Facile selective synthesis of 2-methyl-5-amino-1,2,4-oxadiazolium bromides as further targets for nucleophilic additions

Article abstract of DOI:10.1039/c8nj01682h

The reaction of aminonitrones R¹C(NH₂) = N⁺(Me)O^- (R¹ = Alk, Ar) with isocyanides R²NC (R² = Alk, Ar; 1.2 equiv.) and Br₂ (1 equiv.) conducted in CHCl₃ (RT, 5 min) gives 2-methyl-5-amino-1,2,4-oxadiazolium bromides in good to excellent yields (65-95%; 16 examples). These species are highly electrophilically activated and 5-cyclohexylamino-2-methyl-3-phenyl-1,2,4-oxadiazolium bromide, taken as a model compound for the reactivity study, reacts rapidly under mild conditions with hydroxylamine, hydrazine, or benzamidine, to give 5-cyclohexylamino-3-phenyl-1,2,4-oxadiazole (88%), 5-cyclohexylamino-3-phenyl-1,2,4-triazole (95%), and 2-cyclohexylamino-4,6-diphenyl-1,3,5-triazine (64%), respectively. Treatment of the oxadiazolium salt with excess water provides N-benzoyl-N′-cyclohexylurea (95%).

Full text of DOI:10.1039/c8nj01682h

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Facile Selective Synthesis of 2-Methyl-5-amino-1,2,4-oxadiazolium Bromides as
Further Targets for Nucleophilic Additions
Mikhail V. Il’in,a Dmitrii S. Bolotin,a,* Vitalii V. Suslonov,b and Vadim Yu. Kukushkina
a Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab. 7/9, Saint Petersburg, Russian
Federation. Eꢀmail: d.s.bolotin@spbu.ru
b Center for Xꢀray Diffraction Studies, Saint Petersburg State University, Universitetskii Pr., 26, Saint Petersburg,
Russian Federation
Abstract
Reaction of aminonitrones R1C(NH2)=N+(Me)O– (R1 = Alk, Ar) with isocyanides R2NC (R2 = Alk,
Ar; 1.2 equiv.) and Br2 (1 equiv.) conducted in CHCl3 (RT, 5 min) gives 2ꢀmethylꢀ5ꢀaminoꢀ1,2,4ꢀ
oxadiazolium bromides in good to excellent yields (65–95%; 16 examples). These species are
highly electrophilically activated and 5ꢀcyclohexylaminoꢀ2ꢀmethylꢀ3ꢀphenylꢀ1,2,4ꢀoxadiazolium
bromide, taken as a model compound for the reactivity study, react rapidly under mild conditions
with hydroxylamine, hydrazine, or benzamidine, to give 5ꢀcyclohexylaminoꢀ3ꢀphenylꢀ1,2,4ꢀ
oxadiazole (88%), 5ꢀcyclohexylaminoꢀ3ꢀphenylꢀ1,2,4ꢀtriazole (95%), and 2ꢀcyclohexylaminoꢀ4,6ꢀ
diphenylꢀ1,3,5ꢀtriazine (64%), respectively. Treatment of the oxadiazolium salt with excess water
provides NꢀbenzoylꢀN’ꢀcyclohexylurea (95%).

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Cationic azaheterocyclic compounds are of importance due to their substantial synthetic
potential and also their presence in natural products and functional materials.1 Several general
routes to construct such systems include direct protonation, alkylation, or vinylation of a nitrogen
atom of azaheterocycles (Scheme 1, a), formal displacement of the O+ moiety in the cationic
oxoheterocycles (b), heterocyclization via functionalization of sideꢀchain accompanied by addition
to the N atom (c), or cyclization of a sideꢀchain of the acyclic N+ꢀcontaining moiety (d).1eꢀg
R1
R4
R1
R4
b
a
R2NH2
R2X
N
O
–X–
–H2O
R3
R3
R1
R4
R2
N
R3
R1
R2
R3
R1
R4
R2
R3
N
N
d
c
R4
Scheme 1. General routes to cationic azaheterocycles.
Direct derivatization of 1,2,4ꢀoxadiazoles generally yields two isomeric products, namely, 2ꢀ
and 4ꢀsubstituted 1,2,4ꢀoxadiazoles (Scheme 2). While 4ꢀsubstituted 1,2,4ꢀoxadiazoles can be
selectively prepared via the reaction of chloroximes and highly reactive nitrilium salts,2 selective
generation of 2ꢀsubstituted 1,2,4ꢀoxadiazolium salts has not yet been achieved. The only reported
synthetic route to 2ꢀsubstituted 1,2,4ꢀoxadiazolium salts is the alkylation of 1,2,4ꢀoxadiazoles which
required either relatively harsh conditions (Me2SO4, 110 °C, 4 h) or the use of (Me3O)[BF4] (a very
reactive and moistureꢀsensitive alkylation agent) and gave ca. 1:1 mixture 2ꢀalkylꢀ and 4ꢀalkylꢀ
1,2,4ꢀoxadiazolium salts.3
2

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R3
N
O
N
O
N
O
2R3X
–2X–
2
R1
R2
R1
R2
R1
R2
N
N
N
R3
2-Substituted
1,2,4-oxadiazolium salts
4-Substituted
1,2,4-oxadiazolium salts
Scheme 2. The alkylation of 1,2,4ꢀoxadiazoles.
Reactions involving the soꢀcalled isocyanide dihalides, X2C=NR (X = Cl, Br, I; IUPAC
name: carbonimidic dihalides) – generated in situ from isocyanides and X2 (Scheme 3, a) –
typically lead to coupling of the CNR moiety with one (b) or two (c, d) nucleophilic centers
(Scheme 3). These reactions have been employed for generation of some neutral heterocycles
(other than 1,2,4ꢀoxadiazoles),4 but not positively charged heterocyclic systems.
Nu1
X
R
b
N
Nu1 –X–
X
R
X2
c
Nu2
–X–
C
N
R
N
a
X
Nu1
Nu1
R
d
N
Nu2
–2X–
Nu2
Scheme 3. Utilization of isocyanide dihalides for the reaction with two nucleophilic centers.
In this work, we report a novel synthetic strategy for selective generation of 2ꢀsubstituted 5ꢀ
aminoꢀ1,2,4ꢀoxadiazolium salts (R = Me) that is based on condensation between aminonitrones and
isocyanide dibromides. We have also found these 1,2,4ꢀoxadiazolium salts to readily react with
various nucleophiles, viz. hydroxylamine, hydrazine, benzamidine, water, to furnish 1,2,4ꢀ
oxadiazole, 1,2,4ꢀtriazole, 1,3,5ꢀtriazine, or ureide, respectively, in high yields.
3

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For the purpose of finding optimal reaction conditions, PhC(NH2)=N+(Me)O– and CyNC
were chosen as model substrates. Our initial experiments indicated that passing Cl2 through a stirred
solution of the aminonitrone PhC(NH2)=N+(Me)O– and CyNC in acetonitrile (RT, 15 min) gave the
1
expected 2ꢀmethylꢀ5ꢀcyclohexylaminoꢀ1,2,4ꢀoxadiazolium chloride (23% H NMR yield) along
with a mixture of byꢀproducts from which the starting aminonitrone hydrochloride was isolated in
32% yield. We believe that relatively low yield of the desired product obtained in the initial
experiment was due to protonation of the aminonitrone (by HCl formed), which reduced
nucleophilicity of the latter. Therefore we reasoned that addition of a base scavenger might improve
the outcome of the reaction. After substantial experimentation involving variation of base, X2, and
1
solvent we found that substantially better yields (as judged by H NMR) of the target 1,2,4ꢀ
oxadiazoium salt 4 (Scheme 4) were obtained via the use of Et3N and Br2 in CHCl3, whereas much
lower yields were obtained with inorganic bases (M2CO3, M = Na, K, Cs) and Cl2 or I2. While the
1
product yield obtained with Et3N was nearly quantitative (by H NMR; Table 1; Entries 1–2), its
isolation from the reaction mixture presented a problem as it was poorly separable from [Et3NH]Br.
Changing the base to Bn3N solved the problem and the pure product was isolated in 93%. Upon
variation of the reaction time we found that 5 min was sufficient for the completion of the reaction
(Entries 2–4) and the use 1.2 eqiv. of CyNC gave the optimal results (Entries 4–6).
Table 1. Optimization of the reaction conditions.
Br2, R3N,
CHCl3,
conditions
Me
Ph
Me
Ph
O
Br
O
N
N
NH
Cy
C
N
Cy
–[R3NH]Br
N
NH2
4
Yield of
heterocycle
(%)
Equivs.
of CyNC
Duration
(min)
Entry
Base
1
2
3
4
5
6
1.5
1.5
1.5
1.5
1.2
1.0
Et3N
Bn3N
Bn3N
Bn3N
Bn3N
Bn3N
15
15
5
2
5
ca. 100
ca. 100
ca. 100
91
ca. 100
89
5
4

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Having optimized the conditions, we studied the substrate scope of the reaction (Scheme 4).
In general, it proceeded smoothly and furnished 1–16 in good to excellent yields (65–95%). The
nature of R1 substituents in the tested aminonitrones did not significantly affect the yield of the
1
product. The H NMR yield of 1 (prepared from the aliphatic aminonitrone) was 85%, whereas
1
adducts 2–8 (prepared from aromatic aminonitrones) were formed in nearly quantitative H NMR
yields. The nature of R2 group in R2NC displayed a greater influence on the product yield. For the
bulky R2 substituents (11–13), the yields were 80–85% (full conversion). Aryl isocyanides reacted
with the aminonitrones in the presence of Br2 and gave oxadiazolium salts 15–16 in quantitative
yields. Compound 13 appear to be inseparable from adamantyl ammonium bromide, generated as
byꢀproduct, by column chromatography due to similar retention times and by recrystallization and
therefore 13 was characterized in the reaction mixture.
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Br2 (1.2 equiv.);
Me
Me
O
Bn3N (1.0 equiv.);
CHCl3, RT, 5 min
Br
O
N
N
N
C
N
R2
NH
R2
–[Bn3NH]Br
R1
NH2
R1
1–16 (65–95%)
Me
Me
Me
O
N
Br
O
Br
N
N
NH
NH
N
R
1, 72% (85%)
2, R = NMe2, 88% (ca. 100%)
3, R = Me, 93% (ca. 100%)
4, R = H, 93% (ca. 100%)
5, R = Cl, 85% (ca. 100%)
6, R = Br, 92% (ca. 100%)
Me
Me
O
Br
O
Br
N
N
NH
NH
N
N
N
N
7, 90% (ca. 100%)
8, 88% (ca. 100%)
CF3
Me
Me
O
O
N
Br
Br
N
NH
NH
N
N
Me
9, 91% (ca. 100%)
10, 86% (ca. 100%)
Me
Me
O
O
N
Br
Br
N
NH
NH
Me
N
Me
N
Me
Me
Me
Me Me
Me
11, 70% (81%)
12, 65% (80%)
Me
O
N
Br
Me
O
N
Br
NH
S
NH
N
O
N
O
13, (85%)
14, 95% (ca. 100%)
Me
Me
Br
O
N
NH
Me
O
Br
N
N
NH
N
15, 93% (ca. 100%)
16, 90% (ca. 100%)
OMe
Isolated yields are given. 1H NMR yields are given in parentheses.
Scheme 4. Substrate scope for aminonitrones and isocyanides.
6

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Compounds 1–16 were unknown before this work and characterized by HRESI+ꢀMS, IR, 1H
and 13C{1H} NMR spectroscopies (see Supporting Information). In addition, 4 and 6 were studied
by singleꢀcrystal Xꢀray diffraction (Figure 1). These are the first examples of molecular structures
of 2ꢀsubstitutedꢀ5ꢀaminoꢀ1,2,4ꢀoxadiazolium salts and comparison of bond distances in them and
corresponding neutral 5ꢀaminoꢀ1,2,4ꢀoxadiazoles is of interest. Comparison of bond lengths in 4
and 17 (Figure 1; see next section for generation of 17) indicates the shortening of the O(1)–N(1),
C(1)–N(2), and C(2)–N(3) distances in 4 (other bond lengths overlap within 3σ) as compared to 17
most likely because of significant charge delocalization in the 1,2,4ꢀoxadiazole ring and the N atom
of the NHCy moiety of 4.
Bond
4
17
O(1)–N(1)
N(1)–C(1)
C(1)–N(2)
N(2)–C(2)
C(2)–O(1)
C(2)–N(3)
1.402(3)
1.322(4)
1.342(4)
1.331(4)
1.366(4)
1.304(4)
1.4457(14)
1.3129(17)
1.3702(17)
1.3174(17)
1.3522(16)
1.3303(17)
Figure 1. Molecular structures of 4 (top) and 17 (bottom) showing the atomic numbering scheme.
Thermal ellipsoids are given at the 50% level. In the table, selected bond lengths are given.
7

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The charged character of these heterocyclic systems makes them suitable substrates for
reactions with nucleophiles, which are likely to proceed in this case faster compared to nonꢀcharged
congeners.1g In some instances, reaction with nucleophiles can lead to the formation of new
heterocycles via ANRORC rearrangement.5 Azaheterocyclic cations can also react with radical
species, though the radical reactions are substantially less common.6
For neutral 1,2,4ꢀoxadiazoles, ANRORC rearrangements were observed only for ring
systems bearing strong electronꢀwithdrawing groups such as perfluoroalkyl.7 Because of the
positive charge on 2ꢀmethylꢀ5ꢀaminoꢀ1,2,4ꢀoxadiazolium core, these species—by contrast to
uncharged 1,2,4ꢀoxadiazoles—can be expected to be more reactive toward nucleophiles. We found
that 4 was easily transformed to corresponding 5ꢀaminoꢀ1,2,4ꢀoxadiazole (17) and 2ꢀaminoꢀ1,2,4ꢀ
triazole (18) in high yields via [2 + 3]ꢀANRORC reaction (Scheme 5,
a and b, respectively).
Generation of 17 proceeded regioselectively and the isomeric 3ꢀaminoꢀ1,2,4ꢀoxadiazole was not
detected in the reaction mixture. Direct reactions of benzamidoxime and benzamidrazone with
CyNC and Br2 gave complex mixtures of unidentified products at temperature range from –18 to
60 °C in CHCl3, MeCN, or MeOH and corresponding 17 and 18 were not detected in these mixtures
even by HRESIꢀMS. This experiment indicates that 17 and 18 cannot be prepared by this method
starting from amidoximes or amidrazones.
8

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H
N
a
b
O
N
N
N
NH2OH (3 equivs.);
EtOH, reflux, 3 h
NH2NH2 (3 equivs.);
EtOH, reflux, 3 h
NH
NH
N
–[MeNH2OH]Br
–[MeNH2OH]Br
Me
17, 88% (95%)
O
18, 95% (ca. 100%)
Br
N
NH
N
4
O
O
–[MeNH2OH]Br
–[MeNH2OH]Br
N
N
N
NH
H2O:EtOH (1:4, v/v);
reflux, 48 h
PhC(NH2)NH
(3 equivs.);
H
N
NH
EtOH, reflux, 48 h
c
d
19, 64% (76%)
20, 95% (ca. 100%)
Scheme 5. Utilization of 4 for synthesis of aminoheterocycles and ureides.
The reaction of 4 with benzamidine required longer time (48 h vs. 3 h for 17–18; Scheme 5,
) and led to 2ꢀaminoꢀ1,3,5ꢀtriazine 19 (64%; full conversion of 4). This provides an attractive
c
alternative to generation of 2ꢀaminotriazines (like 19) from cyanuric chloride as it involves only
two chemical operations and does not require the use of reactive organometallic species under inert
and dry atmosphere.8
In addition to generation of the fiveꢀ and sixꢀmembered heterocycles, we found that 4 can be
utilized for preparation of acyclic ureides. Compound 4 reacted with excess of H2O (H2O:EtOH
mixture 1:4, v/v, reflux, 48 h) giving ureide 20 in quantitative 1H NMR yield (Scheme 5,
d).
Compounds 17–20 were unknown before this work and characterized by HRESI+ꢀMS, IR,
1H and 13C{1H} NMR spectroscopies, and also by singleꢀcrystal Xꢀray diffraction (see Figure 1 and
Supporting Information).
Condensation of aminonitrones with isocyanide dibromides in presence of an organic base
leads to selective formation of 2ꢀsubstituted 5ꢀaminoꢀ1,2,4ꢀoxadiazolium salts. This is the first
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example of employing isocyanide dihalides for constructions of positively charged heterocyclic
systems. Unlike aldonitrones,9 5ꢀaminoꢀ1,2,4ꢀoxadiazolium salts thus obtained are poorly
represented in current literature and aminonitrones have not been employed in preparation of
charged heterocyclic systems (a handful of literature reports describes redox transformations into
acyclic compounds10 and syntheses of neutral heterocyclic species where aminonitrones act as
nucleophiles10d, 11).
We established that 2ꢀmethylꢀ1,2,4ꢀoxadiazolium salts are substrates for addition of various
nucleophiles (such as hydroxylamine, hydrazine, benzamidine, and water) giving rise to diverse
heterocyclic cores, such as 5ꢀaminoꢀ1,2,4ꢀoxadiazoles, 2ꢀaminoꢀ1,2,4ꢀtriazoles, 2ꢀaminoꢀ1,3,5ꢀ
triazines featured in many biologically active compounds.12
Acknowledgements
This work was supported by Russian Science Foundation (grant 17ꢀ73ꢀ20004). Physicochemical
studies were performed at the Center for Magnetic Resonance, Center for Xꢀray Diffraction Studies,
and Center for Chemical Analysis and Materials Research (all belonging to Saint Petersburg State
University). Prof. Dr. Mikhail Krasavin is thanked for valuable suggestions.
10

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References
1.
(a) B. D. Krane, M. O. Fagbule and M. Shamma, J. Nat. Prod., 1984, 47, 1–43; (b) A.
Schmidt, Adv. Heterocycl. Chem., 2003, 85, 67–171; (c) I. Mancini, A. Sicurelli, G. Guella,
T. Turk, P. Macek and K. Sepcic, Org. Biomol. Chem., 2004, 2, 1368–1375; (d) N. J.
Martin, S. Prado, G. Lecellier, O. P. Thomas and P. Raharivelomanana, Molecules, 2012,
17, 12015–12022; (e) D. Sucunza, A. M. Cuadro, J. AlvarezꢀBuilla and J. J. Vaquero, J.
Org. Chem., 2016, 81, 10126–10135; (f) P. Gandeepan and C. H. Cheng, Chem. Asian J.
,
2016, 11, 448–460; (g) S. Sowmiah, J. M. S. S. Esperança, L. P. N. Rebelo and C. A. M.
Afonso, Org. Chem. Front., 2018, 5, 453–493.
2.
R. AbuꢀElꢀHalawa, P. B. ShresthaꢀDawadi and J. C. Jochims, Chem. Ber., 1993, 126, 109–
116.
3.
4.
M. R. Dobler, Org. Biomol. Chem., 2004, 2, 963–964.
(a) T. Soeta, A. Matsumoto, Y. Sakata and Y. Ukaji, J. Org. Chem., 2017, 82, 4930–4935;
(b) L. El Kaim, L. Grimaud and P. Patil, Org. Lett., 2011, 13, 1261–1263; (c) H. Yu, Y. Z.
Li, Q. Liu, M. S. Zhang and W. L. Sun, Chin. Chem. Lett., 2012, 23, 130–132; (d) B. Mirza,
Tetrahedron Lett., 2016, 57, 146–147.
5.
(a) H. C. Van der Plas, Adv. Heterocycl. Chem., 1999, 74, 1–253; (b) H. C. Van der Plas,
Acc. Chem. Res., 1978, 11, 462–468.
6.
7.
8.
9.
J. Tauber, D. Imbri and T. Opatz, Molecules, 2014, 19, 16190–16222.
A. P. Piccionello, A. Pace and S. Buscemi, Chem. Heterocycl. Comp., 2017, 53, 936–947.
E. Weerapana, R. Banerjee and D. R. Brown, Synlett, 2013, 24, 1599–1605.
(a) I. A. Grigor'ev, Nitrones: novel strategies in synthesis, John Wiley & Sons, Inc., 2008;
(b) L. L. Anderson, Asian J. Org. Chem., 2016, 5, 9–30; (c) N. A. Bokach, M. L. Kuznetsov
and V. Y. Kukushkin, Coord. Chem. Rev., 2011, 255, 2946–2967; (d) A. Brandi, F.
Cardona, S. Cicchi, F. M. Cordero and A. Goti, Chem.–Eur. J., 2009, 15, 7808–7821; (e) C.
Najera and J. M. Sansano, Org. Biomol. Chem., 2009, 7, 4567–4581.
11

New Journal of Chemistry
Page 12 of 13
View Article Online
DOI: 10.1039/C8NJ01682H
10.
11.
(a) H. G. Aurich and J. Trosken, Chem. Ber., 1972, 105, 1216–1223; (b) A. R. Forrester and
R. H. Thomson, J. Chem. Soc., 1965, 1224–1231; (c) B. Trzewik, D. Cież, M. Hodorowicz
and K. Stadnicka, Synthesis, 2008, 2008, 2977–2985; (d) B. Trzewik, T. Seidler, E.
Brocławik and K. Stadnicka, New J. Chem., 2010, 34, 2220–2228.
(a) P. S. Branco, S. Prabhakar, A. M. Lobof and D. J. Williams, Tetrahedron, 1992, 48,
6335–6360; (b) C. Z. Dong, A. AhamadaꢀHimidi, S. Plocki, D. Aoun, M. Touaibia, N.
MeddadꢀBel Habich, J. Huet, C. Redeuilh, J. E. Ombetta, J. J. Godfroid, F. Massicot and F.
Heymans, Bioorg. Med. Chem., 2005, 13, 1989–2007; (c) B. N. Naidu and M. E. Sorenson,
Org. Lett., 2005, 7, 1391–1393; dP. W. Seale and W. K. Warburton, J. Chem. Soc., 1974, 1,
85–88.
12.
(a) A. Pace and P. P., Org. Biomol. Chem., 2009, 7, 4337–4348; (b) M. Ispikoudi, M.
Amvrazis, C. Kontogiorgis, A. E. Koumbis, K. E. Litinas, D. HadjipavlouꢀLitina and K. C.
Fylaktakidou, Eur. J. Inorg. Chem., 2010, 45, 5635ꢀ5645 ; (c) J. V. dos Anjos, R. A. W.
Neves, S. C. do Nascimento, R. M. Srivastava, S. J. de Melo and D. Sinou, Eur. J. Med.
Chem., 2009, 44, 3571–3576; (d) W. Kemnitzer, J. Kuemmerle, H. Z. Zhang, S. Kasibhatla,
B. Tseng, J. Drewe and X. Cai Sui, Bioorg. Med. Chem. Lett., 2009, 19, 4410ꢀ4415; (e) L.
E. Kiss, H. S. Ferreira, L. Torrao, M. J. Bonifacio, P. N. Palma, P. SoaresꢀdaꢀSilva and D.
A. Learmonth, J. Med. Chem., 2010, 53, 3396–3411; (f) R. A. W. Neves Filho, C. Aguiar da
Silva, C. S. Borges da Silva, V. P. Brustein, D. M. A. F. Navarro, F. A. Brayner dos Santos,
L. C. Alves, M. G. S. Cavalcanti, R. M. Srivastava and M. G. CarneiroꢀDaꢀCunha, Chem.
Pharm. Bull., 2009, 57, 819ꢀ825; (g) C.ꢀH. Zhou and Y. Wang, Curr. Med. Chem., 2012, 19,
239–280; (h) R. S. Keri, S. A. Patil, S. Budagumpi and B. M. Nagaraja, Chem. Biol. Drug
Des., 2015, 86, 410–423; (i) R. Kharb, P. C. Sharma and M. S. Yar, J. Enzyme Inhib. Med.
Chem., 2011, 26, 1–21; (j) R. Kharb, M. S. Yar and P. C. Sharma, Curr. Med. Chem., 2011,
18, 3265–3297; (k) P. Singla, V. Luxami and K. Paul, Eur. J. Med. Chem., 2015, 102, 39–
57; (l) S. Batra, Z. Tusi and S. Madapa, Antiinfect. Agents Med. Chem. , 2006, 5, 135–160.
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New Journal of Chemistry
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DOI: 10.1039/C8NJ01682H
Table of contents
Reaction of aminonitrones with isocyanides and Br2 gives 2-methyl-5-amino-1,2,4-oxadiazolium
bromides, which are convenient precursors for other heterocycles and ureides.