Superoxide-mediated synthesis of N-aminoaziridines from N-aminoheterocycles and olefins

Article abstract of DOI:10.1080/00397910500214185

Oxidation of 3-amino-2-methyl-4(3H)-quinazolone and N-aminophthalimide by superoxide ion generated in situ in the presence of olefinic substrates gives rise to the formation of N-aminoaziridine derivatives. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500214185

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Superoxide‐Mediated Synthesis
of N‐Aminoaziridines from
N‐Aminoheterocycles and
Olefins
S. Singh a & K. N. Singh a
a Department of Applied Chemistry, Institute of
Technology, Banaras Hindu University, Varanasi, India
Version of record first published: 18 Aug 2006.
To cite this article: S. Singh & K. N. Singh (2005): Superoxide‐Mediated Synthesis of
N‐Aminoaziridines from N‐Aminoheterocycles and Olefins, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:19, 2597-2602
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Synthetic Communicationsw, 35: 2597–2602, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500214185
Superoxide-Mediated Synthesis of
N-Aminoaziridines from
N-Aminoheterocycles and Olefins
S. Singh and K. N. Singh
Department of Applied Chemistry, Institute of Technology,
Banaras Hindu University, Varanasi, India
Abstract: Oxidation of 3-amino-2-methyl-4(3H)-quinazolone and N-aminophthalimide
by superoxide ion generated in situ in the presence of olefinic substrates gives rise to
the formation of N-aminoaziridine derivatives.
Keywords: N-Aminoaziridines, 18-crown-6 ether, olefins, superoxide
Aziridines have attracted considerable attention in recent years because of
their easy conversion into high polymers, their use as aminoalkylating
agents, and their powerful physiological actions.[1–3] There exists a family
of heterocyclic compounds, aminated on nitrogen, whose oxidation in the
presence of alkenes gives N-aminoaziridines.[4] The reactive intermediates
in these oxidations have been assumed to be aminonitrenes.[4] The N-amino-
aziridines are of high synthetic importance because they could provide a new
route to a-hydrazino acids, which are natural constituents of peptide anti-
biotics.[5–7] They also act as inhibitors of enzymes that metabolize the corre-
sponding a-amino acids.[8,9]
Received in India May 10, 2005
Address correspondence to K. N. Singh, Department of Applied Chemistry,
Institute of Technology, Banaras Hindu University, Varanasi 221005, India. E-mail:
knsinghbhu@yahoo.co.in
2597

2598
S. Singh and K. N. Singh
Certain aminonitrenes are capable of adding to olefins to yield N-amino-
aziridines. However, there exist only a few useful syntheses of N-amino-
aziridines. The present study has been undertaken with an objective to assess
the role of superoxide ion[10] and to develop a new synthetic route to
N-aminoaziridines (Scheme 1).
During the present course of reaction, superoxide ion was generated in
situ by the phase-transfer reaction of KO2 with 18-crown-6 ether in sodium-
dried toluene and allowed to react with the substrates, 3-amino-2-methyl-
4(3H)-quinazolone (1) and N-aminophthalimide (2), in the presence of
olefins. As a result, the substrate 1 reacted with cyclohexene, styrene, and
indene to afford 7-(3,4-dihydro-2-methyl-4-oxoquinazolin-3-yl)-7-azabicyclo
[4.1.0] heptane (1a); 1-(3,4-dihydro-2-methyl-4-oxoquinazolin-3-yl)-2-phenyl-
aziridine (1b); and 2,3-benzo-6-(3,4-dihydro-2-methyl-4-oxoquinazoline-3-
yl)-6-azabicyclo [3.1.0] hexane (1c), respectively, whereas the substrate 2
reacted with cyclohexene, styrene, 2,2,4-trimethylpent-2-ene, and mesityl
oxide to provide 7-phthalimido-7-azabicyclo [4.1.0] heptane (2a); 2-phenyl-
1-phthalimido-aziridine (2b); 3-t-butyl-2,2-dimethyl-1-phthalimidoaziridine
(2c); and 3-acetyl-2,2-dimethyl-1-phthalimidoaziridine (2d), respectively,
albeit in low yields (Table 1).
The isolated yields reported in Table 1 were achieved by the use of a 4.0-
fold molar excess of KO2 and a 2.0-fold molar excess of 18-crown-6 over the
substrate 1/2 in toluene. The optimum molar ratio of N-amino compound 1/2
and olefin was 1 : 5. Use of larger amounts of olefin did not improve the yield,
but use of smaller amounts caused a decrease in the yield. Usually the reaction
was conducted for 6–10 h at room temperature under a dry nitrogen atmos-
phere. The mixture was then quenched and worked up to furnish the
product (1a–c and 2a–d). Each reaction was monitored on TLC to check
the completion of the reaction. The products were identified based on their
physical and spectroscopic data.
EXPERIMENTAL
Melting points were measured in open capillaries and are uncorrected. IR
spectra were recorded on a JASCO FT/IR-5300 spectrophotometer. NMR
spectra were run on a JEOL FT-NMR spectrometer FX-90Q and the
chemical shifts are expressed as d/ppm, using TMS as internal reference.
Scheme 1.

Superoxide-Mediated Synthesis
2599
Table 1. Reaction of KO2 with N-amino compounds 1/2 in the presence of olefins
Yieldsa
(%)
Reactant
Product
43
48
37
32
39
55
68
aIsolated mass yields are based on N-amino compounds 1/2.
Potassium superoxide and 18-crown-6 were procured from E. Merck and were
used as received. Dry DMF (Aldrich) was stored over molecular sieves (48A)
prior to use. The substrate 3-amino-2-methyl-4(3H)-quinazolone (1) was
prepared in two steps using literature procedures.[11,12] N-Aminophthalimide
(2) was obtained by the reaction of phthalimide and 96% hydrazine hydrate
in ethyl alcohol.[13] Cyclohexene was prepared from cyclohexanone using
an established method.[14]

2600
S. Singh and K. N. Singh
Reaction of Superoxide Ion Generated in situ with N-Amino
Compounds (1/2) in the Presence of Olefins: General Procedure
Sodium-dried toluene (80 ml) was placed into a three-necked, round-bottom
flask fitted with a dropping funnel, an inlet nitrogen bubbler, a magnetic
stirrer, and a Liebig condenser guarded with a calcium chloride tube.
Potassium superoxide (0.68 g, 0.0096 mol) and 18-crown-6 ether (1.27 g,
0.0048 mol) were weighed under nitrogen atmosphere using an atmosbag
and were transferred into the flask. The olefin (0.012 mol) and N-amino
compound 1/2 (0.0024 mol) were added to the stirred reaction mixture.
Nitrogen was bubbled continuously, and the reaction mixture was stirred mag-
netically for 6–10 h at room temperature until the starting material was
consumed as indicated by TLC. The solvent was removed with a rotary eva-
porator, and the residue was treated with dichloromethane. It was filtered, and
the filtrate was dried over anhydrous sodium sulphate. Evaporation of
the solvent furnished a residue, which was recrystallized or passed through
a column to get the pure aziridine derivative.
Physical and Spectral Data
1a: mp 127–1298C. CHN analysis (%): C15H17N3O(255) calcd. C, 70.59; H,
6.66; N, 16.47. Found C, 70.55; H, 6.61; N, 16.45. IR (KBr, cm21): 778, 1595,
and 1668; 1H NMR (90 MHz, CDCl3): 1.40 (m, 4H, CH2); 2.18 (m, 4H, CH2);
2.60 (m, 5H, CH3 þ CH); 7.50 (m, 3H, ArH); 8.10 (d, 1H, ArH).
1b: mp 1238C. CHN analysis (%): C17H15N3O(277) calcd. C, 73.64; H,
5.41; N, 15.16. Found C, 73.60; H, 5.41; N, 15.13. IR (KBr, cm21): 778,
1
1592, and 1668; H NMR (90 MHz, CDCl3): 2.65 (s, 3H, CH3); 2.88 (dd,
1H); 3.10 (dd, 1H); 3.70 (dd, 1H); 7.45 (s, 5H, ArH); 7.6 (m, 3H, ArH);
8.12 (m, 1H, ArH).
1c: mp 1828C. CHN analysis (%): C18H15N3O(289) calcd. C, 74.74; H,
5.19; N, 15.53. Found C, 74.48; H, 5.24; N, 15.39. IR (KBr, cm21): 781,
1
1698, and 1668; H-NMR (90 MHz, CDCl3): 2.72 (s, 3H, CH3); 3.48 (d, 2H,
CH2); 3.74 (m, 1H); 4.24 (d, 1H); 7.36 (m, 4H, ArH); 7.64 (m, 3H, ArH);
8.18 (m, 1H, ArH).
2a: mp 136–1378C. CHN analysis (%): C14H14N2O2 (242) calcd. C,
69.42; H, 5.78; N, 11.57. Found C, 69.40; H, 5.73; N, 11.54. IR (KBr,
cm21): 710, 720, 890, 992, 1155, 1710 (br), 1765, and 1780; 1H NMR
(90 MHz, CDCl3): 1.35 (m, 4H, CH2); 2.10 (m, 4H, CH2); 2.72 (m, 2H); 7.7
(m, 4H, ArH).
2b: mp 1508C. CHN analysis (%): C16H12N2O2 (264) calcd. C, 72.72; H,
4.54; N, 10.60. Found C, 72.70; H, 4.50; N, 10.55. IR (KBr, cm21): 700, 748,
885, 980, 1150, 1712 (br), 1765, and 1780; 1H NMR (90 MHz, CDCl3): 2.75
(dd, 1H); 2.85 (dd, 1H); 3.5–3.7 (dd, 1H); 7.45 (m, 5H, ArH); 7.70 (m, 4H,
ArH).

Superoxide-Mediated Synthesis
2601
2c: mp 758C. CHN analysis (%): C16H20N2O (272) Calcd. C, 70.58; H,
7.35; N, 10.29. Found C, 70.46; H, 7.41; N, 10.35. IR (KBr, cm21): 700,
778, 888, 980, 1076, 1150, 1725 (br), and 1770; 1H NMR (90 MHz,
CDCl3): 1.18 (s, 9H, 3 ꢀ CH3); 1.28 (s, 3H, CH3); 1.60 (s, 3H, CH3); 2.78
(s, 1H); 7.76 (m, 4H, ArH).
2d: mp 688C. CHN analysis (%): C14H14N2O3 (258) calcd. C, 65.12; H,
5.43; N, 10.85. Found C, 65.20; H, 5.36; N, 10.88. IR (KBr, cm21): 708, 788,
1
880, 980, 1070, 1150, 1712 (br), and 1779; H NMR (90 MHz, CCl4): 1.40
(s, 6H, 2 ꢀ CH3); 2.28 (s, 3H, CH3CO); 3.10 (1H, CH); 7.78 (m, 4H, ArH).
ACKNOWLEDGMENT
The authors are thankful to Council of Scientific and Industrial Research,
New Delhi, India, for financial support.
REFERENCES
1. Atkinson, R. S. In Azides and Nitrenes: Reactivity and Utility; Scriven, E. F. V.,
Ed.; Academic Press: New York, 1984; p. 247.
2. Jones, D. W.; Thornton-Pett, M. Mild thermal route to phthalimidonitrene and its
reaction with activated benzenes to give 2H- and 3H-azepines; X-ray crystal
structure analysis of an isolable 2H-azepine. J. Chem. Soc., Perkin Trans 1
1995, 7, 809–815.
3. Atkinson, R. S.; Barker, E. Aziridination of alkenes using 3-acetoxyaminoquina-
zolin-4-(3H) ones in the presence of tertiary amines: evidence for an azaimide
(N-nitrene) intermediate. J. Chem. Soc., Chem. Commun. 1995, 8, 819–820.
4. Atkinson, R. S.; Grimshire, M. J.; Kelly, B. J. Aziridination by oxidative addition
of N-aminoquinazolones to alkenes: Evidence for non-involvement of N-nitrenes.
Tetrahedron 1989, 45 (10), 2875–2886.
5. Kapron, J. T.; Santarsiero, B. D.; Vederas, J. C. N-Phthalimidoaziridines by dia-
stereoselective addition to a, b,-unsaturated amides: A route to chiral b-substi-
tuted a-hydrazino acid derivatives. J. Chem. Soc. Chem. Commun. 1993, 13,
1074–1076.
6. Schmidt, U.; Riedl, B. The total synthesis of antrimycin Dv. J. Chem. Soc. Chem.
Commun. 1992, 17, 1186–1887.
7. Chen, S.; Chrusciel, R. A.; Nakanishi, H.; Raktabutr, A.; Johnson, M. E.; Sato, A.;
Weiner, D.; Hoxie, J.; Saragovi, H. U.; Greene, M. I.; Kahn, M. Design and
synthesis of a CD4 b-turn mimetic that inhibits human immunodeficiency virus
envelope glycoprotein gp120 binding and infection of human lymphocytes.
Proc. Natl. Acad. Sci. USA 1992, 89, 5872–5876.
8. Scaman, C. H.; Palcic, M. M.; McPhalen, C.; Gore, M. P.; Lam, L. K. P.;
Vederas, J. C. Inhibition of cytoplasmic aspartate aminotransferase from porcine
heart by R and S isomers of aminooxysuccinate and hydrazinosuccinate. J. Biol.
Chem. 1991, 266, 5525–5533.
9. Lam, L. K. P.; Arnold, L. D.; Kalantar, T. H.; Kelland, J. G.; Lane-Bell, P. M.;
Palcic, M. M.; Pickard, M. A.; Vederas, J. C. Analogs of diaminopimelic acid

2602
S. Singh and K. N. Singh
as inhibitors of meso-diaminopimelate dehydrogenase and LL-diaminopimelate
epimerase. J. Biol. Chem. 1988, 263, 11814–11819.
10. (a) Singh, S.; Verma, M.; Singh, K. N. Superoxide ion induced oxidation of
g-lactones to g-ketocarboylic acids. Synth. Commun. 2004, 34 (24), 4471–4475;
(b) Shukla, A. K.; Verma, M.; Singh, K. N. Superoxide-induced deprotection of
1,3-dithiolanes: A convenient method of dedithioacetalization. Indian J. Chem.
2004, 43B, 1748–1752; (c) Shukla, A. K.; Singh, S.; Singh, K. N. Henry and Knoe-
vengel type condensation reactions initiated by tetraethylammonium superoxide in
aprotic medium. Indian J. Chem. 2001, 40B, 391–393; (d) Kumar, R.; Singh, K. N.
Tetraethylammonium bromide-catalysed phase-transfer reaction of potassium
superoxide with hydrazones and tosylhydrazones. Indian J. Chem. 2001, 40B,
579–583.
11. Errede, L. A. Acylanthranils. 1. The pathway of quinazolone formation in the
reaction of acylanthranils with anilines. J. Org. Chem. 1976, 41 (10), 1763–1765.
12. Errede, L. A.; McBrady, J. J.; Oien, H. T. Acylanthranils. 2. The problem of
selectivity in the reaction of acetylanthranils with anilines. J. Org. Chem. 1976,
41 (10), 1765–1768.
13. Drew, H. D. K.; Hatt, H. H. Chemiluminescent organic compounds. Part I.
Isomeric simple and complex hydrazides of phthalic acid and mode of
formation of phthalazine and isoindole rings. J. Chem. Soc. 1937, 16–26.
14. Furniss, B. S.; Hannaford, A. J.; Rogers, V.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry, 4th ed.; ELBS and Longman:
London, 1978; p. 332.