Synthesis of isoxazolo[4,5-e][1,4]diazepin-5-ones from 5-acyl-4- (haloacetylamino)isoxazoles

Article abstract of DOI:10.1016/j.mencom.2012.03.011

Treatment of 5-benzoyl-4-(iodoacetylamino)isoxazoles with alcoholic ammonia leads to isoxazolo[4,5-e][1,4]diazepin-5-ones, whereas the analogous chloroacetylamino derivatives are converted into a mixture of the deacylated 4-aminoisoxazoles and isoxazolo- [4,5-d]pyrimidines.

Full text of DOI:10.1016/j.mencom.2012.03.011

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 85–86
Synthesis of isoxazolo[4,5-e][1,4]diazepin-5-ones
from 5-acyl-4-(haloacetylamino)isoxazoles
Victor P. Kislyi,* Evgenia B. Danilova and Victor V. Semenov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: vkislyi@yandex.ru
DOI: 10.1016/j.mencom.2012.03.011
Treatment of 5-benzoyl-4-(iodoacetylamino)isoxazoles with alcoholic ammonia leads to isoxazolo[4,5-e][1,4]diazepin-5-ones,
whereas the analogous chloroacetylamino derivatives are converted into a mixture of the deacylated 4-aminoisoxazoles and isoxazolo-
[4,5-d]pyrimidines.
Although various heterocyclic analogues of 1,4-benzodiazepines
possessing biological activity1,2 have been extensively studied,
information on isoxazolo[1,4]diazepines is limited.3–6 4-Amino-
isoxazole-3-carboxamides 1a,b (Scheme 1), which are available by
cyclization of O-alkylated hydroxyiminonitriles,7,8 we reasoned
herein, could serve as precursors to isoxazolo[4,5-e][1,4]diazepin-
5-ones 3 and/or isoxazolo[4,3-e][1,4]diazepine-5,8-diones. To our
knowledge, no synthesis of isoxazolo[4,5-e][1,4]diazepin-5-ones
3 has been published so far.
Table 1 Ammonolysis of 2a–d (MeOH, 20°C).a
Yields, %
Compound
Time/h Conversion (%)
1
3
4
2a
2b
2c
2d
48
48
72
48
97
95
96.8
98.2
72
0.2
0.3
18
–
–
54
10
97
100
–
2
aYields on converted 2a–d (measured from NMR spectra of the evaporated
reaction mixtures). For experimental details, see Online Supplementary
Materials.
Intermediate haloacetylated compounds 2 were obtained by
heating of aminoisoxazoles 1 with HalCH2C(O)Hal (Hal = Cl, Br)
in toluene in the absence of a base. Although acetylation with
ClCOCH2Cl in the presence of triethylamine proceeds at room
temperature, the chloroacetylated products in this case are con-
taminated with diacetylated ones.
When chloroacetylated derivatives 2 were allowed to react
with ammonia in methanol, a mixtures of parent aminoisoxazole
1, isoxazolodiazepine 3 and isoxazolopyrimidine 4 were obtained.
In the case of aminoisoxazoles 2a,b bearing two electron-with-
drawing groups, deacetylation is the only process (Table 1).
Both N-deacetylation and closure into pyrimidine ring are not
usual reactions for the similar systems. Acyclic aminoacetyl-
amino benzophenones,2 3,4-epoxy-2-quinolones, 3-amino-2(1H)-
quinolones and 3-hydroxyquinolones were previously reported9 as
side products which commonly accompany the preparation of benzo-
diazepines. 3,4-Epoxyquinolones could be prepared with yields up
to 64% by processing in mixture of liquid NH3 and THF.10
It seems reasonable to assume that unusually high rate of
N-deacetylation in case of aminoisoxazoles bearing carbamoyl
substituents results from the low electron density on the nitrogen
atom of amide group. In order to confirm this hypothesis, we
measured the basicities of these compounds spectrophotome-
trically (Table 2). Basicities measured could be compared with
pKa of 4-amino-3,5-dimethylisoxazole (+3.8),11 unsubstituted
isoxazole (–2.28),11 4-nitroaniline (+1.0),12 and 2,4-dinitroaniline
(–4.25).13
As established from UV spectra11(a) of 3-, 4- and 5-amino-
isoxazoles and then confirmed by 15N NMR spectroscopy,11(b)
there is a significant difference in the site of the first protona-
tion and of the metal ion coordination.3 3-Amino and 5-amino-
isoxasoles are protonated at the isoxazole ring nitrogen. In
contrast, 4-aminoisoxazoles are monoprotonated at the amino
group. 4-Aminoisoxazoles bearing electron-withdrawing groups
are considerably weaker bases than 4-nitroaniline and alkyl-sub-
stituted 4-aminoisoxazoles. Low basicities of the amino group
and low electron densities in chloroacetamide moiety correlate
R1
NH2
R1
HN C(O)CH2Hal
HalCH2C(O)Hal
PhMe, 50–80 °C
N
N
C(O)R2
1a–d
C(O)R2
O
O
2a–e
O
Table 2 Basicities of aminoisoxazoles 1a,c,d in sulfuric acid solutions.a
CH2Cl
N
R1
R1
HN
UV spectrum in
MeOH [l/nm (e)]
UV spectrum in
Compound
pKa
NH3
for 2a–d
N
H2SO4b [l/nm (e)]
N
+
1a–d
+
N
N
O
O
R2
1a
1c
360 (13700)
262 (7700)
286 (16000)
284 (16600)
–1.9±0.05
–1.8±0.1
R2
3a–d
4a–d
358 (15 900)
259 (11 900)
227 (19 600)
a R1 = C(O)NH2, R2 = Ph, Hal = Cl
b R1 = C(O)NHBn, R2 = Ph, Hal = Cl
c R1 = R2 = Ph, Hal = Cl
1d
331 (8700)
225 (14400)
230 (15600)
–1.2±0.05
d R1 = Ph, R2 = Me, Hal = Cl
e R1 = C(O)NHBn, R2 = Ph, Hal = Br
a H0 values for different concentrations of sulfuric acid were taken from
ref. 14. b 60% H2SO4 for 1a, 1c and 50% H2SO4 for 1d.
Scheme 1
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 85–86
Table 3 Preparation of 3b at room temperature.
R1
HN C(O)CH2Hal
NH3
NH3
Run
Time/h
Conversion (%)
Ratio 1b:3b
N
C(O)R2
– NH2C(O)CH2Hal
O
1: 2b + NH3
2: 2b + NaIa + NH3
48
24
24
24
95
85
490:1
4.1:1
1:3.1
1:9.9
2
R1
HN C(O)CH2Hal
NH2
R1
NH2
3: 2e + NH3
100
100
N
N
O
C(O)R2
4: 5b + NH3
OH
R2
O
a Equimolar amount of NaI was added.
A
1
R1
HN C(O)CH2Hal
R1
HN C(O)CH2I
NaI,
MeCN
NH3
OH
O
3a–d
R1
R1
NH2
N
N
C(O)R2
C(O)R2
5a–d
15 min
HN
CH2Hal
CH2Hal
O
O
NH
NH
2a–d
N
N
O
O
OH
OH
Scheme 3
R2
R2
– 2 H2O
4
B
C
in case of deactivated and/or sterically hindered systems, iodo-
acetylated derivatives provide better yields of the fused diazepines
than analogous chloroacetylated or bromoacetylated ones.
Other diazepines 3a,c,d were synthesised under the conditions
for preparation of 3b. Isoxazolodiazepine 3d was obtained in good
yield from iodoacetylated compound 5d. 5-Iodomethyl- or 5-amino-
methylisoxazolo[4,5-d]pyrimidine similar to 4d was not detected.
The structures of the prepared compounds were confirmed
by microanalysis, HRMS, H NMR and UV spectral data (see
Online Supplementary Materials).
The procedure developed can be recommended for the prepara-
tion of similar isoxazolo[4,5-e][1,4]diazepin-5-ones from the cor-
responding deactivated electron-poor isoxazole derivatives.
Scheme 2
with high rates of deacetylation, but in case of the direct nucleo-
philic attack of ammonia on carbonyl group of the chloroacetyl
moiety one should expect approximately equal rates of deacetyla-
tion because the basicities of aminoisoxazoles are not different
in fact. However, ammonolysis affords fundamentally different
products at relatively small changes in the amino group basicities.
Based on these findings we assume that the main reaction path-
way (Scheme 2) includes a rapid nucleophilic attack of ammonia
on the ketone group with the formation of the intermediate hemi-
aminal A (aminal group is not strongly electron-withdrawing).
Next, the key intermediate B is formed, which is favoured by
the presence of 3-positioned electron-withdrawing group (e.g.,
carbamoyl) in the isoxazole ring. Further cleavage of the amide
bond results in deacylation to give aminoisoxazoles 1. When
R1 is phenyl, elimination of two water molecules is preferential
to produce isoxazolopyrimidine 4. Since ketone group is more
electrophilic than carbamoyl one, a direct ammonia-assisted
cleavage of amide bond does not make a considerable contribution
in total yields of aminoisoxazoles 1. In case of electron-rich rings
such as benzene, thiophene and similar rings, the ketone group is
insufficiently electrophilic and a halogen substitution proceeds
more quickly than the addition of ammonia to the ketone group.
The bromoacetylated compound 2e and iodoacetylated com-
pound 5b affords predominantly diazepine 3b (Scheme 3, Table 3).†
Iodoacetylated compounds 5a–d were prepared by the Finkelstein
reaction in acetonitrile and isolated before the cyclization.
When the Finkelstein reaction and treatment with ammonia
were conducted sequentially in the same vessel without isolation
of iodoacetylated compound 5b, the parent aminoisoxazole 1b
was predominantly formed (Table 3, run 2). On the other hand,
when the process was carried out in liquid ammonia, iodides gave
lower yields than bromides.16
1
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.03.011.
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yield (3%). An attempt to use hexamethylenetetramine (hexamine)
instead of ammonia under the conditions previously published6,17
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aldehyde produces isoxazolones and dihydropyrimidines. Hence,
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†
General procedure for the preparation of isoxazolo[4,5-e][1,4]diazepines
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Res., Miniprint, 1980, 4777.
3a–d. 5% Methanolic ammonia (4–8 ml) was added to 1 mmol of halo-
acetylated aminoisoxazoles 5a–d or 2e. After 1–2 days, volatiles were
evaporated under vacuum and chromatography on a dry column15 with a
mixture of benzene and ethyl acetate (10:1, then 1:1) as eluent gave, after
recrystallization from ethanol (methanol), the colourless analytical sample
of 3a–d.
Received: 2nd September 2011; Com. 11/3791
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