Ebrahim H.
Ghazvini Zadeh
a,
Bahaa El-Dien M.
El-Gendy
ab,
Alex G.
Pop
a and
Alan R.
Katritzky
*ac
aCenter for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200. E-mail: katritzky@chem.ufl.edu.Address; Fax: +352-392-919; Tel: +352-392-0554
bDepartment of Chemistry, Faculty of Science, Benha University, Benha, Egypt 13511
cDepartment of Chemistry, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
First published on 14th November 2011
Enantiopure N-(Cbz, Fmoc, Boc, or Ac)-1H-1,2,4-triazole- (8a–p, and 8f′) and previously unknown N-Cbz-1,2,4-triazine-derived α-amino acids (11a–d, 11d′, 13a,b, and 13a′) were synthesized using microwave irradiation. Reaction conditions led unexpectedly to simultaneous cyclization, deprotection and acetylation of N-Boc-aminoacylamidrazones 7m,n to afford N-acetyl-1H-1,2,4-triazoles 8o,p.
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Fig. 1 Selected nonproteinogenic α-amino acid-derived 1,2,4-triazoles. |
The most notable protocol used to access such 1,2,4-triazoles is the one devised by Borg and co-workers but this protocol suffers from relatively harsh conditions (180–200 °C), limited versatility and moderate yields.12 We now introduce an efficient microwave-assisted two-step protocol for the synthesis of a variety of chiral N-(Cbz, Fmoc, or Boc)-3-(α-aminoacyl)-1H-1,2,4-triazoles (8a–n, and 8f′) in yields of 54–72% over two steps.‡
In addition, we now disclose a new series of 1,2,4-triazines as new α-amino acid derivatives (11a–d, 11d′, 13a,b, and 13a′) of potentially high proteolytic stability.13–15 Such novel amino acid derivatives may mimic 1,2,4-triazines currently used for treatment of hypertension, inhibition of platelets,16antimalarials,17anticonvulsants,18 antibacterials19 and antidepressants.20
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Scheme 1 Synthetic approach toward the synthesis of N-(Cbz, Fmoc, Boc or Ac)-3-(α-aminoacyl)-1H-1,2,4-triazoles (8a–p, and 8f′). Reagents and conditions: (a) DIPEA (1 equiv) CH3CN, rt., 5 h; (b) CH3CN, reflux, 2 h; (c) HOAc, 130 °C, 1 h; (d) HOAc, microwave (50 W), 140 °C (5 min). |
The reaction of 5 with amidrazone 6 was carried out in dry COMPOUND LINKS
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Download mol file of compoundacetonitrile either at room temperature or with heating to reflux, and yielded 7 as white solids. DIPEA enhanced the rate of the coupling reaction and preserved the base-labile Fmoc group (Table 1).
Entry | Acyl Amidrazone 7 | R1 | Pg | % |
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound1H-1,2,4-triazole 8 |
Pg | % |
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a
HOAc, Δ (1 h).
b microwave (50 W), 130 °C (5 min).
c
HOAc (2%) in COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundethanol, Δ (2 h). d microwave in HOAc (100 W), 180 °C (10 min). |
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1 | a | CH(CH3)2 | Cbz | 73 | a | Cbz | 90a |
2 | b | CH2C6H5 | Cbz | 72 | b | Cbz | 89a |
3 | c | H | Cbz | 85 | c | Cbz | 80b |
4 | d | CH(CH3)CH2CH3 | Cbz | 75 | d | Cbz | 84a |
5 | e | methylene-3-indole | Cbz | 69 | e | Cbz | 90b |
6 | f | CH3 | Cbz | 80 | f | Cbz | 75b |
7 | f′ | CH3 (D,L) | Cbz | 74 | f′ | Cbz | 90a |
8 | g | CH(CH3)2 | Fmoc | 79 | g | Fmoc | 90a |
9 | h | H | Fmoc | 75 | h | Fmoc | 89a |
10 | i | CH2CH(CH3)2 | Fmoc | 71 | i | Fmoc | 80b |
11 | j | CH2OtBu | Fmoc | 77 | j | Fmoc | 84a |
12 | k | CH2Ph | Fmoc | 76 | k | Fmoc | 90b |
13 | l | methylene-3-indole | Fmoc | 72 | l | Fmoc | 75b |
14 | m | H | Boc | 91 | m | Boc | 79c |
15 | n | CH3 | Boc | 71 | n | Boc | 83c |
16 | m | H | Boc | 91 | o | Ac | 90d |
17 | n | CH3 | Boc | 71 | p | Ac | 89d |
The presence of two sets of chemical shifts in the 1H and 13C NMR spectra of acylamidrazones 7 in COMPOUND LINKS
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Download mol file of compoundDMSO-d6 demonstrates the existence of two isomers 7(Z) and 7(E). The free energy of activation (ΔG≠) for 7f was calculated from variable temperature NMR to be 18.2 Kcal/mol (Fig. 2).
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Fig. 2 Isomeric forms 7(Z) and 7(E). |
Cyclization of 7 into COMPOUND LINKS
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Download mol file of compound1H-1,2,4-triazole 8 was examined following different literature procedures.12 Low yields (<10%) of 8 were obtained when 7a–c were heated at their melting points for 20 min,12 or when stirred in conc. H2SO4 for 1 h.12 However, heating 7 at 130 °C in HOAc for 1 h successfully led to 1H-1,2,4- triazoles 8 in 84–90%. Alternatively, microwave irradiation (5 min, 50 W at 140 °C) of 7 in COMPOUND LINKS
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Download mol file of compoundacetic acid (0.3 g/1 mL) accelerated the reaction rate, providing yields of 75–90%.
Cyclization of N-Boc-aminoacylamidrazones 7m,n in boiling COMPOUND LINKS
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Download mol file of compoundacetic acid for 1 h afforded a number of products by TLC. Control over the reaction results was achieved when 7m,n and cat. HOAc were stirred in boiling COMPOUND LINKS
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Download mol file of compoundEtOH, which yielded exclusively N-Boc-3-(α-aminoacyl)-1H-1,2,4-triazoles 8m,n. On the other hand, when 7m,n were subjected to microwave irradiation of 100 W at 180 °C, N-acetyl-1H-1,2,4-triazole-derived amino acids 8o,p were isolated in 89–90% yields, perhaps through simultaneous cyclization, deprotection and acetylation of 7m,n (Scheme 1). HPLC on a Chiralcel-OD column (hexanes: iPrOH, 2:
3) confirmed the enantiomeric purity of 8f (Table 1, entry 6); the L-enantiomer 8f showed a single peak with retention time of 11.59 min, whereas the racemic mixture 8f′ showed two peaks with retention times of 11.60 and 12.54 min (See page 22 in the Supplementary information†).
The synthesis of N-Cbz-α-amino acid-derived 1,2,4-triazines 11a–d, and 11d′ was inspired by the work of Saraswathi.21,22Amino acid hydrazides are important synthetic intermediates and have been used recently for the preparation of azadipeptide nitriles as highly potent and proteolytically stable inhibitors of papain-like COMPOUND LINKS
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Download mol file of compoundcysteine proteases.23 We have used amino acid hydrazides 9a–g,a′,f′ to prepare N-Cbz-α-amino acid-derived 1,2,4-triazines 11a–d,a′ and 13a,b,a′ by reaction with 2,4′-dibromoacetophenone 10 and acenaphthenequinone 12 respectively (Schemes 2 and 3). Firstly, amino acid hydrazides 9 and 2,4′-dibromoacetophenone 10 were heated under reflux in COMPOUND LINKS
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Download mol file of compoundEtOH/HOAc and the reaction was catalyzed by KOAc to afford 1,2,4-triazines 11c,d and 11d′ in 28–43% yields (Scheme 2). The use of microwave irradiation (50 W, 95 °C, 1 h) resulted in cleaner reactions and increased the yield in the cases of 11a,b. HPLC on a Chirobiotic T column (4.6 × 250 mm, flow rate of 0.4 mL/min, COMPOUND LINKS
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Download mol file of compoundMeOH:COMPOUND LINKS
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Download mol file of compoundH2O with 0.1% TFA), confirmed the enantiomeric purity of 11d; the L-enantiomer 11d showed a single peak with retention time of 6.05 min, whereas the racemic mixture 11d′ showed two peaks with retention times of 6.42 and 7.0 min.
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Scheme 2 Route towards the synthesis of N-Cbz-1,2,4-triazine-derived α-amino acids (11a–d, 11d′). Reagents and conditions: (a) NH2NH2.H2O, THF, 15 min, rt; (b) 9 (2 equiv.), KOAc, HOAc, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundEtOH, reflux, 7 h; (c) 9 (2 equiv.) KOAc, HOAc, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundEtOH, microwave (50 W, 95 °C, 1 h). |
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Scheme 3 Synthesis of [1,2-e][1,2,4]triazines 13. |
Zhao and his co-workers reported the synthesis of tri-substituted 1,2,4-triazines using arylhydrazide and 1,2-diones in the presence of excess NH4OAc at 180 °C.24 This method was successful when N-Cbz-amino acid hydrazides 9 and 1,2-acenaphthenedione 12 were heated under microwave irradiation in the presence of 2 equiv. of NH4OAc to prepare N-Cbz-aminoacyl-derived 3,5,6-trisubstituted 1,2,4-triazines 13a,b and 13a′ in 61–68% yields (Scheme 3, Table 3).
Entry | 9 | R1 | 11 | mp (°C) | Yield (%) |
---|---|---|---|---|---|
a
KOAc, HOAc, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundEtOH, microwave (50 W, 95 °C, 1 h). b KOAc, HOAc, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundEtOH, reflux, 7 h. |
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1 | a | CH(CH3)2 | a | 96.0–98.0 | 61a |
2 | b | CH2C6H5 | b | 141.0–143.0 | 40a |
3 | c | H | c | 132.0–134.0 | 43b |
4 | f | CH3 | d | 139.0–140.0 | 28b |
5 | f′ | CH3 (D,L) | d′ | 57.0–59.0 | 30b |
Entry | 5 | Pg | R1 | 9 | mp (°C) | Yield % |
---|---|---|---|---|---|---|
1 | a | Cbz | CH(CH3)2 (L) | a | 163.0–165.025 | 86 |
2 | o | Cbz | CH(CH3)2 (D,L) | a′ | 126.0–128.0 | 90 |
3 | b | Cbz | CH2C6H5 | b | 153.0–155.023 | 94 |
4 | c | Cbz | H | c | 93.0–95.026 | 70 |
5 | d | Cbz | CH(CH3)CH2CH3 | d | 159.0–161.0 | 87 |
6 | e | Cbz | methylene-3-indole | e | 163.0–165.0 | 90 |
7 | f | Cbz | CH3 (L) | f | 111.0–113.026 | 78 |
8 | f′ | Cbz | CH3 (D,L) | f′ | 116.0–118.0 | 80 |
9 | i | Fmoc | CH2CH(CH3)2 | g | 165.0–167.0 | 75 |
Footnotes |
† Electronic supplementary information (ESI) available: Experimental data for compounds. See DOI: 10.1039/c1md00177a |
‡ Example: Synthesis of 8f according to method A: (S)-Benzyl 1-(3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethylcarbamate: A solution of (S)-benzyl (1-(2-(amino(pyridin-2-yl)methylene)hydrazinyl)-1-oxopropan-2-yl)carbamate (0.68 g, 2.0 mmol) in COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundglacial acetic acid (1.00 mL) was heated to reflux for 1 h. The solution was poured over cold brine (20 mL) and the precipitate was filtered and washed with COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundwater. The resulting white solid was suspended in COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundmethanol (5 mL) and was filtered and dried in vacuo to afford the title product as white microcrystals (0.55 g, 1.7 mmol, 86%). mp 156.0–158.0 °C. 1H NMR (COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundDMSO-d6, 300 MHz) δ 14.53 (br s, 1H), 8.68 (d, J = 4.2 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 7.5 Hz, 1H), 7.82 (br s, 1H), 7.49 (t, J = 5.7 Hz, 1H), 7.42–7.22 (m, 5H), 5.04 (s, 2H), 4.85 (quin, J = 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H). 13C NMR (COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundDMSO-d6, 75 MHz) δ 155.6, 149.5, 137.6, 137.1, 128.3, 127.7, 124.6, 121.2, 65.3, 44.8, 20.1. Anal. Calcd. for C17H17N5O2 (323.36): C, 63.15; H, 5.30; N, 21.66. Found: C, 63.10; H, 5.32; N, 21.82. |
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