formation of 1,4ꢀbenzothiazepinꢀ5ꢀones. The
reaction gave colored polymeric compounds, whose forꢀ
mation can be attributed to polycondensation of the open
product of the Ugi reaction. This unfavorable reaction
route may be facilitated by high concentrations of the
starting reactants (10—20% solutions). However, the use
of dilute (1—2%) solutions did not furnish the target prodꢀ
ucts, nor did the addition of bases (triethylamine or
potash) to the reaction mixture for increasing the alkylaꢀ
tion rate of the mercapto group.
In view of the results obtained, successive condensaꢀ
tion of four reactants was chosen for the synthesis of the
target products. First, thiosalicylic acid was alkylated with
chloroacetone in a concentrated methanolic solution in
the presence of a base and then the other components,
amine and isocyanide, were added to the same solution
4ꢀMorpholinylꢀC H4
4ꢀMeOC H CH
6 4 2
6
multicomponent synthesis based on mixing of all comꢀ
ponents.
To elucidate the potential provided by the variation of
the side substituents, we synthesized a series of comꢀ
pounds 4a—l (see Scheme 3). The selection of isocyanides
corresponded to general rules applicable to other variants
of the Ugi reaction. The use of isocyanides with electronꢀ
releasing substituents results in high yields of the target
products, while electronꢀwithdrawing substituents deꢀ
crease the reactivity of isocyanides. For example, we were
unable to prepare the 1,4ꢀbenzothiazepinꢀ5ꢀone from
4ꢀnitrophenyl isocyanide. The structures of the comꢀ
pounds 4 formed can be confirmed without difficulty,
because numerous literature analogies are available.7
The mass spectra of 1,4ꢀbenzothiazepinꢀ5ꢀones contain
molecular ion peaks with relatively low (1—10%) intenꢀ
sity, which correspond to the calculated mass. The
,8,11
(
Scheme 3).
The reaction products were purified by parallel flash
chromatography. This variant rules out the intermolecuꢀ
lar alkylation and allows one to reach high yields of
1
H NMR spectra show signals for the side groups (amine
and isocyanide residues) and characteristic signals of the
1
,4ꢀbenzothiazepinꢀ5ꢀones (up to 90%). It is noteworthy
thiazepine ring (two doublets for the CH group in the
2
that cyclization of keto acids is a wellꢀknown and widely
used version of the Ugi reaction.11 However, we were the
first to apply the oneꢀpot strategy that includes the prepaꢀ
ration and further cyclization of a keto acid. The effiꢀ
ciency of this method is not inferior to that of the direct
regions of 4.5—4.0 and 3.0—2.2 ppm with a spinꢀspin
coupling constant of 12—14 Hz).
The transformation we describe is a variant of fourꢀ
component condensation, which obeys the regularities
3
established back in classical Ugi´s works. Indeed, the

1234
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Mironov et al.
1
Table 1. H NMR (DMSOꢀd ) and mass spectra (EI, 70 eV) of 1,4ꢀbenzothiazepinꢀ5ꢀones 4a—l
6
Comꢀ
pound
1H NMR spectrum
Mass spectrum,
m/z (Irel (%))
(δ, J/Hz)
4
a
9.35 (br.s, 1 H, NH); 7.59 (d, 2 H, Ph, J = 7.3); 7.37—7.13 (m, 7 H, Ph and C H S);
445 [M]+ (7), 282 (100),
191 (17), 177 (10), 91 (85)
6
4
6
.75 (d, 2 H, C H NMe , J = 9.2); 6.49 (d, 2 H, C H NMe , J = 9.2); 5.92 (d, 1 H,
6 4 2 6 4 2
NСH Ph, J = 16.2); 4.37 (d, 1 H, NСH Ph, J = 16.2); 4.13 (d, 1 H, SСH ,
2
2
2
J = 11.9); 2.86 (s, 6 H, 2 Me); 2.27 (d, 1 H, SСH , J = 11.9); 1.61 (s, 3 H, Me)
2
4
b
9.31 (br.s, 1 H, NH); 7.51 (dd, 1 H, С H О, J = 1.8, J = 0.8); 7.29—7.13 (m, 4 H,
435 [M]+ (8), 272 (100),
4
3
C H S); 6.77 (d, 2 H, C H NMe , J = 9.2); 6.49 (d, 2 H, C H NMe , J = 9.2);
6
4
6
4
2
6
4
2
6
.45 (d, 1 H, С H О, J = 3.2); 6.39 (dd, 1 H, С H О, J = 3.2, J = 1.8); 5.70 (d, 1 H,
4 3 4 3
NСH Het, J = 16.4); 4.40 (d, 1 H, NСH Het, J = 16.4); 4.19 (d, 1 H, SСH ,
2
2
2
J = 12.2); 2.86 (s, 6 H, 2 Me); 2.53 (d, 1 H, SСH , J = 12.2); 1.72 (s, 3 H, Me)
271 (20), 203 (34), 69 (21)
475 [M] (6), 460 (5),
2
+
4
4
c
d
9.29 (br.s, 1 H, NH); 7.50 (d, 2 H, C H ОMe, J = 8.5); 7.35—7.15 (m, 4 H,
6
4
C H S); 6.87 (d, 2 H, C H ОMe, J = 8.5); 6.76 (d, 2 H, C H NMe , J = 9.0);
312 (100), 284 (71),
121 (92), 107 (16)
6
4
6
4
6
4
2
6
.49 (d, 2 H, C H NMe , J = 9.0); 5.83 (d, 1 H, NСH Ar, J = 15.9); 4.31 (d, 1 H,
6 4 2 2
NСH Ar, J = 15.9); 4.11 (d, 1 H, SСH , J = 12.2); 3.78 (s, 3 H, ОMe); 2.27
2
2
(
d, 1 H, SСH , J = 12.2); 1.61 (s, 3 H, Me)
2
8.80 (d, 1 H, Py, J = 1.8); 8.54 (dd, 1 H, Py, J = 4.7, J = 1.8); 8.34 (br.s, 1 H, NH);
.10 (d, 1 H, Py, J = 4.7); 7.46 (dd, 1 H, Py, J = 4.8, J = 4.7); 7.35—7.19 (m, 4 H,
C H S); 6.92 (d, 1 H, C H (ОMe) , J = 8.8); 6.57 (d, 1 H, C H (ОMe) , J = 2.6);
463 [M]+ (12), 449 (10),
283 (89), 269 (27),
191 (35), 92 (100)
8
6
4
6
3
2
6
3
2
6
5
3
.32 (dd, 1 H, C H (ОMe) , J = 8.8, J = 2.6); 5.14 (d, 1 H, NСH Py, J = 16.3);
6
3
2
2
.02 (d, 1 H, NСH Py, J = 16.3); 4.20 (d, 1 H, SСH , J = 12.9); 3.83 (s, 3 H, ОMe);
2
2
.70 (s, 3 H, ОMe); 2.94 (d, 1 H, SСH , J = 12.9); 1.56 (s, 3 H, Me)
2
4
4
e
f
8.26 (br.s, 1 H, NH); 7.52 (dd, 1 H, С H О, J = 1.8, J = 0.8); 7.24—7.08 (m, 4 H,
C H S); 7.03 (d, 1 H, C H (ОMe) , J = 8.8); 6.48—6.44 (m, 3 H, C H (ОMe) and
С H О); 6.24 (dd, 1 H, C H (ОMe) , J = 8.8, J = 2.6); 5.05 (d, 1 H, NСH Het,
452 [M]+ (9), 436 (5),
272 (100), 271 (19),
204 (64), 176 (13)
4
3
6
4
6
3
2
6
3
2
4
3
6
3
2
2
J = 16.5); 4.96 (d, 1 H, NСH Het, J = 16.5); 4.24 (d, 1 H, SСH , J = 12.6); 3.83
2
2
(
s, 3 H, ОMe); 3.72 (s, 3 H, ОMe); 2.92 (d, 1 H, SСH , J = 12.6); 1.71 (s, 3 H, Me)
2
9.01 (br.s, 1 H, NH); 7.75 (d, 2 H, C H СF , J = 8.2); 7.61 (d, 2 H, C H СF , J = 8.2);
512 [M]+ (11), 493 (8),
350 (100), 351 (21),
159 (81), 137 (5)
6
4
3
6
4
3
7
4
.51—7.27 (m, 4 H, C H S); 6.68 (s, 2 H, C H Me ); 5.31 (d, 1 H, NСH Ar, J = 17.4);
6 4 6 2 3 2
.89 (d, 1 H, NСH Ar, J = 17.4); 4.38 (d, 1 H, SСH , J = 13.4); 3.01 (d, 1 H, SСH ,
2
2
2
J = 13.4); 2.18 (s, 3 H, MeAr); 1.69 (s, 3 H, Me); 1.67 (s, 6 H, Me Ar)
2
4
4
g
h
9.05 (br.s, 1 H, NH); 7.53—7.26 (m, 4 H, C H S); 6.73 (s, 2 H, C H Me ); 4.38 (d, 1 H,
394 [M]+ (4), 232 (100),
6
4
6
2
3
SСH , J = 13.9); 3.23 (d, 1 H, SСH , J = 13.9); 2.78—2.73 (m, 1 H, С H ); 2.15 (s, 3 H,
231(20), 218 (11), 204 (12)
2
2
3
5
MeAr); 1.96 (s, 3 H, Me); 1.71 (s, 6 H, Me Ar); 1.03—0.91 (m, 4 H, С H )
2
3
5
8.67 (s, 1 H, Py); 8.45 (d, 1 H, Py, J = 2.7); 7.96 (d, 1 H, Py, J = 6.6); 7.46
461 [M]+ (1), 283 (100),
284 (19), 135 (12),
92 (68)
(
dd, 1 H, Py, J = 6.5, J = 2.7); 7.37—7.28 (m, 4 H, C H S); 6.42 (br.s, 1 H, NH);
6 4
5
.39 (d, 1 H, NСH Py, J = 16.2); 4.66 (d, 1 H, NСH Py, J = 16.2); 4.13 (d, 1 H,
2 2
SСH , J = 12.9); 2.52 (d, 1 H, SСH , J = 12.9); 1.90 (br.s, 3 H, Ad); 1.59 (br.s,
2
2
1
2 H, Ad); 1.47 (s, 3 H, Me)
4
4
i
j
7.50—7.25 (m, 4 H, C H S); 6.69 (br.s, 1 H, NH); 4.27 (d, 1 H, SСH , J = 12.8);
2
410 [M]+ (2), 232 (88),
231 (20), 190 (13),
135 (100)
6
4
2
.92—2.89 (m, 1 H, С H ); 2.75 (d, 1 H, SСH , J = 12.8); 1.91 (br.s, 3 H, Ad); 1.67
3 5 2
(
br.s, 6 H, Ad); 1.58 (s, 3 H, Me); 1.54 (br.s, 6 H, Ad); 0.91—0.84 (m, 4 H, С H )
3 5
+
9.40 (br.s, 1 H, NH); 7.36—7.12 (m, 9 H, Ph and C H S); 6.82 (d, 2 H, C H N,
487 [M] (7), 443 (5),
6
4
6
4
J = 9.1); 6.69 (d, 2 H, C H N, J = 9.1); 5.91 (d, 1 H, NСH Ph, J = 16.1); 4.38
282 (86), 268 (56),
240 (19), 91 (100)
6
4
2
(
d, 1 H, NСH Ph, J = 16.1); 4.13 (d, 1 H, SСH , J = 12.3); 3.72 (t, 4 H, O(CH ) ,
2 2 2 2
J = 4.6); 3.02 (t, 4 H, N (CH ) , J = 4.7); 2.28 (d, 1 H, SСH , J = 12.3);
2
2
2
1
.61 (s, 3 H, Me)
4
4
k
l
9.37 (br.s, 1 H, NH); 7.83 (d, 2 H, C H СF , J = 7.8); 7.62 (d, 2 H, C H СF ,
J = 7.8); 7.35—7.16 (m, 4 H, C H S); 6.83 (d, 2 H, C H N, J = 8.9); 6.69 (d, 2 H,
C H N, J = 8.9); 5.85 (d, 1 H, NСH Ar, J = 16.4); 4.56 (d, 1 H, NСH Ph,
555 [M]+ (9), 540 (6),
350 (100), 191 (46),
177 (18), 159 (60)
6
4
3
6
4
3
6
4
6
4
6
4
2
2
J = 16.4); 4.21 (d, 1 H, SСH , J = 12.5); 3.72 (t, 4 H, O(CH ) , J = 4.7); 3.02 (t, 4 H,
2
2 2
N (CH ) , J = 4.7); 2.40 (d, 1 H, SСH , J = 12.6); 1.60 (s, 3 H, Me)
2
2
2
9.43 (br.s, 1 H, NH); 7.50 (d, 2 H, C H ОMe, J = 8.5); 7.32—7.13 (4 H, m, 4СH,
517 [M]+ (10), 473 (7),
312 (100), 284 (65),
270 (16), 121 (72),
107 (19)
6
4
C H S); 6.86 (d, 2 H, C H ОMe, J = 8.5); 6.82 (d, 2 H, C H N, J = 9.2); 6.69
6
4
6
4
6
4
(
d, 2 H, C H N, J = 8.9); 5.87 (d, 1 H, NСH Ar, J = 15.9); 4.28 (d, 1 H,
6 4 2
NСH Ar, J = 15.9); 4.10 (d, 1 H, SСH , J = 12.2); 3.78 (s, 3 H, ОCH ); 3.72
2
2
3
(
t, 4 H, O(CH ) , J = 4.6); 3.02 (t, 4 H, N(CH ) , J = 4.6); 2.25 (d, 1 H, SСH ,
2 2 2 2 2
J = 12.2); 1.61 (s, 3 H, Me)

Synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1235
replacement of chloroacetone by bromoacetophenone
results in a sharp decrease in the degree of conversion of
the reactants at the second stage, which precluded isolaꢀ
tion of the target product. The replacement of methanol
by another, less polar solvent also has an adverse effect.
These analogies would enable the proper choice of the
starting compounds and the reaction conditions in the
further development of this method for the preparation of
DMSOꢀd6—CCl4 system with Me4Si as the internal standard.
Mass spectra were recorded on a Varian MAT 311A instrument
at an accelerating voltage of 3 kV and an ionization energy of
7
0 eV with direct sample injection into the ion source. The
melting points were not corrected.
NꢀBenzylꢀNꢀ(1ꢀtertꢀbutylcarbamoylꢀ1ꢀmethylethyl)ꢀ2ꢀmerꢀ
captobenzamide (3). Acetone (0.2 mmol), tertꢀbutyl isocyanide
(
0.2 mmol), and benzylamine (0.2 mmol) were added to a soluꢀ
tion of thiosalicylic acid (0.2 mmol) in methanol (0.25 mL).
After keeping at ~20 °C for 24 h, the reaction mixture was
diluted with water and extracted with chloroform (2 mL), and
the organic layer was separated and applied onto silica gel. The
product was purified by flash chromatography (silica gel 40/5µ,
1
,4ꢀbenzothiazepinꢀ5ꢀone derivatives.
Thus, we proposed an original oneꢀpot method for the
synthesis of 1,4ꢀbenzothiazepinꢀ5ꢀone derivatives based
on a combination of Sꢀalkylation and fourꢀcomponent
Ugi condensation. The scope and limitations and the
routes for further development of this method were eluciꢀ
dated. The method can provide an alternative to the solidꢀ
state syntheses of combinatorial libraries of 1,4ꢀbenzoꢀ
thiazepinꢀ5ꢀones.
elution with a 9 : 1 chloroform—ethanol mixture). Yield 43 mg
1
(
56%), m.p. 127—128 °C. H NMR (DMSOꢀd ), δ: 8.85 (br.s,
6
1
H, NH); 7.40—7.12 (m, 9 H, Ph and C H S); 5.66, 4.46
6 4
(
1
both d, each 1 H, NCH Ph, J = 15.8 Hz); 3.83 (s, 1 H, HS);
.41 (s, 6 H, 2 Me); 1.18 (s, 9 H, Bu ). Found (%): C, 68.54;
2
t
H, 7.27; N, 7.35. C H N O S. Calculated (%): C, 68.75;
2
2
28
2
2
H, 7.29; N, 7.29.
,4ꢀBenzothiazepinꢀ5ꢀones 4a—l (general procedure). Poꢀ
1
Experimental
tassium carbonate (0.22 mmol) and chloroacetone (0.22 mmol)
were added to a solution of thiosalicylic acid (0.22 mmol) in
methanol (0.25 mL). The reaction mixture was stirred for 1 h at
~20 °C and then isocyanide (0.2 mmol) and primary amine
(0.2 mmol) were added. After keeping at ~20 °C for 24 h, the
reaction mixture was diluted with water and extracted with
chloroform (2 mL) and the organic layer was separated and
The reactions were monitored and the product purity was
checked by TLC on Silufolꢀ254 and Sorbfilꢀ254 plates in chloꢀ
roform and chloroform—ethanol solvent systems (9 : 1; 15 : 1;
0 : 1). The H NMR spectra were recorded on a Bruker
DRXꢀ400 spectrometer (400 MHz) in DMSOꢀd6 or in a
1
2
Table 2. Yields, melting points, and elemental analysis data for 1,4ꢀbenzothiazepinꢀ5ꢀ
ones 4a—l
Comꢀ
pound
Yield
(%)
M.p./°С
Found
Calculated
Molecular
formula
(
%)
C
H
N
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
51
55
84
52
64
50
50
36
39
71
91
74
148—149
203—204
180—181
173—174
145—146
163—164
237—238
125—126
105—106
225—226
147—148
152—153
70.05
6.15
6.07
5.71
5.75
6.17
6.11
5.45
5.40
5.39
5.31
5.25
5.27
6.66
6.60
6.68
6.72
7.29
7.31
5.89
5.95
5.13
5.05
6.08
6.00
9.40
9.44
9.75
9.66
8.80
8.84
9.18
9.07
6.38
6.19
5.56
5.47
7.00
7.11
9.03
9.11
6.72
6.83
8.55
8.62
7.64
7.57
8.04
8.12
C H N O S
2
6
27
3
2
7
0.11
66.38
6.21
67.98
8.21
64.95
4.79
63.66
3.72
61.12
0.94
69.93
0.05
70.34
0.28
69.78
0.24
68.81
9.00
62.67
2.70
67.45
7.31
C H N O S
2
4
25
3
3
6
C H N O S
2
7
29
3
3
6
C H N O S
2
5
25
3
4
6
C H N O S
2
4
24
2
5
6
C H F N O S
2
6
27
3
2
2
6
g
h
i
C H N O S
23 26 2 2
7
C H N O S
2
7
31
3
2
7
C H N O S
2
4
30
2
2
7
j
C H N O S
28 29 3 3
6
k
l
C H F N O S
29 28 3 3 3
6
C H N O S
2
9
31
3
4
6

1236
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Mironov et al.
applied onto silica gel. The product was purified by flash
6. J. Slade, J. L. Stanton, D. BenꢀDavid, and G. C. Mazzenga,
J. Med. Chem., 1985, 28, 1517.
7. A. Nefzi, N. A. Ong, M. A. Giulianotti, J. M. Ostresh, and
R. A. Houghten, Tetrahedron Lett., 1999, 40, 4939.
8. M. K. Schwarz, D. Tumelty, and M. A. Gallop, J. Org.
Chem., 1999, 64, 2219.
chromatography (silica gel 40/5µ, elution with a 9 : 1 chloroꢀ
1
form—ethanol mixture). The H NMR and mass spectra of the
obtained compounds are listed in Table 1 and the yields, melting
points, and elemental analysis data are in Table 2.
9
. N. K. Terrett, Combinatorial Chemistry, Oxford University
Press, 1998, 186 p.
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Received December 29, 2003