Synthesis of chiral α-amino acid-derived 1 H -1,2,4-triazoles and 1,2,4-triazines

Ebrahim H. Ghazvini Zadeh; Bahaa El-Dien M. El-Gendy; Alex G. Pop; Alan R. Katritzky

doi:10.1039/C1MD00177A

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DOI: 10.1039/C1MD00177A (Concise Article) Med. Chem. Commun., 2012, 3, 52-55

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Synthesis of chiral α-amino acid-derived 1H-1,2,4-triazoles and 1,2,4-triazines†

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

Received 8th July 2011 , Accepted 8th October 2011

First published on 14th November 2011

Abstract

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.

Introduction

In order to develop peptides as therapeutic agents, it is often necessary to introduce structural motifs which improve bioavailability and slow down biodegradation.^1–3 Thus, diverse 1,2,4-triazoles have been designed and synthesized as amide bond isosteres^4–6 or mimics^7,8 to achieve these two important goals. For example, 1,2,4-triazole derivatives of L-tryptophan 1, developed as ghrelin receptor (GHS-R1a) ligands,⁹ which were shown to include potent agonists, partial agonists, and antagonists for the GHS-1a receptor. In addition, lysine scaffolds bearing the 1,2,4-triazolyl moiety 2 have been reported recently as histone deacetylase (HDAC) inhibitors¹⁰ showing high metabolic stability and potency in enzyme and cell-based assays. Moreover, dipeptido-1,2,4-triazole derivatives 3 exhibit high levels of CNS activity similar to the well known pharmaceutical insomnia sedative Triazolam 4 (Fig. 1).¹¹


	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

Results and discussion

The synthesis of N-(Pg)-α-amino acyl conjugates of 1H-1,2,4- triazole was envisaged to involve coupling of N-(Pg)-α-amino acylbenzotriazoles 5 with 2-pyridylamidrazone 6 to afford the corresponding N-(Pg)-α-aminoacylamidrazones 7, followed by cyclization of 7 to 1H-1,2,4-triazoles 8 (Scheme 1).


	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 acetonitrile 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).

Table 1 Percentage yields of aminoacylamidrazones 7a–n, 7f′ and aminoacyl-1H-1,2,4-triazoles 8a–p, and 8f′

Entry	Acyl Amidrazone 7	R¹	Pg	%	1H-1,2,4-triazole 8	Pg	%
a HOAc, Δ (1 h). b microwave (50 W), 130 °C (5 min). c HOAc (2%) in ethanol, Δ (2 h). d microwave in HOAc (100 W), 180 °C (10 min).
1	a	CH(CH₃)₂	Cbz	73	a	Cbz	90^a
2	b	CH₂C₆H₅	Cbz	72	b	Cbz	89^a
3	c	H	Cbz	85	c	Cbz	80^b
4	d	CH(CH₃)CH₂CH₃	Cbz	75	d	Cbz	84^a
5	e	methylene-3-indole	Cbz	69	e	Cbz	90^b
6	f	CH₃	Cbz	80	f	Cbz	75^b
7	f′	CH₃ (D,L)	Cbz	74	f′	Cbz	90^a
8	g	CH(CH₃)₂	Fmoc	79	g	Fmoc	90^a
9	h	H	Fmoc	75	h	Fmoc	89^a
10	i	CH₂CH(CH₃)₂	Fmoc	71	i	Fmoc	80^b
11	j	CH₂O^tBu	Fmoc	77	j	Fmoc	84^a
12	k	CH₂Ph	Fmoc	76	k	Fmoc	90^b
13	l	methylene-3-indole	Fmoc	72	l	Fmoc	75^b
14	m	H	Boc	91	m	Boc	79^c
15	n	CH₃	Boc	71	n	Boc	83^c
16	m	H	Boc	91	o	Ac	90^d
17	n	CH₃	Boc	71	p	Ac	89^d

The presence of two sets of chemical shifts in the ¹H and ¹³C NMR spectra of acylamidrazones 7 in DMSO-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).


	Fig. 2 Isomeric forms 7(Z) and 7(E).

Cyclization of 7 into 1H-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 acetic acid (0.3 g/1 mL) accelerated the reaction rate, providing yields of 75–90%.

Cyclization of N-Boc-aminoacylamidrazones 7m,n in boiling acetic 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 EtOH, 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 [thin space (1/6-em)] :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 cysteine 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 EtOH/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, MeOH:H₂O 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.


	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, EtOH, reflux, 7 h; (c) 9 (2 equiv.) KOAc, HOAc, EtOH, microwave (50 W, 95 °C, 1 h).


	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).

Table 2 Synthesis of N-Cbz-α-amino acid-derived 1,2,4-triazines 11

Entry	9	R¹	11	mp (°C)	Yield (%)
a KOAc, HOAc, EtOH, microwave (50 W, 95 °C, 1 h). b KOAc, HOAc, EtOH, reflux, 7 h.
1	a	CH(CH₃)₂	a	96.0–98.0	61^a
2	b	CH₂C₆H₅	b	141.0–143.0	40^a
3	c	H	c	132.0–134.0	43^b
4	f	CH₃	d	139.0–140.0	28^b
5	f′	CH₃ (D,L)	d′	57.0–59.0	30^b

Table 3 Synthesis of N-Pg-amino acylhydrazides 9

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

Conclusions

α-Amino acid-derived N-(Cbz, Fmoc, Boc, or Ac)-1H-1,2,4-triazoles (8a-p, and 8f′) and previously unknown N-Cbz-1,2,4-triazines (11a–d, 11d′, 13a,b, and 13a′) were synthesized in moderate to high yields with retention of chirality in the case of 8 and 11. We were not able to achieve good separation in the case of 13 using the HPLC columns we have in our laboratory. The devised synthetic protocol for 1H-1,2,4-triazole- (8a–p, and 8f′) is general, scalable, and the reaction conditions are mild, reproducible and compatible with different protecting groups.

Notes and references

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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 glacial 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 water. The resulting white solid was suspended in methanol (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 (DMSO-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 (DMSO-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.