Chemistry and Biological Activity of [1,2,3

Send Orders for Reprints to [email protected] Current Organic Chemistry, 2018, 22, 1-35

1

REVIEW ARTICLE

Chemistry and Biological Activity of [1,2,3]-Benzotriazine Derivatives Ghodsi Mohammadi Ziarani*, Manizheh Mostofi and Negar Lashgari Department of Chemistry, Alzahra University, Tehran, P.O. Box 1993893973, Iran

ARTICLE HISTORY Received: July 30, 2018 Revised: October 29, 2018 Accepted: October 29, 2018 DOI: 10.2174/1385272822666181109123711

Abstract: [1,2,3]-Benzotriazines represent an interesting category of heterocyclic compounds. Various synthetic methods, key reactions and biological aspects have been highlighted. In particular, some analogues have shown antitumor activity. [1,2,3]Benzotriazin-4-one derivatives are applied extensively as herbicides, insecticides and nematicides. Incorporation of these compounds into the human food chain is a cause of concern, since their toxicity to man is well documented. This review is an attempt to discuss synthesis, chemical reactions, applications and pharmacological aspects of [1,2,3]benzotriazine analogues from 1957 till date. Ghodsi Mohammadi Ziarani

Keywords: [1,2,3]- Benzotriazines, [1,2,3]- BenzotriazineN-oxide, [1,2,3]- Benzotriazin-4(3H)-one, 4- Hydroxy- [1,2,3]-benzotriazines, Coupling agent, HOOBt.

1. INTRODUCTION Benzotriazines are six-membered compounds containing three nitrogen atoms, which are annulated with benzene ring. Depending on the position of nitrogen atom, two different benzotriazine systems i.e., [1,2,3]-benzotriazine 1 and [1,2,4]-benzotriazine 2 are possible (Fig. 1). This review focuses on [1,2,3]-benzotriazines and their aromatic derivatives as an interesting category of heterocycles.

methyl-2H-pyrrolium hexachloroantimonate (DOMP) 5 [5, 6] and 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt) 6 (Fig. 2) [7]. N

N

1 N

7

N2

7

6

N3

6

4

5 1

1 N

8

N 4

5

N2

S

S P

MeO

O 8

N

N

N N

OMe

Ph O

Ph P O

O 4

3

3

N

2

Fig. (1). Numbering of two different benzotriazine derivatives 1 and 2.

Heterocyclic compounds constitute a large group of organic molecules exhibiting a wide range of biological activities that are the basis of life and society. The majority of pharmaceutical products that mimic natural products with biological activity are heterocyclic in nature. [1,2,3]-Benzotriazin-4-one is a commonly used motif in a variety of pharmaceutical and agrochemical compounds [1]. For example, azinphos-methyl and azinphos-ethyl are broadly used in agriculture, acaricides in crop protection [2], agriculture insecticides dimethoxy ester of benzotriazinedithiophosphoric acid (DBD) 3 [3, 4]. In addition, they are used as a coupling reagent for the synthesis of polyamides for instance, the activating reagents [(1,2,3-benzotriazine-4-one)-3-yl] diphenyl phosphate (BTDP) 4, 5-(3,4-dihydro-4-oxo-[1,2,3]-benzotriazin-3-yloxy)-3,4-dihydro-1-

Address correspondence to this author at the department of chemistry, Alzahra university, Tehran, Iran; Tel: +982188041344; Fax: +982188041344; E-mail: [email protected], [email protected]

1385-2728/18 $58.00+.00

N

N N O

N N

O

OH

N Me

5

SbCl6

O 6

Fig. (2). Specific aspects of [1,2,3]-benzotriazine derivatives 3-6.

[1,2,3]-Benzotriazine represents a widely used lead structure with multitude of interesting applications in the numerous pharmacological fields; thus, various pharmacological activities have been reported and explored till date [8]. Numerous publications have described the synthesis of [1,2,3]benzotriazines possessing a variety of pharmacological activities, such as anti-inflammatory activity, [9] cardiovascular activity [1013], antitumor activity [14], and dehydrogenase inhibitory activity. For instance, N (3)-(1-R-4-carboxypyrazole-5-yl)-[1,2,3]-benzotriazin-4 (3H)-one 7 [15], possesses central nervous system activity [16-21] and antimicrobial activities [22, 23]. Furthermore, [1,2,3]benzotriazin-4- (3H)-ones 8 have attracted considerable attention because of potential pharmacological properties, such as sedative, © 2018 Bentham Science Publishers

2 Current Organic Chemistry, 2018, Vol. 22, No. 00

Mohammadi Ziarani et al.

N

O

N

OH

N N

Cl

N

N NH

N

O R

N

7

N NH

O

OH

8

9 O

N F

N

N

N

O O 10

Fig. (3). The structure of biologically active benzotriazines 7-10.

N

N N

N

NH2OSO3H, KOH

N NH2

N

60 °C, 12 h

DMF, 20 °C, 6 h

13

12 (83%)

11 N

N

Pb(OAc)4, CH2Cl2

HC

N N

C hu, pyrex, THF

CN

H

CH3

Mercury lamp, 100 W 14 (76%)

15 (40%)

Scheme 1. Transformation of annulated pyrazolamines 12 into annulated trimethyl-5, 8-methano-[1,2,3]-benzotriazine 14.

diuretic, anesthetic, antiarthritic, antitumor, and antitubercular activities in the field of bioorganic and medicinal chemistry [24]. On the other hand, [1,2,3]-benzotriazine compounds showed antitumor activity, partly by increasing free radicals production and partly by depletion of intracellular catalase, glutathione peroxidase, glutathione reductase, and reduced glutathione. Recently, some new [1,2,3]-benzotriazine and their derivatives have been synthesized and used as local anesthetics activity in vivo and exhibited a good activity comparable or superior to that of lidocaine [25]. Some analogues have shown potent pharmacological activity and may be considered as a widely used lead structure with various interesting applications in the multitude pharmacological fields [26]. 4-hydroxy- [1,2,3]-benzotriazines9 showed a significant antitumor activity [27]. S 47445 (8-cyclopropyl-3- [2-(3-fluorophenyl) ethyl]-7,8-dihydro-3H- [1, 3] oxazino[6,5-g][1,2,3]-benzotriazine4,9-dione 10 is an -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors positive allosteric modulator for treating cognitive decline in ageing, dementia, and Alzheimer’s disease (AD) [28]. Also, this compound exhibited antidepressant activity for treating mood disorders (Fig. 3) [29]. This review is an attempt to discuss the chemical reactions, applications and pharmacological aspects of [1,2,3]-benzotriazine analogues systematically reported since 1957 up to now.

2. [1,2,3]-BENZOTRIAZINE DERIVATIVES (4S, 7R)-7,8,8-Trimethyl-4, 5,6,7-tetrahydro-4, 7-methano-2Hindazole 11 and hydroxylamine-O-sulfonic acid underwent reaction

in the presence of KOH to afford 83% yield of (4S, 7R)-7,8,8trimethyl 2-amino-4, 5,6,7-tetrahydro-4, 7-methano-2H-indazole 12. The oxidation of compound 12 with lead tetra acetate furnished (5S, 8R)-8,9,9-trimethyl-5, 6,7,8-tetrahydro-5, 8-methano- [l, 2,3]benzotriazine 14 through the intermediate (4S, 7S)-7,8,8-trimethyl4, 5,6,7-tetrahydro-2H-4, 7-methanoindazol-2-ium-2-ylidene) amide 13. Furthermore, the irradiation of 14 in tetrahydrofuran led to loss of nitrogen to produce 3-ethynylcyclopentane-carbonitrile 15 in quantitative yield (Scheme 1). 5,8-Methano-tetrahydro- [1,2,3]benzotriazine14 was proved to be an excellent central nervous system stimulant [30]. [1,2,3]-Benzotriazine derivatives 17 were prepared through oxidation of 1-amino-1H-indazole 16 with lead tetra acetate. The synthesis of some alkaloids by the Diels-Alder reaction [31] of [1,2,3]-benzotriazine with enamines was investigated. A mixture of [1,2,3]-benzotriazine 17 and pyrrolidineenamine of acetophenone 18 in chloroform in the presence of zinc bromide was heated in a sealed glass tube up to 100°C to afford 2-phenylquinoline derivatives 19 in reasonable yield (Scheme 2) [32]. Takai and coworkers developed a synthetic route for the preparation of piperidine derivatives with [1,2,3]-benzotriazine at the 4-position. Upon the treatment of 2-nitrobenzaldehyde 20 with 4-aminopiperidine 21 in ethanol the intermedite22 was obtained. Afterward, the reaction of the intermediate 22 with the corresponding bromo-ketones 23 led to the Schiff bases 24. The latter compound was reduced with NaBH4 to give the product 25. Then, catalytic hydrogenation of 25 in the presence of Pd-C and Raney nickel

Chemistry and Biological Activity of [1,2,3]-Benzotriazine Derivatives

Current Organic Chemistry, 2018, Vol. 22, No. 00 3

R4 R3

R3

N N

1) Pb(OAc)4, CaO CH2Cl2, - 8 °C, 1.5 h

H N N

N

R2

R1 ZnBr2, CHCl3 Seald glass tube 90-100 °C, 2 h

17 (55-65%)

16

R2 CH2 18

N N

R1

2) r.t., 3 h

R1

R4

19 (40-69%)

R1, R2, R3, R4= H, OMe R2, R3= OCH2O Scheme 2. Synthesis of [1,2,3]-benzotriazines 17 from indazoles 16 and Diels-Alder reaction with pyrrolidineenamines 18.

O X NO2

NH2

H + HN

NO2

Br

EtOH

23 N

Reflux, 4-5 h

O

TEA, EtOH Reflux, 5-6 h

NH

20

21

22 HO

NO2

X HN

NaBH4 N

N X

24 (45-60%)

N

EtOH, r.t., 2 h NO2

O

25 (50-67%) N N

NH2

N

H2 (g, 50 psi) Pd/C (10%) Raney Ni

NaNO2, HCl HN

N

N

0 °C, 2 h X HO

HO X= H, Cl, Br

26 (33-50%)

27 (58-63%) X

Scheme 3. Synthesis of piperidine derivatives with [1,2,3]-benzotriazine at the 4-position 27.

produced 26. Finally, 1-(2-Phenyl-2-hydroxyethyl)-4-(3,4-dihydro[1,2,3]-benzotriazin-3-yl) piperidine 27 was obtained by diazotization and cyclization of 26 (Scheme 3). Further, the [1,2,3] benzotriazine derivatives 27 were screened for antihypertensive, antiinflammatory and antiulcer activity in spontaneously hypertensive, female Wistar strain and male Wistar strain rats, respectively.The results showed that the hypertensive activity for the synthesized compounds were relatively small compared with those of quinazolnone derivatives. Meanwhile, the compounds exhibited good anti-inflammatory and antiulcer activity. The minimum effective dose of inhibition was about 50mg/kg [33].

immediately underwent intramolecular cyclization to give the corresponding (dihydro- [1,2,3]-benzotriazinyl) lithium intermediates 31, which were trapped with a variety of acylating agents 32 or 33 exclusively to provide the desired products in moderate to good yields. Also,introduction of an alkyl group at the 3-position of 3,4dihydro-[1,2,3]-benzotriazine was subsequently carried out after the treatment of 28 with BuLi 29 as described. BnBr 35 was added for the preparation of 36. However, benzylation proceeded slowly even at room temperature, and the corresponding desired products 34 and 36 were isolated in low-to-moderate yields (Scheme 4) [34]. 2.2. [1,2,3]-Benzotriazin-4 (3H)-one Derivatives

2.1. 3-Substituted [1,2,3]-Benzotriazine Derivatives

2.2.1. 3-Hydroxy- [1,2,3]-Benzotriazin-4 (3H)-one

An efficient one-pot procedure for the preparation of 3substituted 3,4-dihydro- [1,2,3]-benzotriazine derivatives 34 and 36 from 2-bromobenzyl azides 28 was described. The reaction of these azides with BuLi 29 in THF at -78 °C generated o-lithiobenzylazides 30 via the Br/Li exchange. These lithium compounds

Lu and Liu developed a route to polyamides 41 based on the polycondensation of a typical active diester, 3,3´-(isophthaloyldioxy) bis(4-oxo-3,4-dihydro-[1,2,3]-benzotriazine) 38. The active diester 38 was obtained by the treatment of HOOBt 6 and isophthaloyl chloride 37 in aprotic solvents. Finally, the active di-



R2COCl or (R2CO)2 32 33

N

N3

R1

Li

BuLi 29

N N3

THF, -78 °C, 5 min

34 (54-83%) BnBr

R1

30 (70-80%)

28

N

O

NLi

R1

R1

R2

N

THF, -78 °C-r.t., 12 h Br

N

N

35

31 (60-75%)

N N

THF, -78 °C- r.t., 12 h

Bn

R1

R1= H, Me, C6H5 R2= Me, EtO, t-BuO, C6H5, 2-ClC6H4, 2-MeC6H4

36 (38-44%)

Scheme 4. Reaction of o-bromobenzylazides 28 with butyllithium.

N

O

O

N

N N

NEt3, DMF

+ Cl OH

Cl

N THF, 0-10 °C, 2 h

O

O

O

6

N O

O

O

N

N

N

N O

38 (88%)

37

O

O

N

Me 39

+ 2 NH

H2N-R-NH2 40 DMSO, r.t., 48 h

R

N

NH

O

N OH

O

n

6

41 (72%) R= -(CH2)6-, -C6H4-O-C6H4-

Scheme 5. Synthesis of polyamides 41 from active O, O´-diacyl derivatives 38 of N-hydroxy compounds 6 and diamines 40 under mild conditions.

N

OC

6

CO

OC Re

Br

Br

Br

N N

2-

N OH

N N

O

NEt4

O

2 NEt4

O KOH, MeOH r.t., 12 h

Br

Re OC CO CO

43 (72%)

42

N N N

AgBF4, ROH 44 r.t., 1 h R= H, Me, Et

N

N

O O

O

OR OC CO CO

O

Re

OC CO CO n 45

N

Re

46 (80%)

Scheme 6. Synthesis of a Re (CO)3 complex 43 using a bridging ligand 3-hydroxy- [1,2,3]-benzotriazin-4 (3H)-one 6 and the metallamacrocycle 46.

ester 38 was reacted with diamines 40 under mild conditions at room temperature in the presence of N-methyl-2-pyrrolidone 39 and organic solvents such as dimethyl sulfoxide without any catalyst (Scheme 5) [35].

Severin and coworkers synthesized the ionic rhenium complex [ReBr (C7H4N3O2)(CO)3][NEt4]2 43 through the reaction of [ReBr3 (CO) 3][NEt4]2 42 with HOOBt 6 in the presence of base KOH. In order to induce macrocyclization, the remaining bromo ligand of



N

N N O

N 3

NEt3, THF

N N

O O

+ Fe(NO3)3.9 H2O

N

OH

O

N

O

Fe O

N

N

N

III

N

O 47

6

48 (98%) Scheme 7. Preparation of tris(HOOBt)iron(III) 48.

R2

1) SOCl2, Benzene Reflux,15 min-3 h

NH2 OH

R1

2) NH2SiMe3 50 Benzene, r.t., 12 h

O 49

R2

R2

NH2

N

NaNO2, HCl, H2O NH

R1

SiMe3

4

oC,

N N

R1 30 min

OH

O

O

52 (36-68%)

51 (60-70%)

R1= H, Me, OMe, I R2= H, Me, OMe, Cl, NO2 R1, R2= -CH=CH-CH=CHScheme 8. Synthesis of 3,4-dihydro-3-hydroxy-4-oxo- [1,2,3]-benzotriazine derivatives 52.

O N

HO

N N

SOCl2, DCM

NH OH

+

R

O

O O

N

N

Reflux, 12 h O

6

53

N

O H N

O R

O O

54 (88-94%)

R= Ala, Gly, Ile, Leu, Met, Phe, Val Scheme 9. Preparation ofHOOBt esters of Fmoc amino acids 54.

complex 43 was abstracted with AgBF4 in alcohol 44. A neutral metal macrocycle [Re- (CO)3(C7H4N3O2)]n 45 was obtained upon abstraction of [NEt4]Br from complex 43. A plausible explanation of this data was in coordinating solvents, which generated the monomeric solvent adducts 46 (Scheme 6) [36]. Ichinoki et al. investigated a strong chelation and reaction of the 3 equivalent deprotonated form of HOOBt 6 with Fe (NO3)3.9H2O 47 in Et3N/THF produced tris-(chelate) 48. The target complex, Fe (HOOBt)3 48, was prepared in nearly quantitative yield [37, 38]. In addition, HOOBt was applied for the selective chelating reagent of Fe (III) ion as Fe (HOOBt)3 48 (Scheme 7) [39]. 3-Hydroxy- [1,2,3]-benzotriazin-4 (3H)-one derivatives 52 were a privileged additive in the synthesis of peptides using either the carbodiimide or the active ester method. The compounds 51were synthesized by reaction of thionyl chloride with anthranilic acid 49 to produce unstable sulfonamide anhydride. The latter upon treatment with 2-(trimethylsilyl) amine 50 led to trimethylsilylatedhydroxamic acid 51 which was hydrolyzed, diazotized and the ring was closed to afford the corresponding compounds 52 in good yield (Scheme 8) [40]. Preparation of N-9-fluorenyl methyl oxycarbonyl (Fmoc) amino acid HOOBt esters 54 was described by Jakobsen et al. The

Fmoc amino acid 53, HOOBt6 and thionylchloride were reacted in dichloromethane solvent to produce the compound 54. In addition, HOOBt esters of Fmoc amino acid 54 was used as an advantageous coupling agent in peptide synthesis (Scheme 9) [41, 42]. Kraft and Zaleski described the photochemical decomposition of HOOBt 6 which led to the ring-opened diradical structure 55. Compound 55 lost N2 upon warming to yield the quite unstable diradical 56 which underwent unimolecular recombination via formation of the 4-membered -lactam ring 57 within 10 ns to produce the oxime ketene 58 (Scheme 10) [43]. In another research, HOOBt 6 was reacted with N, N´dicyclohexylcarbodiimid (DCC) to form the intermediate compound 59 with which HOOBt 6 was converted into 3-[2-azidobcnzoyloxy]-4-oxo-3, 4-dihydro-l, 2,3-benzotriazine 60. Finally, compound 60 on losing urea molecule and then further reaction with benzyl amine 61 afforded the final compound 62 (Scheme 11) [44]. Zhu et al. developed a sensitive method based on tertiary amine labeling for the analysis of gibberellins (GAs) by capillary electrophoresis (CE) coupled with electrochemiluminescence (ECL) detection. GA3 63 was tagged with 2-(2-aminoethyl)-1-methylpyrrolidine (AEMP) 64 using DCC and HOOBt 6 as coupling agents in



N N

N

OH

N

hn, Xe lamp, 1000 W Pyrex schlenk flask

N

N O

O

OH 12 h, 288 K

O

N

6

OH

N2

N

OH

55 (65%)

O OH 57

56

N 298 k C

O

58 Scheme 10. Photolysis of 3-hydroxy-[1,2,3]-benzotriazin-4-one 6.

N

N N

N

O

O HN

N N

N

N N

N

N

OH

DCC, THF

O 6

r.t., 1 h

Toluene, 110 °C Reflux, 2 h

N

OH

O 6

O

O

O

N3

O

60 (82%)

59 (75%) NH2

N

N3

N H

61 DMF, r.t., 1 h

62 (85%) Scheme 11. Reaction of 3-hydroxy-[1,2,3]-benzotriazin-4-one 6.

N OH

N

OH

NH2 +

CO HO

N Me

H 63

N HO OH

DCC MeCN, r.t., 24 h

64

O

H

O 6

H

O C O

N

N H

Me

Me 65

OH Scheme 12. Labeling of GA3 63 with AEMP 64 using DCC and HOOBt 6 as coupling agents.

acetonitrile to produce GA3-AEMP-derivative 65. GA3 63, DCC and HOOBt 6 were dissolved in acetonitrile, followed by being shaken for 10 min, and then AEMP 64 was added into the mixture. The resultant mixture was incubated for 24 hours at room temperature. The prepared product was used as the standard to validate and quantify GAs in samples (Scheme 12) [45]. Yin and coworkers prepared the AEMP 64 of indole-3-acetic acid 66. In brief, 66, DCC, and HOOBt 6 were dissolved in acetonitrile and then AEMP 64 was added into the mixture, which was shaken for several min. The resulting mixture was incubated for 24 hours at room temperature to produce their AEMP-derivatives 67 (Scheme 13) [46].

HOOBt 6 was used as a coupling additive that completed the acylation by color change. Unfortunately, HOOBt 6 was reported to give a relatively higher degree of racemization than other azole derivatives in the presence of N, N’-diisopropylcarbodiimide (DIC) when poly (ethylene glycol)-cross-linked polyamide (PEG)-bound dipeptide was used for peptide synthesis. Fully protected amino acid esters of HOOBt 69 were stable crystalline solids stored for long periods at low temperature. Fmoc-amino acid esters 69 with HOOBt 6 were used for N-acylation with polydimethylacrylamide resin in solid-phase synthesis. Fmoc-amino acid esters 69 with HOOBt 6 were prepared in high yields (Scheme 14) [47].



N

N

OH

N O

H2N

O

+

N

N H

Me

6

O

DCC MeCN, r.t., 24 h

Me

66

N

HN

OH

N H

64

67

Scheme 13. The coupling of indole-3-acetic acid 66 to AEMP 64 with DCC and HOOBt 6 as coupling agents. N

N N

OH

O

HO

N

6

NHFmoc

O

N

DIC MeCN, r.t., 24 h

O

N

O

68

NHFmoc

O

Oligopeptide

69 (70-80%)

Scheme 14. HOOBt 6 as a reagent for formation of active esters. O NH2 1)

Cl3C

O H N

H

H2NOH, H2O, HCl 72 Na2SO4, 60 °C, 2 h 2) H2SO4, 90°C, 3 h

70

O

R

71

R

NH2 R

H2O2

OH

30 °C, 24 h

O 73 (55-70%)

O 49 (45-65%)

O

N H

R

1) SOCl2, Py 80 °C, 1 h

OH O 78 NaNO2, HCl (aq, 2 N)

2) NH3 (g, 1 atm.) 76 r.t., 1-2 h N R

77

O

R N H

Benzene 80-150 °C, 5-6 h

O

75 (50-65%)

O r.t., 1-2 h

75 NO2

Cl 74

NH3 (g, 1 atm.) 76

O

R

Cl

O

NH2 R

NO2 R

NH2

NiCl2, NaBH4 r.t., 2-3 h

NH2 O 77 (44-680%)

O 79 (50-65%) N NH

0 °C, 2-3 h O 80 (70-84%) R= 4-Me, 6-Me, 7-Me, 6-OMe, 4-OMe, 4-NO2, 5-NO2, 6-Cl, 7-Cl

Scheme 15. Synthetic routes to benzotriazinone compounds 80.

Woodland and Ostah developed a synthetic route for the preparation of [1,2,3]-benzotriazin-4-one derivatives 80 via is at in derivatives 73 in Sandmeyer process [48]. The latter compounds were prepared through the intramolecular Mitsuno bucyclodehydration [49] of aniline derivatives 70 by a mixture of chlorohydrate 71 and hydroxylamine reagents 72. Upon oxidation of is at in derivatives 73 with hydrogen peroxide afforded the 2-aminobenzoic acids 49 in moderate yield. Then, the latter compound on reaction of the phosgene 74 gave isatoic anhydride derivatives 75. Subsequently, Compound 75 on treatment with ammonia 76 gave the desired aminobenzamide 77. In other route to these compounds, the reaction of compounds 2-nitrobenzoic acid derivatives 78 with thionyl chloride and ammonia 76 gave the nitrobenzamide 79. Then, the reducing system of nickel (II) chloride-sodium borohydride converted the nitroamide 79 into 2-aminobenzamide derivatives 77. Finally, synthesis of substituted benzotriazinones 80, was carried out through

the diazotization of the substituted 2-aminobenzamide 77 (Scheme 15) [50, 51]. 2.2.2. 3-Substituted [1,2,3]-benzotriazin-4 (3H)-one Two series of [1,2,3]-benzotriazin-4-one derivatives containing thiourea 86 and acylthiourea 88 were designed and synthesized. 2Aminobenzamides 77 were cyclized to [1,2,3]-benzotriazin-4-one 81. Through N-alkylation of [1,2,3]-benzotriazin-4-one 8 at the 3 position with 2-(3-bromopropyl) isoindoline-1, 3-dione 81 as an alkylation agent, compound 82 was readily prepared. After wards, compound 82 was hydrolysied to 3-(3-aminopropyl)[1,2,3]benzotriazin-4(3H)-one 84 in the presence of hydrazine 83 through Gabriel’s primary amine synthesis [52]. Finally, the title compounds 86 were synthesized by the reaction of aryl isothiocyanates 85 with intermediate 84 in acetonitrile. Also, aroylisothiocyanates 87 reacted with amine 84 to produce the title compounds 88



O

Br

N NH2

N

1) NaNO2, HCl 0 °C-r.t., 2 h

81

O

NH

NH2 O

N

N

2) NH3.H2O r.t., 3-4 h

N K2CO3, MeCN Ar (g), 60 °C, 4 h

O

77

O N

O

N O

82 (51%)

8 (95%) Ar1-N=C=S 85

N

N N

H N

H N

MeCN, r.t., 8-12 h N

N2H4.H2O 83 EtOH, DCM 50 °C, 6 h

O N NH2

Ar2 C

O

N 87

C

S

N

N N

DCM, r.t., 8-12 h

84 (82%)

S

86 (74-92%)

O

N

Ar1

O

H N

H N S

Ar2 O

88 (68-88%) Ar1= C6H5, 2-FC6H4, 3-FC6H4, 4-FC6H4, 4-ClC6H4, 4-IC6H4, 2-OMeC6H4, 3-MeC6H4, 4-CF3C6H4, 4-CNC6H4, 4-NO2C6H4, 3-Py, 4-Py, 5-ClPy-2-yl, 5-BrPy-2-yl, 2ClPy-4-yl Ar2= C6H5, 2-ClC6H4, 3-BrC6H4, 2-FC6H4, 4-FC6H4, 2-OCF3C6H4, 4-NO2C6H4, 4-OMeC6H4, 2,5-(OMe)2C6H3 Scheme 16. Synthetic route of [1,2,3]-benzotriazin-4 (3H)-one derivatives 86 and 88.

(Scheme 16). Most of the tested compounds showed good nematicidal activity against M. incognitaat the concentration of 10.0 mg L-1 in vivo in comparison with avermectin and fenamiphosnematicides. Compounds 86 and 88 showed excellent nematicidal activity with the inhibition rate of 51.3% and 58.3%at the concentration of 1.0 mg L-1, respectively [53]. [1,2,3]-Benzotriazin-4- (3H)-ones 91 were synthesized through the reaction of 2-amino-N-phenylbenzamide 89 in the presence of tbutyl nitrite (TBN) 90 along with tetrabutylammonium Iodide (TBAI) as the catalyst under mild conditions in good yields. When tetrabutylammonium bromide (TBAB) and tetrabutylammonium chloride (TBAC) were used as the catalyst, the reaction yields slightly decreased (Scheme 17) [54]. NH2 R2

t-BuNO2, TBAI 90

O

N R2

N N

MeCN, 60 °C, 12 h R1

NH 89

R1

O 91 (47-77%)

R1= Me, OMe, F, Cl, Br R2= 4-Me, 4-MeO, 5-F, 5-Cl, 5-Br Scheme 17. Synthetic routes to [1,2,3]-benzotriazin-4- (3H)-ones 91.

Wang et al. synthesized [1,2,3]-benzotriazin-4-one derivatives 98 through anthranilic acids 49. The desired isatoic anhydrides 75 were readily prepared via the annulation’s reaction with Triphosgene (bis(trichloromethyl) carbonate (BTC) 92. Various substituents at nearly every position of the benzene ring were well tolerated. Subsequently, 75 reacted with ammonium 93 to afford anthra-

nilamides 77. Finally, [1,2,3]-benzotriazin-4-ones 94 were synthesized from 77 through the combination of diazotization, nucleophilic addition and cyclization in one pot. A series of [1,2,3]benzotriazin-4-one derivatives 98 were synthesized through the reaction of 3-bromoalkyl- [1,2,3]-benzotriazin-4-ones 96 with potassium salt of 2-cyanoimino-4-oxothiazolidine in the presence of potassium iodide. The latter compound was in turn prepared by Nalkylation’s of 94 at 3-position, using dibromoalkane 95 as alkylation’s agent. In fact, they attempted to introduce 2-cyanoiminothiazolidin-4-one 97 moieties into the [1,2,3]-benzotriazin-4-one structure (Scheme 18). Both in vivo and in vitro nematicidal activities of [1,2,3]-Benzotriazine derivatives bearing 2-cyanoiminothiazolidin-4-one 98 moieties against the cucumber root-knot nematode disease caused by Meloidogyneincognita were evaluated. Despite no direct inhibition in vitro, some of them exhibited good in vivo inhibitory activities at 10.0 mg L-1compared with lead compoundsfenamiphos and avermectin [55]. Synthesis of some [1,2,3]-benzotriazine derivatives 107 using 2-(4-oxo-6-phenyl [1,2,3] benzotriazin-3 (4H)-yl) acetohydrazide 103 as a starting material was described. Diazotized compound 100 was obtained from 5-phenyl methyl anthranilate 99 which cyclized to 6-phenyl- [1,2,3]-benzotriazine ethyl acetate 102 on reaction with ethyl glycinate 101. The addition of hydrazine hydrate 83 in the presence of ethanol to compound 102 gave the corresponding acetohydrazide derivative 103. When compound 103 was reacted with 5,5-dimethyl-1, 3-cyclohexanedione (dimedone) 104 in the presence of toluene, the corresponding triazine-acetohydrazide derivative 105 was formed. Furthermore, the new diazepinone derivative 107 was prepared via the reaction of enaminone 105 with 2-(4-nitrobenzylidene) malononitrile106 in ethanol and trimethylamine (Scheme 19). Induced carrageen pawedema model is anappropriate test for evaluating antiinflammatory drugs. Carrageenan is


O NH2

Cl3C

R OH


O O 92

H N

CCl3 R

1) THF, - 10 °C, 30 min 2) -10- -5 °C, 1 h 3) r.t., 18 h

O 49

Br

n

N R

N N

1) K2CO3, acetone Reflux, 5-8 h 2) r.t., 30 min

O

O 77 (73-94%)

95

94 (84-92%)

O

NH2 1) 60 °C, 5-8 h 2) r.t., 30 min

Br

NH

2) DMF, r.t., 2.5 h

R

O

N

R

NH2

(NH4)2CO3, dioxane 93

O 75 (85-95%)

N 1) NaNO2, HCl (aq, 5 N) H2O, 0 °C, 20 min

O

Br n

O 96 (46-62%)

S

KN

O

N N CN 97

N

R

KI, DMF Reflux, 100 °C, 2 h

n

O

R= H, 6-Me, 6-MeO, 7-CF3, 7-F, 7-Cl, 7-Br, 7-NO2 n= 0-4

S

N

N

N

CN

98 (32-46%)

Scheme 18. Synthetic route of [1,2,3]-benzotriazin-4 (3H)-ones 98.

Cl NH2

N

OMe

Ph H2O, 0 °C, 1-2 h

O

O 1) H2N

NaNO2, HCl

OMe

Ph

N

N OEt

101

2) AcONa, r.t., 15 min

102 (68%)

Me

HO

N2H4.H2O 83

N

Ph

NH2

N H

N

O

104

N

O

N

Ph

N H

H N

Me Me

O

O

EtOH, 2 h, r.t.

Me

O

N

OEt

O

100 (80%)

N

O

N

Ph

H2O, r.t., 1 h

O

99

N

Toluene, reflux, 4 h

103 (77%)

105 (70%)

O

O2N NO2 H N

H NC

CN

EtOH, NMe3 Reflux, 12 h

NH

CN

N

106 O

NH2 O

N H

N

107 (44%)

O Me

Me

Scheme 19. Synthetic pathway of diazepinone derivative 107.

a strong chemical targeted for the release of inflammatory and proinflammatory mediators in carrageen paw edema, for measurement of rat paw volume, and for the calculation of the percentage of rat paw volume that assists in the intensity of the edema. The pharmacological screening showed that many of these compounds had

good anti-inflammatory activity which is similar to the result obtained by carrageen. On the other hand, the results obtained from test compounds compared with control group of indomethacin showed anti-inflammatory effect, but they were not as significant as those of indomethacin [56].



Cl (CH2)4Cl N R1

N Ni(cod)2 or (S,S)-L10 110 111

N O

R2

+

R1

N R2

1,4-Dioxane, r.t., 48 h

O

109

108

112 (65-79%) O

O N N Ni

R1= 6-Me, 6-OMe, 7-Br R2= H, 2-F, 2-Cl, 4-F, 4-Cl

Ni(cod)2

(S,S)-L10

Scheme 20. Nickel-catalyzed denitrogenativetransannulation of N-substituted-[1,2,3]-benzotriazin-4(3H)-one 111.

O Paraffin oil

NH

Reflux, 300 °C, 3 h N

O 250-300 °C, 5 h

N N

a 115 (31%)

N Ph

b

Air (1 atm.)

O a

O

1-Methylnaphthalene

N

114

113

Reflux, 250 °C, 48 h O

O

116 N N H 116

117 (65%)

Scheme 21. Pyrolysis of 3-phenyl-[1,2,3]-benzotriazin-4-one 113.

In another research, Liu and coworkers developed a synthetic route started with an annulation between N-substituted- [1,2,3]benzotriazin-4 (3H)-one 108 and the alkyne 109 having a bulky naphthalene ring. In this procedure, in the presence of bis (1,5cyclooctadiene) nickel (0) [Ni (cod) 2], (cod=1,5-cyclooctadiene) 110 the annulation of 108 with 109 gave the desired axially chiral product 112 with 70-81% ee and almost complete regioselectivities, albeit in only 20% yield. In addition, the cyclopropylidiene-linked ligand (S, S)-L10 111, having an isopropyl substituent, exhibited excellent yield and good enantioselectivity (70-91%) (Scheme 20) [57]. 3-Phenyl- [1,2,3]-benzotriazin-4-one 113at 250-300ºC abstracts hydrogen from the solvent to give benzanilide 114. Then, the intermediate 114 rearranged to phenanthridin-6-one 115 in liquid paraffin at 300°C and 1-phenylbenzoazet-2(1H)-one 116 in boiling 1-methylnaphthalene at 250ºC. The latter compound underwent thermal decomposition and rearrangement to the major product 9-acridones 117 (Scheme 21) [58].

The thermolysis of the structurally related 3-alkenyl-[1,2,3]benzotriazin-4(3H)-ones 121 produced 3-substituted quinolin4(1H)-ones 123. To a solution of ethanolamine or propanolamine 118 in water at room temperature was added isatoic anhydride 75. The mixture was then diazotised by addition of a solution of sodium nitrite and hydrochloric acid. The reaction mixture was filtered to yield 3-(2-hydroxyethyl)-[1,2,3]-benzotriazin-4 (3H)-one 120. Introduction of the vinyl side-chain was achieved in each case in high yield and without cleavage of the benzotriazinone ring by treating the tosylate (OTs) derivative of the appropriate 3-(hydroxyalkyl) benzotriazinone 120 with potassium t-butoxide in t-butyl alcohol at room temperature. Thermolysis of the 3-vinyl or 3-propenyl derivatives121 in hot paraffin oil and in boiling 1-methylnaphthalene gave a mixture of products from which the known 3-methylquinolin-4 (1H)-one 123 was isolated (12-70%) as the sole identifiable product. Inexplicably, decomposition of the 3-vinyl or 3-propenyl [1,2,3]-benzotriazinone121 in paraffin oil at 250ºC through rearrangement of intermediate (E)-1-vinyl or propenyl benzoazet-2


H N


RCH(OH)CH2NH2 118

O

Reflux, H2O 100 °C, 15 min

N

2) t-BuOK, t-BuOH r.t., 4-5 h

O 120 (70-81%)

N

Paraffin oil 1-Methylnaphthalene

N

Reflux, 250 °C, 2 h

R

R

H N

N R

O

O

R= H, Me

R

0-5 °C, 0.5 h

R

119 (50-66%)

1) p-TsCl, Py 0 °C, 2-3 h

OH

N

O

75

N

NaNO2, HCl (aq, 5 N)

OH

H N

O O

N

NH2

O

121 (84-97%)

122

123 (12-70%)

Scheme 22. Thermolysis of 3-alkenyl-[1,2,3]-benzotriazin-4(3H)-ones 121.

H N

1) NaNO2, HCl (aq, 2 N) H2O, 0 °C, 30 min

NH2 O

N

N

N Ar

O 2) ArNH2, NaOAc 70 0 °C, 3 h

OMe 99

EtOH

N

Reflux, 3 h

Ar

O

OMe

125 (60-78%)

124 N

N

1) Ni(cod)2, Dppf 110 127

N +

N

Ar

N

THF, 60-110 °C, 12 h

O

Ph 126

125 (78%)

Ar

O 130 (24-87%)

P Ph Fe

- N2

Ni (0)

Dppf

Ph

- Ni (0)

P Ph Ln Ni

NiLn N

Ar

NiLn

126

N

N O 128

O 129A

Ar

Ar

O 129B

Ar= C6H5, Bn, 4-MeC6H4, 4-OMeC6H4, 4-CF3C6H4 Scheme 23. Ni (0)-Catalyzed reaction of [1,2,3]-benzotriazin-4 (3H)-ones 124 with 2,3-dimethylbuta-1,3-diene 125.

(1H)-one 122 proceeded smoothly and cleanly to 3-phenylquinolin4(1H)-one 123 in much greater yield (Scheme 22) [59]. N-Aryl-[1,2,3]-benzotriazin-4(3H)-one 125 was readily prepared from arylamine 70 in two steps; methyl anthranilate 99 was diazotized by NaNO2 and then coupled with arylamine 70 to give methyl 2-[3-(4-aryl)triaz-2-enyl]benzoate 124. Subsequent heating in refluxing ethanol prompted six-membered ring closure to afford 125 in 60-78% yield over two steps. Afterwards, [1,2,3]benzotriazin-4 (3H)-ones 125 were reacted with 1,3-dienes 126 in the presence of a Ni (cod)2 110 to give a variety of 3,4dihydroisoquinolin-1(2H)-ones 129. Oxidative insertion of nickel (0) into the triazinone moiety prompted extrusion of dinitrogen to

give a five-membered ring aza nickel acyclic intermediate 128. Subsequent insertion of a carbon-carbon double bond of 126 into the nickel-carbon bond gave seven membered ring azanickelacyclic intermediate 129A, which was in equilibrium with zwitterionic allylnickel species 129B which followed by allylicamidation afforded 3,4-dihydroisoquinolin-1(2H)-ones 130. Under the optimized reaction conditions using 1,1´-bis(diphenylphosphino) ferrocene (Dppf) 127 as the ligand, various benzotriazinones 124 were subjected to the catalytic reaction with 1,3-dienes 126. Substrates 125 possessing an aryl group on the nitrogen atom reacted smoothly to afford the corresponding products 130 in high yield (Scheme 23) [60].



O NO2

N

Pb(OAc)4

H N

R

N H

1) SnCl2.2H2O AcOH, HCl 0 °C, 0.5 h

R

N

N

N N

N

DCM, r.t., 0.5 h

2) 0 °C-r.t., 0.5 h

O 131

O

O

132

133

R

O N m-CPBA, CHCl3

N

N N

Reflux, 6 h

R

N

+

O

R

O

O

135 (30-40%)

134 (50-60%)

R= H, Me, C6H5, 4-BrC6H4, 4-MeC6H4, 4-OMeC6H4, 4-NO2C6H4, Bn, CH2OMe, CH(Me)OEt, THP-2-yl Scheme 24. Synthesis of [1,2,3]-benzotriazine 1-oxides 134 and 2-oxides 135.

N

HCl (aq, 5 N), CuSO4 CaCl2 N

+

H

H

P

MeO

+

S MeO

P

O 8(75%)

S

OMe

N

KOH (aq, 10%), CuSO4 CaCl2

3

143

144

S

N N

Reflux, 100 °C, 2-3 h

SH

OMe

N N

O

NH

Reflux, 100 °C, 2-3 h

S

O

N

OH

+

P

MeO

SH

OMe O 144

142 (80%) Scheme 25. Hydrolysis of azinphosmethy l3.

NH2

N

OMe O 99

H N

N

1) NaNO2, HCl 0 °C, 1-2 h

OMe 2) RNH2 (aq, 40%) 139 0 °C, 2-3 h

N

R EtOH

N N R

Reflux, 5-6 h O 140 (70-82%)

O 141 (60-70%)

R= H, Me, Bn, OBn, (CH2)2Cl, CH2CONH2 Scheme 26. Synthetic route of 3-alkyl or 3-aryl- [1,2,3]-benzotriazin-4-ones 141.

Boulton and coworkers published a strategy on peracidoxidation of 3-substituted [1,2,3]-benzotriazin-4 (3H)-ones 133 to form 3-substituted [1,2,3]-benzotriazin-4(3H)-one 1-oxides 134 and 2oxide 135. The tautomeric structure 132 was isolated through cyclization of 2-nitrobenzoylhydrazine derivatives 131 in the present of lead tetraacetate. Next, compound 132 converted to 133via deoxygenation and migration of R group to N (3) position. Finally, 3Substituted derivatives 133 were oxidized by m-chloroperoxybenzoic acid (m-CPBA) in refluxing chloroform to form the oxides [1,2,3]-benzotriazin-4 (3H)-one 1-oxide 134 and 2-oxide 135 (Scheme 24) [61]. The effect of layer and of interlayer cations of smectites on the hydrolysis of azinphosmethyl (dimethoxy-S-((4-oxo-1,2,3-benzotriazine-3(4H)-ylmethyl)phosphorodithioate) 3 as an organophosphorous insecticide was investigated. Hydrolysis of the pesticide

was catalyzed by Ca-hectorite but was not catalyzed by Canontronitenor by Ca-montmorillonites. The Mg and Cu-hectorites and Cu-montmorillonite also showed catalytic activity. The catalytic activities of the Ca2+ and Cu2+cations as exchange cations of the smectite and as salts were compared. When azinphosmethyl3 was hydrolyzed in acid medium yielded [1,2,3]-benzotriazin-4 (3H)-one 8, but in alkaline medium yielded 3-hydroxymethyl[1,2,3]-benzotriazin-4(3H)-one 142. Accordingly, the product of the catalytic hydrolysis of azinphosmethyl by smectites and CuSO4 could be the [1,2,3]-benzotriazine. Finally, the hydrolysis of azinphosmethyl3 involved the adsorption of the pesticide into the interlayer space of the smectites, forming a bidentate complex with the interlayer cations (Scheme 25) [62]. Methyl anthranilate 99 was diazotized and the resulting diazonium salt coupled with alkylamine 139 according to the method of LeBlanc and Vaughan [63], to afford 1-aryl-3-methyltriazenes



Me O Cl

NH2

O H2N

O

S O

OMe

Cl N2H4, H2O 83

NH2

H2N

r.t., 90 h

S

C O

142

Cl

H N

O

NH2 AcOH, EtOH Reflux, 4 h

H2N

S O

Cl

1) AcOH, H2O r.t., 0 °C

O

N

S

H2N

O

2) NaNO2, 5 °C, 6 h

Me

N N

Ph

145 (86%)

HCl (aq, 1 N ), H2O N

N

O

143 (41%)

Cl

Me

H N

O

144

O

NH2

N

O

100 °C, 1 h

N

S

H2N

N

O

NH2

O

Ph

147 (28%)

O

Cl HCl (aq, 7 N ), H2O

146 (57%)

NH2

O

100 °C, 15 min

N3

S

H2N

O

O

148 (76%) Scheme 27. Synthesis and acidic hydrolysis of 6-sulfamyl- [1,2,3]-benzotriazin-4 (3H)-one 146.

NH2 R2

N

KI, TBHP Cs2CO3, AcOH

O

N

R2

N

+ MeNO2 HN

N2 (g), 120 °C, 12 h

R1

O

150

149

R1

151 (50-98%)

R1= H, n-Bu, i-Pr, t-Bu, C6H5, Bn, 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 2-OMeC6H4, 3-OMeC6H4, 4-OMeC6H4, 2-CF3C6H4, 3-CF3C6H4, 4-CF3C6H4, 4-FC6H4, 4-ClC6H4, 4-IC6H4, Naphthyl, Cy R2= H, 6-Me, 6-OMe, 7-F, 7-Cl, 7-Br Scheme 28. Synthesis of N-substituted-[1,2,3]-benzotriazin-4(3H)-ones 151.

NH2 R2

H N

N TBAI, MeCN

N N

R1 + t-BuONO 60 °C, 12 h

O 152

R2

R1

O 90

153 (70-99%)

R1= H, n-Bu, i-Pr, t-Bu, C6H5, Bn, 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 2-OMeC6H4, 3-OMeC6H4, 4-OMeC6H4, 2-CF3C6H4, 3-CF3C6H4, 4-CF3C6H4, 4-FC6H4, 4-ClC6H4, 4-IC6H4, Naphthyl, Cy R2= H, 6-Me, 6-OMe, 7-F, 7-Cl, 7-Br Scheme 29. TBAI-catalyzed synthesis of [1,2,3]-benzotriazin-4 (3H)-ones 153.

140, which were cyclized by heating in ethanolic solution to give the [1,2,3]-benzotriazin-4-ones 141 (Scheme 26) [64]. Gadekar and Frederick described a preparation method for the 3-amino-benzotriazine 147. Accordingly, the ester 142 was first converted to the hydrazide 143 using hydrazine hydrate 83. Reaction of 143 with acetophenone 144 produced the acylhydrazone145, which on diazotization in acetic acid afforded 146. Finally, the methylbenzylidene protecting group was removed by heating 146 in hydrochloric acid (aq, 1 N) to form 147. However, when this hydrolysis was carried out in hydrochloric acid (aq, 7 N), the amino azide 148 was obtained (Scheme 27) [65].

Yan et al. synthesized [1,2,3]-benzotriazin-4 (3H)-ones 151 through potassium iodide/t-butyl hydroperoxide (KI/TBHP)mediated oxidative cyclization of 2-aminobenzamides 149 with nitromethane 150 in the presence of acetic acid at high temperature (Scheme 28) [66]. In another research, a mild and efficient protocol was developed for the synthesis of [1,2,3]-benzotriazin-4-(3H)-ones 153 via TBAIcatalyzed (tetrabutylammonium iodide) reaction of TBN 90 and 2aminobenzamides 152 under acid-free conditions in high yields (Scheme 29) [67].



NO2

NO2

O

X

H2N

+

R1

2,6-Lutidine O

R2

H N

NMP, 25 °C, 16 h

O

O R1

O

O 154

78

155

NH2 SnCl2.2H2O

R2

H N

NMP, EtOH 25 °C, 16 h

N

O

NaNO2, AcOH, H2O

R1

N

R2

O

R1

25 °C, 16 h

O

O

O 157

156 N TFA (aq, 95%), H2O

O

N

N

R2

N

25 °C, 1 h

O R1

OH

O 158 (46-83%)

R 1=

C6H4, -CH=CH-C6H4 R2= H, 6-Me, 7-CF3, 7-Cl X= Cl, OH

Scheme 30. Solid-phase synthesis of [1,2,3]-benzotriazin-4- (3H)-ones 158 via diazotization of 2-aminobenzamides 156.

O

O O

O HO

O

OH

O

160 X

H2N

X

N H

DMF, r.t., 15 h

OH O

159

ROH, DCC 162

O

O OR

N

X

0 °C-r.t., 4-24 h O

161

163 ,

X=

,

, O

F N

F R=

, F

N N

,

F F

O

N O

Scheme 31. Facial synthesis of reagents containing a terminal maleimido ligand linked to an active ester 163.

Makino and coworkers developed a solid-phase synthesis of [1,2,3]-benzotriazin-4- (3H)-ones 158 through the precursors of 2nitrobenzoyl chloride or hydroxide 78 and solid-supported amines 154. 3-Aminobenzoic acid ester 154 was reacted with 2nitrobenzoyl chloride or hydroxide 78 and 2,6-lutidine to give 155 using SynPhaseLanterns. The Lantern derivatives 155 were reacted with SnCl2.2H2O in mixture of solvents ethanol and N-methyl-2pyrrolidone (NMP) to give 2-aminobenzamide 156 with high purity. In the next step, the cyclization of 156 through diazotization of arylamines with NaNO2 in acidic solvents such as AcOH/H2O was performed to produce [1,2,3]-benzotriazin-4- (3H)-ones 157. Compounds on Wang-type solid-supports were cleaved off when treated with highly acidic solvents such as trifluoroacetic acid (TFA) to produce the final product 158 (Scheme 30) [68]. The amino acid 159 was reacted with maleic anhydride 160 to give the corresponding maleamino or maleanilo acid 161, which, without isolation were reacted with the appropriate hydroxyl compounds 162 such as N-hydroxysuccinimide, 3,4-dihyro-3-hydroxy-

4-oxo-1, 2,3-benzotriazine6 and pentafluorophenol using DCC, whereby the derivatives of ester 163 simultaneously were produced (Scheme 31) [69]. Santagada and coworkers synthesized a class of [1,2,3]benzotriazinone 167 and of 3-hydroxy-[1,2,3]-benzotriazinone 169 and also, some intermediates 4-substituted-piperazines. All the reactions were carried out by microwave, which was composed by appropriate ramping and holding steps. The general procedure was alkylation of starting [1,2,3]-benzotriazin-4(3H)-one 8 with bromochloroetane derivatives 164 and K2CO3 in DMF to give chloroalkyl-[1,2,3]-benzotriazin-4(3H)-one derivatives 165. 3-Hydroxy[1,2,3]-benzotriazin-4(3H)-one 6 was also reacted with bromochloroetane derivatives 164 in the presence of NaOH in absolute ethanol to give the corresponding 3-chloroalkoxy-[1,2,3]-benzotriazin-4(3H)-one derivatives 168. Condensation reaction of compounds 165 or 168 with desired 4-substituted-piperazines 166 was performed in DMF in the presence of K2CO3, NaI, under reflux to give respectively the final compounds 167 or 169. The synthesized



N N

N

Br(CH2)nCl 164

N NH

8

N N

N

Cl

n

MW, K2CO3, DMF 80-120 °C, 5-20 min

O

N

N

O

X

N

X

167 (80-92%)

HN

165 (90-96%)

N n

O

166 MW, K2CO3 NaI, DMF 80-120 °C, 5-60 min N

Br(CH2)nCl 164

N N

O

OH

N

N N

MW, NaOH, EtOH 55 °C, 5-20 min

O

Cl

N

n

O

6

N

168

N

N O

X

N n

O

n= 0-3 X= Cl, Br, I

169 (85-94%)

Scheme 32. Microwave-assisted synthesis of 3-substituted [1,2,3]-benzotriazinone derivatives 167 and 169.

N

N K2CO3, CuI, N2 (g)

N NH

+

Ar-X

N DMF, 150 °C, 6 h

Ar

O

O 8

N

170

171 (54-90%)

Ar= C6H5, 4-MeC6H4, 2,4,6-Me3C6H2, 4-C6H4CHO, 4-NO2C6H4, 2-Py, 3-Py, 3-QN, 3-C4H3S X= I, Br Scheme 33. N-Arylation of [1,2,3]-benzotriazin-4 (3H)-one 8 containing an -NHCO- moiety.

products were transformed into the corresponding hydrochloride salts using dry HCl in anhydrous diethyl ether. Synthesis by microwave irradiation gave the desired compounds in better yields than those obtained by conventional heating (Scheme 32). Serotonin (5hydroxytryptamine, 5-HT) is an important molecule in medicinal chemistry, and several 5-HT receptor subtypes have been found by molecular biological methods as well as by specific agonists or antagonists. Particular attention has been focused on 5-HT1A because this receptor plays an important role inthe central nervous system (CNS) modulating a number of behaviors such as impulsivity, sexual behavior and food intake. Meanwhile, several agonists for this receptor exhibit anxiolytic and antidepressant properties in man. Some resulting active compounds were characterized by a good selectivity profile for the 5-HT1A subtype receptor [70]. N-Aryl heterocyclic compounds of [1,2,3]-benzotriazinone 171 were synthesized from aryl halides and heterocyclic compounds containing an –NHCO moiety by using a catalytic amount of copper catalyst in satisfactory yields. This catalytic reaction was applicable to the synthesis derivatives of N-aryl-2-pyridone, -2pyrrolidone, -1(2H)-isoquinolone, -1(2H)-phthalazinone, -4(3H)quinazolinone and -[1,2,3]-benzotriazin-4 (3H)-one 8. A facile copper-catalyzed Ullmann condensation [71] was used, which was applicable to N-arylation of various heterocyclic compounds containing an –NHCO moiety for e.g., 2-pyridone, 2-pyrrolidone, 1(2H)-isoquinolone, 1(2H)-phthalazinone, 4(3H)-quinazolinone and [1,2,3]-benzotriazin-4 (3H)-one. In this published synthetic route, a mixture of an aryl (heteroaryl) halide 170, [1,2,3]-benzotriazin-4

(3H)-one 8, K2CO3, and CuI in DMF was stirred at 150 ºC for 6 hours under nitrogen atmosphere to produce the compound 171 (Scheme 33) [72]. The characteristics of amide bond forming reactions of 3(diethoxyphosphoryloxy)-[1,2,3]-benzotriazin-4 (3H)-one (DEPBT) 173 were compared to those of other highly effective phosphonium, uronium and guanidinium salt coupling reagents used in the racemization study. A residue prone to racemization, such as serine derivatives 172, was subjected to the following protocol in order to determine yielded and extent of epimerization in compound 174. The activated carboxyl intermediate was stored in the presence of N, N´-diisopropylethylamine (DIEA) for a specific time period. The activated intermediate was then allowed to react with benzylamine 61, which quenched the intermediate, and the resulting ratio of enantiomers was determined by chiral HPLC. The results indicated that DEPBT 173 was the coupling reagent, which showed the best yield with the lowest extent of racemization (Scheme 34) [73]. A Strategy for selective alkylation at the 3-position of the benzotriazinone substrates was developed to incorporate a range of substituents at this site. Thus, the dicarboxylic acids 78 were firstly hydrogenated to give the amines 49. The compounds 49 were converted to the isatoic anhydrides 75 with triphosgene 175. Selective ring opening at C-4 yielded the substituted amides 152 which were cyclized to the benzotriazinonecarboxylic acids 177 by nitrosation. The carboxylic acids were converted with thionyl chloride and ammonia 76 to two series of benzotriazinones 178, bearing carboxamide groups at the C-7 or C-8 positions. During the ammonolysis



N O BocHN

C

N

OH

H

O

N

H2N O

O

P

OEt

O

OEt BnO

173

N H

+

NHBoc DIEA, DCM r.t., 6 h

OBn 172

174

61

Scheme 34. Racemization studies of reactivated intermediates for Boc-Ser (Bn)-OH 172.

Cl H2 (g, 50 psi.) Pd/C (10%)

NO2 R1 CO2H

NH2

Cl

Cl

O O

Cl O

H N

Cl Cl

R1

175

R1 CO2H

DMF, r.t., 7-8 h

O

THF, 40-50 °C, 3 h

O 75 (97-98%)

49 (60-77%)

78 R2NH2 (aq, 40%) 176

N

NH2 NaNO2, HCl (aq, 0.5 N)

R1

NHR2

N

N R3

2) NH3 (Conc.), THF 76 25 °C, 24 h

R2

O

O 152 (65-79%) 1) SOCl2, DMF Reflux, 12 h

N

R1

0 °C, 1-2 h

25 °C, 0.5 h

O

177 (75-81%)

N N

R1= 3-CO2H, 4-CO2H R2= Me, Et, C6H5, (CH2)2Cl, CH2CO2Me R3= 7-CONH2, 8-CONH2

R2

O 178

Scheme 35. Synthesis of carboxamide derivatives of 3,4-dihydro-4-oxo-[1,2,3]-benzotriazine-7-carboxamide and 3,4-dihydro-4-oxo-[1,2,3]-benzotriazine-8carboxamide 178.

NH2

1) NaNO2, HCl (aq, 2 N) 0 °C, 1-2 h

N

NHAr UV-Vis OMe

OMe 2) Ar-NH2, r.t., 2-3 h 70

O 99 N

H2NNH2, Raney Ni 83

N N

Ar

N

N

N NHAr OMe

Reflux, 3-4 h O 179A

O 179B NH2

NH2

(CH2OH)2

H N

NHAr Reflux, 2-3 h

EtOH, 60-65 °C, 1-2 h

O 171 (60-65%)

EtOH, piperidine

N

O 149 (50-65%)

180 (80%)

If: Ar= 2-NO2C6H4 Ar= 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4 Scheme 36. Reductive fission of [1,2,3]-benzotriazines 171 with hydrazine 83 and Raney nickel.

step, the methyl ester group of compound 177 was converted to an amide 178 (Scheme 35) [74]. The triazenes 179A was obtained of diazotization methyl antranilate 99 and then treatment with aryl amine derivatives 70. Inspection of models confirmed that only the cis-isomers 179B had a favourable juxtaposition of substituents for amine-ester interaction. The triazine ester 179B cyclized to the benzotriazinone 171 in ethanol containing either water or base such as piperidine. The [1,2,3]-

benzotriazin-4 (3H)-ones benzotriazinones 171 were efficiently reduced to the expected 2-aminobenzamides 149 upon treatment with hydrazine 83 and Raney nickel (HRN) in ethanol. 2-Amino-N(2-nitrophenyl) benzamide 149 was identified by its cyclization in boiling ethyleneglycol to 2-(2-aminophenyl) benzimidazole180 (Scheme 36) [75]. Murakami and coworkers developed a synthetic method for the preparation of 3-(imino) isoindolin-1-ones 184 in yields ranging



Me

R2

N

Me N N

R3

+

C

N CpPd (p-allyl), PMe3 183

R2 N

N

R1

R3

Dioxane, 110 °C, 18 h

O

O

Me

181

Me R1

184 (90-99%)

182 Pd

R1= Me, C=ONPh2, C6H5, 4-OMeC6H4, 4-ClC6H4, 4-CF3C6H4, 2-OMeC6H4, 2-Pyridyl R2= H, OMe, CO2Me R3= H, OMe Scheme 37. Pd (0)-Catalyzed reaction of [1,2,3]-benzotriazin-4 (3H)-ones 181 with 2,6-xylyl isocyanide 182.

N

N

NO2

N

P(OEt)3 186 Reflux, 2 h

O 185

N

N

N

N N

N

H N

N

O

O 188 (55%)

187 N

H N KOH, H2O

N N OH

Reflux, 1 h O 189 (65%) N

N N

H N

N HNO3 (aq, 75%)

N

H N

NO2

N HF, 0-5 °C, 5-6 h

O

O 188

NO2

190 (42%)

Br2, AcOH

N

N

H N

Br

N

r.t., 5-6 h O

191 (54%)

Br

Scheme 38. Hetero aromatic ring systems derived from [1,2,3]-benzotriazin-4- (3H)-one 185.

from 90 to 99% via the reaction of [1,2,3]-benzotriazin-4(3H)-ones 181 with isocyanides 182 using the CpPd(-allyl) 183 along with PMe3 as catalyst (Scheme 37) [76]. The compound 188 was synthesized from the reaction of 3,4dihydro-2- (2-nitrophenyl)-[l,2,3]-benzotriazin-4(3H)-one 185 under reflux with triethylphosphite 186. The formation of benzotriazolo[2,1-b][1,2,3]-benzotriaziniumbetaine 188 was described through a nitrene intermediate 187 in which the N-electrons of the triazine ring interacted with the developing nitrene. Finally, the alkaline hydrolysis of 188 afforded 2-(2-carboxyphenylamino) benzotriazole 189, nitrated with 75% nitric acid gave dinitro deriva-

tive 190, and brominated with bromine in glacial acetic acid gave a dibromo derivative 191, respectively (Scheme 38) [77]. Nomoto and coworkers found that reaction of the benzotriazinone 192 with Lawesson's reagent 193 in toluene afforded the thione 194. Methylation of 194 with MeI 195 in alkaline medium produced the methyl sulfide 196 that was then oxidized to give the methyl sulfone 197 by treatment with KMnO4 in a mixture of CHCl3, and AcOH. Reaction of 197 with 3-(4-piperidinyl)-1,2,3,4tetrahydro-2-oxo-3-quinazoline 198 in dimethyl sulfoxide (DMSO) at ambient temperature afforded the final product 199 (Scheme 39). Cardiotonicactivity of the test compounds was evaluated in anesthe-



S S MeO

N

MeO

P

N

OMe

S

MeO

N

S 193

NH

MeO

P

NH

MeO Toluene, 100 °C Reflux, 4 h

O

N

S 194 (78%)

192 MeO

MeI, NaOH (aq, 2 N)

N

195

H2O2 (aq, 30%), AcOH 0 °C, 30 min

N

MeO

NH

O

S

Me

O 197 (83%)

196 (89%) O N

N N

MeO

SMe HN

N

KMnO4, CHCl3

N

MeO

MeOH, r.t., 2 h

MeO N

N N

MeO N 198 HCl, NEt3 DMSO, r.t., 18 h

N

O NH

199 (70%)

Scheme 39. Reaction of 6,7-dimethoxy-[1,2,3]-benzotriazin-4(3H)-one 192.

R N

N

R N

120 °C, Ar (g, 1 atm.)

N

h, l< 380 nm

N O

O

- N2

200

h, l> 400 nm

201 (20-30%)

C

R

O

202 (35-50%)

R= Me, Ph Scheme 40. Thermal decomposition of 1-methyl or 1-phenyl- [1,2,3]-benzotriazin-4 (1H)-one 200.

tized open chest dog protocol. The results of the test compounds were determined by measuring percent increase in maximum dP/dt of left ventricular pressure (LVdP/dt max, %) after i.v. administration (1mg/kg) in anesthetized rnongrel dogs. The potency of cardiotonic activity of the test compounds was compared with amrinone (1.0 mg/kgi.v.). Relative potency was calculated as the ratio of the LVdP/dt max of each compound to that of amrinone (amrinone=1) in the same dogs. The 6,7-dimethoxy-[1,2,3]benzotriazine-tetrahydro-2-oxo-3-quinazolinyl group 199 showed relatively potent cardiotonic activity similar to that of amrinone. Other 6,7-dimethoxy-l, 2,3-benzotriazine derivatives, however, was generally less potent than amrinone and the 6,7dimethoxyquinazoline derivatives [78]. 2.3. [1,2,3]-Benzotriazin-4 (1H)-one Derivatives Thermal decomposition of 1-methyl and 1-pheny- [1,2,3]benzotriazin-4(1H)-one 200 above 120 ºC under steam of argon

produced 1-methyl and 1-phenylbenzazetinone 201. The compounds 201 which were trapped in solid argon at 15 K, near-UV irradiation converted partially into its iminoketene isomers 202, and the reverse conversion of 202 in to 201 was effected with longer wavelength irradiation (Scheme 40) [79]. 2.4. 4-Substituted [1,2,3]-Benzotriazine Derivatives The thermolysis of 4-anilino- [l, 2,3]-benzotriazine derivatives 203 in hot formamide to give 3-arylquinazolin-4 (3H)-ones 212 in high yield was described. In hot acetamide-diglyme 4-(4nitroanilino)-[1,2,3]-benzotriazine 203 gave a high yield of 3substituted 4-(4-nitrophenylimino)-3,4-dihydro- [l, 2,3]-benzotriazine 205. 4-Arylaminobenzotriazines 203 lost only N2 to give benzazete-derived products 207. The ketenimine intermediates 208 reacted with traces of water in the formamide 206 yielding theanthranilamides 209. The latter compound reacted with formamide 206 to generate the formamidines 210. Next, treatment of 210 with



O Me

N

NH2 204

N

Diglyme, Reflux, 5 h N

H2N N

NAr

N

NAr

O

O 205 (95%)

N H NHAr

NH2 206

203

NH

NH

NH2

NH2 206

207

O

H2O, reflux, 0.5 h NAr

C

NAr

Reflux, 0.5-1.5 h

H

NHAr

208

209 (80-85%)

O

O N

NH2

H

H

NH2

206

N H

Me N

211 NHAr

N

Reflux, 2-4 h

Reflux, 1.5-3 h O

Ar

O

210 (45-90%)

212 (50-80%)

Ar= C6H5, 4-CNC6H4, 4-NO2C6H4 Scheme 41. Conversion of 4-arylamine-[l,2,3]-benzotriazines into 3-arylquinazolin-4(3H)-ones 212 with formamide 206 and methylformamide 211.

1) NaNO2, HCl (aq, 10 N) 0 °C, 3 h

NH2

CN

2)

213

N

H2N

N

CN

R1

N

H N

EtOH, piperidine

R1

R2

N

Reflux, 3 h NH

215 (80-84%)

R2

N

R1

R2

216 (60-70%)

214 N

N2 HCl (aq, 2 N)

KOH (aq, 10%)

N

NH 0 °C, 4 d

Reflux, EtOH, 2 h

NH2

N R1, R2= H, CN, NO2,

N

N

HN

HN

R1

N

NH2 R2

217 (90-100%)

R1

R2

218 (90-100%)

Scheme 42. Intramolecular cyclization of diazonium intermediate 217 to 4-(2,4-disubstituted-2-aminophenyl)-[1,2,3]-benzotriazine derivatives 218.

methylformamide 211 afforded the cyclized quinazolinones 212 with loss of ammonia. The water liberated in the conversion of compounds 209 into 210 was recycled to react with the ketenimines 208. Only a catalytic amount of water, therefore, was required to bring the reaction to completion (Scheme 41) [80]. 2-Cyanophenyltriazenes 215 were prepared through diazotization of 2-aminobenzonitrile 213. Cyclization of 2-cyanophenyltriazenes 215 generally closely parallels that of the 2-methoxyphenyl analogues. 1-(2-Cyanophenyl)-3-phenyltriazene 215 cyclized smoothly in 95% ethanol containing piperidine. Assignment of structure to the products of cyclization of 2-cyanophenyltriazenes was complicated because the 4-imino- [1,2,3]-benzotriazines initially formed 216 underwent Dimroth-type rearrangement [81] to the isomeric series 218 via an intermediate diazonium species 217. This rearrangement proceeds spontaneously when the 4-imino-

benzotriazines bear electron-attracting substituents on the 3-aryl groups 216. The product from the ethanol-piperidine cyclization of the cyanotriazene 215 was assigned structure 216 because its electronic absorption spectrum was similar to spectra of related 3substituted 4-imino-1, 2,3-benzotriazines, and in hydrochloric acid quantitatively rearranged to the isomer 218 (Scheme 42) [82]. Thermolysis of 4-(4-cyano or 4-nitroanilino)-[l, 2,3]-benzotriazine 219 in heteroalicyclic secondary amine 220 (pyrrolidine, piperidine, and morpholine) afforded 3-[2-amino-N-(4-cyano or 4nitrophenyl) benzimidoyl]-4-(4-cyano or 4-nitrophenyl-imino)-3,4dihydro-1,2,3-benzotriazine 222 in addition to the major product 2amino-N2-(4-cyano or 4-nitrophenyl)-N1N1-oxydiethyle-nebenzamidine 221. It seemed plausible that the higher boiling point of morpholine compared with that of pyrrolidine and piperidine was instrumental in diverting the reaction course away from ben-



R1

N

N

H2N NHR2R3 220

N

N

N

+

NH2

NR2R3

R1

Reflux, 86-124 °C, 7-8 h

N

N

R1

N

221 (65-75%)

N

222 (25-30%) R1

NH N R1

O

MeO

219

OMe

N N N

N

N

Reflux, 137-184 °C, 7-8 h

N

AcOH, EtOH NH2

R1

HN

Reflux, 5-6 h

R1

R1 223 (44-75%)

222 (70-80%)

R1= CN, NO2 R2, R3= (CH2)2O(CH2)2, (CH2)4, (CH2)5

Scheme 43. Thermolysis of 4-anilino-[l,2,3]-benzotriazines 219. MeO

HO

EtOH, reflux, 12 h

MeO

R1O

MeO

CN

30 °C, 2 h

R1O

NO2 227 (65-78%)

226 (70-80%)

CN

R1O

CN HNO3

K2CO3, DMF 37 °C, 6 h

224

H2 (g, 50 psi) Pd/C (10%)

MeO

R1-X 225

CN

NaNO2, HCl (aq, 10 N) 0 °C, 2 h

MeO

R1O

NH2

NH2

228 (68-74%)

R2

CN

N

N

R2 N H

229 (76-84%) 70

R1O

N

N

MeO 1) EtOH, reflux, 1 h 2) AcOH, reflux, 2 h

N

NH R2 230 (50-75%)

R1= Et, n-Bu R2= 3-CF3, 4-CF3, 3-OCF3, 4-OCF3, 2-F, 3-F, 4-F, 3-Cl, 3,4-Cl2, 3-Br, 4-Br X= Cl, Br

Scheme 44. Synthetic route to the target compounds 230.

zamidine formation. This view was sustained when higher yields of the by-product 222 were formed when 219 was heated in higher boiling solvents. Only those substrates bearingsubstituents in the anilinomoeity yielded unusual products: This structural feature evidently increases the electron deficiency at C-4, allowing the weakly nucleophilicanilinobenzotriazine to compete effectively with the morpholine. In the absence of a nucleophilic solvent e.g. in diethyleneglycol dimethyl ether the yield of thermolysis product 222 from 219 is markedly increased. Decomposition of 222 in boiling acetic acid, or more prolonged boiling in an acetic acid-ethanol

mixture, gave derivatives of 4-(4-cyano or 4-nitrophenyl)-2phenylquinazoline 223 (Scheme 43) [83]. Compounds 7-substituted-6-methoxy-4-substituted [1,2,3]-benzotriazines 229 were synthesized starting from the intermediates 4substituted-3-methoxybenzonitriles 226 that were prepared by the reaction of different alkyl halides 225 with 4-cyano-2-methoxyphenol 224 in the presence of potassium carbonate in DMF. The selectively nitration of compounds 226 in HNO3 gave the nitro compounds 227 in good yields, followed with the reduction reaction by Pd/C as catalyst to obtain the corresponding 2-amino-4-



N

Br N

Ph

N

N

H N

N

Ar S

Ph

S

Ar

N

r.t., 1 h

NEt3, EtOH r.t., 0.5 h

SH

N N

NaOEt, EtOH

232

N

N

N

Ph ArHN

231

234A

233 H N

OEt

Ar

N S

NH2

NH2

N

N

Ar

N

N

S

N

S

N Ph

Ph

Ph 234B

Ar N

236 (53-60%)

235 (55-65%)

Ar= H, 2,4-Br2C6H3, 2,4-Cl2C6H3 Scheme 45. Reaction of 4-mercapto- [1,2,3]-benzotriazine231 with N-(2,4-dibromophenyl) benzohydrazonyl bromide derivatives 232.

N NH2 N

N

R

N

Pb(OAc)4 N

N

0.02 Torr

DCM, r.t., 0.5 h R 237

R

NH2

Pb(OAc)4 DCM, r.t., 0.5 h

240

N

N N

N N

239 (20-30%)

R

238

N

450 °C

N

N

450 °C 0.02 Torr

R

R 242 (40-50%) N

241

R

R= H, Me, C6H5

243 (10-20%)

Scheme 46. Formation of [1,2,3]-benzotriazines 242 by oxidation of 1-aminoindazoles 237 and 2-aminoindazoles 240.

alkoxy-5-methoxybenzonitrile 228. Compounds 228 were diazotized, coupled with substituted anilines 70, and purified by recrystallization with ethyl acetate to afford triazenes 229. Compounds 229 were boiled in ethanol, then directly were rearranged to the final compounds 230 in refluxed acetic acid after evaporating the ethanol (Scheme 44). The abilities of these compounds to inhibit the VEGFR-2 kinase activity and the proliferation of human microvascular endothelial cells (MVECs) were determined. PTK787 was used as the positive control for VEGFR-2 kinase, and 0.1% (v/v) DMSO was the negative control. The inhibition rate of the compounds against VEGFR-2 kinase at the concentration of 10 g/mL was measured. The concentration of the compounds (M) producing 50% cell growth inhibition (GI50) after 4 days of drug exposure was determined by the MTT assay. 6-Methoxy-4substituted [1,2,3]-benzotriazines had the abilities of inhibiting the vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity [84]. The reaction between 4-mercapto- [1,2,3]-benzotriazine 231 and N-(2,4,-dihalo phenyl)benzohydrazonyl bromide 232 was carried out in ethanol in the presence of triethylamine and the thiohy-

drazonates233 were produced. The latter cyclized to 234A by nucleophile addition of amine to benzotriazine ring. Then, Reversible protonation of the spirocyclic intermediate 234A at N-1 or N-3 of the triazine by aromatization of the newly formed ring gave 234B. Afterwards, opening of the triazine ring with loss of N-3 and N-2 as nitrogen, and protonation of N-1 gave the thiadiazolium ion 235. The compound 233 such thiadiazolium ions added ethoxide ion equivalent at C-2 236 when treated with ethanolic sodium ethoxide and so progression of 235 to the observed product 236 was readily understood. The ease of reaction was notable in view of the stability of simple aryl thiohydrazonates (Scheme 45) [85]. Oxidation of 1-amino-3-substituted indazoles 237 and 2-amino3-substituted indazoles 240 was investigated since it seemed likely that, by analogy with oxidation of 1-aminobenzotriazole and 2aminobenzotriazole and related compounds, nitrogen would be extruded from the resulting nitrenes 238 and 241. The former should lose nitrogen and either collapse to the azabenzocyclobutadiene 239 or fragment further to RCN and benzyne. Compound 241 should lose nitrogen and ring-open to the cyanoacetylene 243, or possibly collapse to the azabenzocyclobutadiene 239. It was


N

N


N

R1MgBr 244

NR1

R1

N

N

N

N Et2O, r.t., 1 h

N Ph

Ph 246

245

242

N

N

Ph

Ph

N

R1

247

NR1R2 R2I 195

N N

Et2O, r.t., 2-3 h

R1, R2= Me, Et

Ph 248 (35-44%)

Scheme 47. The reaction of 4-phenyl[1,2,3]-benzotriazine 242 with Grignard reagents 244.

N

N N

400-500 °C

250 (50-60%)

N 0.01 Torr

R 242 R= H, Me, C6H5

N

R 249

251 (40-50%)

- RC

N

R 239 (20-30%)

Scheme 48. The vacuum pyrolysis of [1,2,3]-benzotriazines 242.

through that common products from the oxidation of 1- and 2aminoindazoles would indicate the intermediacy of 239. Somewhat surprisingly, oxidation of the N-amino-3-substituted indazoles with lead tetra-acetate in dichloromethane did not lead to the loss of nitrogen, but the [1,2,3]-benzotriazines 242 was formed rapidly and almost quantitatively. Similarly, oxidation of 1-aminoindazole 237 and 2-aminoindazole 240 and it could only be isolated when the Naminoindazole was added slowly to lead tetra-acetate in rigorously dried solvents in the presence of excess of powdered calcium oxide to remove acetic acid (Scheme 46) [86]. Nucleophilic addition of alkyl Grignard reagents 244 at N-2 of 4-phenylbenzotriazine 242 led to benzotriazinyl anion 245 which by ring opening converted to intermediate 246 followed by rearrangement to intermediate 247. Finally, quenching of the resulting anion with alkyliodide 195 gave 1-dialkylamino-3-phenylindazoles 248 in 35-44% yield (Scheme 47) [87]. Laser was used as a directed heat source to carry out the vacuum pyrolysis of [1,2,3]-benzotriazine, 4-phenyl and 4-methyl[1,2,3]-benzotriazine 242. The compounds 242 were chosen because these compounds decompose at relatively low temperatures (400-500 °C) in closed systems at 0.01 Torr and gave good yields of biphenylene 251, the product of the dimerization of benzyne 250. Compounds 242 were also potential sources of benzazete (1azabenzocyclobutene), phenylbenzazete and methylbenzazete 239. Provided that the vacuum pyrolyses were carried out under conditions where cyclization of the diradicals 249 formed by extrusion of N2 competes with fragmentation to 250 and RCN (Scheme 48) [88]. 4-Substituted- [1,2,3]-benzotriazines 242 were synthesized by diazotisation of 2-aminobenzylideneamines 253 followed by oxidation of the hydrazones 255. Through the reaction of 2-aminophenyl ketones 252 with hydrazine, amino-hydrazones 253 was obtained.

All the amino-diazo compounds 254 were prepared by diazotisation reaction of amino-hydrazones 253. Thermal cyclization of the amino-diazo compounds 254 resulted in the formation of dihydrobenzotriazine 255 that was followed by oxidative removal of hydrogen on oxidation with mercury(II) oxide to produce 4substituted-[1,2,3]-benzotriazines 242 (Scheme 49) [89]. The syntheses of 4-[1-adamantyl (hydroxy) methyl]-, 4-[1methylcyclohexyl (hydroxy) methyl]-, and 4-(2-hydroxycyclohexyl)-[1,2,3]-benzotriazines 264 were described as structural variants of the usual 4-substituted-immuno-[1,2,3]-benzotriazines that possessed antiarrhythmic activity. The indazoles 258 were obtained from 256 by oxidation with ozone followed by nitrosation and conversion into the corresponding azido derivatives by sodium azide 257 which cyclized upon treatment with hydrazine 84. Compounds 258 were converted to a separable mixture of 1-aminoindazoles 260 and 2-amino indazoles 261, both of which was oxidized to the benzotriazines 262. Reaction of 262 with methylisocyanate 263 yielded the methyl carbamates264. The syntheses of 4-[1-adamantyl (hydroxy) methyl]-, 4-[1-methylcyclohexyl (hydroxy)methyl]-, and 4(2-hydroxycyclohexyl)-1,2,3-benzotriazines are described as structural variants of the usual 4-substituted-immuno-1,2,3-benzotriazines that have been shown to possess anti-arrhythmic activity as their N-2 alkyl halides orsulphonates. These compounds showed a wide variation in aqueous solubility but were devoid of any antiarrhythmic activity both as parent compounds and as their methyl carbamate derivatives 264 (Scheme 50) [90]. 2.4.1. 4-Imino-3-Substituted [1,2,3]-Benzotriazine Derivatives The exposure of 2-azidobenzonitrile 265 to methylmagnesium bromide 266 in THF was carried out at room temperature to afford 3,4-dihydro-4-imino-3-methyl-[1,2,3]-benzotriazines 267 (Scheme 51) [91].


H2NNH2 84

NH2

NH2

AcOH, EtOH Reflux, 8 h

R

NH2

EtOH N2

0 °C, 0.5 h

R

Reflux, 8 h

R

253 (68-83%)

252

NH

NH2

NaNO2, HCl (aq, 5 N) N

O

H N


254 (80-96%) N

HgO

N

N N

EtOH, r.t., 90 min R

R 242 (26-50%)

255

R= H, Me, C6H5, 4-OMeC6H4, 2-NH2C6H4, 2-NH2-4-ClC6H3 Scheme 49. Oxidation of amino-hydrazones 253 with mercury (II) oxide. NH2 N N 1) O3, r.t., 0.5 h 2) NaNO2, HCl (aq, 2 N) 0 °C, 0.5 h

R1

R1 N

Me N H

N H

3) NaN3, r.t., 2 h 257 4) N2H4, EtOH, 50 °C, 1 h 84

256

N

Pb(OAc)4

EtOH, H2O 55 °C, 2 h

258 (37-50%)

R1 260 (20-35%) N N

NH2

R1 261 (14-28%)

Me-N=C=O 263

N

N

N N

N

CaO, DCM

H2N-OSO3H, NaOH 278

Py, reflux, 5-6 h

R1

R2

262 (50-67%)

264 (50-60%) HO

HO Me R1=

,

,

HO

Me NH O R2=

Me

H N

O

,

Me O

Me NH

,

O

O

O

Scheme 50. The Synthesis of 4-alicyclic (hydroxyl) methyl- and 4-hydroxyalicyclic-[1,2,3]-benzotriazine262and their methyl carbamate derivatives 264.

R1

R1

R2

N3

MeMgBr 266

CN

THF, r.t., 1 h

265

N

N N

R2

Me

NH 267 (12-78%)

R1= H, Me R2= H, Me, OMe, Cl, Br Scheme 51. Synthesis of benzotriazines 267 from 2-azidobenzonitrile derivatives 265.

The reaction of aniline derivatives 213 with sodium nitrite in the presence of glycinamide 268 afforded N-arylazoglycinamides 269. Finally, the trizenes with a reactive ester or cyano-substituent in the ortho-position of the benzene ring 269 readily underwent spontaneous cyclization in ethanol solvent to the corresponding (carbamoylmethyl)-[1,2,3]-benzotriazin-4 (3H)-one 270 and 3(carbamoylmethyl)-4-imino-[1,2,3]-benzotriazine 271, respectively (Scheme 52) [92]. The decomposition of 1,3-di-2-cyanophenyltriazene 273 in mineral acids was described by Stevens. 1,3-Di-2-cyanophenyltriazene 273 was formed from diazotization of 2-aminobenzonitrile 213 and coupling with substituted 2-aminobenzonitrile 272. The



N

N

EtOH

NH2

N

O

1) NaNO2, HCl (aq, 2 N) 0 °C, 1-2 h

N

N

H N

O

NH2

X

H2N

2)

270 (85%)

213

N

EtOH

269

NH2

NH2

Reflux, 1 h

O

X

O

268

N

O

N

r.t., 12 h

NH2

H2O, r.t., 15 min

NH

X= CN, CO2Et

271 (68%)

Scheme 52. Synthesis of 3-(carbamoylmethyl)-[1,2,3]-benzotriazin-4(3H)-one 270 and 3-(carbamoylmethyl)-4-imino-[1,2,3]-benzotriazine 271. NH2

1) NaNO2, HCl (aq, 2 N) 0 °C, 1-2 h

N

R1

CN 213

HN CN NC

R3

2)

R1

N N

R2

NH NC

R3

EtOH, 25 °C, 48 h

273

R3

NC

N

HCl (aq, 10 N) R2

R2

H2N

R1

N

274 (60-70%)

272 NaOAc.3H2O, H2O 25 °C, 3 d N

N NH

AcOH EtOH, H2O (1:1)

N

Nitrobenzene anhydrous

R1 R2

N

R1 N NH

Reflux, 1 h

r.t., 90 min

O R3

NC

R1= H, NH2, OH R2= H, CN, OH R3= H, NH2, NMe2

H2N

R2

NC

R3

+

8 (50%)

272 (25-30%)

275 (55-60%)

Scheme 53. Decomposition of 1,3-di-2-cyanophenyltriazene 273. NHR NH2 H N

N NaNO2, HCl (aq, 2 N) Ar

N N

0 °C, 1-2 h

N

SnCl2.2H2O Ar

NR

NAr

HCl, EtOH r.t., 30 min

N H

R 276

278 (50-60%)

277 (65-80%) NHR

RHN EtOH 20-25 °C, 90 min

NH2

NHAr NH

N H

NaOH (aq, 10 N) EtOH, 0 °C-r.t., 2 h

N

280 (45-55%)

279 (65-75%)

+ ArNH2

N H 70

R= H, Me, Et, i-Pr, C6H11 Ar= C6H5, 2-MeC6H4, 3-MeC6H4, 2-MeOC6H4, 4-MeOC6H4

Scheme 54. Decomposition of substituted 4-iminobenzotriazines 277.

former upon treatment with hydrochloric acid was cyclized to 4iminobenzotriazine 274 which by further acid hydrolysis underwent a Dimroth rearrangement to the 4-(2-cyanophenyl) iminobenzotriazine 275. Finally, 4-(2-cyanophenyl)iminobenzotriazine 275 was decomposed to the [1,2,3]-benzotriaz-4(3H)-one 8 and 2-aminobenzonitrile derivatives 272 (Scheme 53) [93].

Treatment of 2-amino-N-alkyl-N´-arylbenzamidines 276, having identical N-substituents, with nitrous acid gave benzotriazines 277 unambiguously. 4-Imino-[1,2,3]-benzotriazines 277 on reduction by stannous chloride dihydrate afforded 3-aminoindazoles 280. The production of 3-aminoindazole 279 from both isomeric benzotriazines 277 and 276 implied that, in their reduction, fission of


N

N


N

N

NHAr

N

EtOH, piperidine

N

Reflux, 2-3 h

CN

HCl (aq, 2 N) Ar

N

25 °C, 3 h

NHAr

NH 281

N

282 (60-81%)

283 (60-74%)

Ar= C6H5, Bn, 2-NH2C6H4, 3-NH2C6H4, 4-NH2C6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4 Scheme 55. Synthesis and rearrangement of 3,4-dihydro-4-imino- [1,2,3]-benzotriazines 282.

N

NH2

1) NaNO2, HCl (aq, 2 N), H2O 0- 5 °C, 0.5 h

R2

R1

N

R1 2)

O

R3NH2

N R3

R2 OH

(aq, 2 N), 2.5 h 70

284

285 (55-96%)

R1= H, Cl R2= H, C6H5 R3= Me, Et, C6H5, Bn Scheme 56. Synthesis of 3,4-disubstituted [1,2,3]-benzotriazine 285 via 2-aminobenzaldehyde or 2-aminobenzophenone 284.

O O N

N

N O

O

O Ph

N N N

420 °C

Ph

287

N H

Ph

288

117 (25%)

289 (25%)

0.03 Torr N

Ph

N

286

H N

N

N

N

N

NO

O

Ph 290

Ph 291

Ph 292 (14%)

Scheme 57. Flash pyrolysis of 4-phenyl-[1,2,3]-benzotriazine 1-oxide 286.

the 2,3-bond was followed by cyclization to an ortho-amidine, which then underwent elimination of an arylamine 70 (Scheme 54) [94]. A series of 3-substituted 3,4-dihydro-4-imino- [l,2,3]benzotriazines 282 were prepared by cyclization of the appropriate 2-cyanophenyltriazenes 281 in ethanol containing piperidine. Triazenes with powerful electron-withdrawing substituents were cyclized directly to substitute 4-anilino- [l, 2,3]-benzotriazines 283. Rearrangement of 3-aryl-3, 4-dihydro-4-imino- [1,2,3]-benzotriazines 282 to the isomeric 4-arylamino- [1,2,3]-benzotriazines 283 occurred in ethanol or hydrochloric acid and was facilitated by electron-withdrawing substituents in the aryl nucleus (Scheme 55) [95]. 2.4.2. 4-Hydroxy-3-Substituted [1,2,3]-Benzotriazinederivatives An approach to the synthesis of 4-hydroxy- [l,2,3]-benzotriazines 285 was developed using 2-aminobenzaldehyde and 2aminobenzophenones 284 as starting materials. Then, the diazonium salt obtainedfrom 284 was coupled with an excess of aqueous amine 70 to produce good yields of 4-aryl-4-hydroxy-3-alkyl or 3-aryl-[1,2,3]-benzotriazines 285 (Scheme 56) [96, 97].

2.5. 4-Substituted [1,2,3]-Benzotriazine 1-Oxide Derivatives The pyrolysis of 4-phenyl- [l, 2,3]-benzotriazine1-oxide 286 was investigated by Adger et al. Pyrolysis of the N-oxide 286 at 420 ºC gave intermediate 287, which converted into 2-phenylbenzazete 1-oxide 288. This would in turn led to 3-phenyl-2, 1benzisoxazole 289 and then rearranged thermally to acridone 117. A similar mechanism proposed to account for the formation of 3phenyl-indazole 292 on heating of N-oxide 286 Formation of 3phenyl-indazole 292 involved a different pathway in terms of the intermediacy of 290 and 2-nitroso-3-phenyl-2H-indazole 291 (Scheme 57) [98]. 2.6. 4-Substituted [1,2,3]-Benzotriazine 2-oxide Derivatives 4-Methoxy and 4-phenoxy- [1,2,3]-benzotriazines 293 were oxidized by m-chloroperbenzoic acid (m-CPBA) to form 2-oxides 294. The 4-methoxy or 4-phenoxy 2-oxides 294 were converted into 4-amino- and 4-hydrazino-derivatives 295. The compounds 295 were hydrolyzed to the acidic 3,4-dihydro-4-oxo- [1,2,3]benzotriazine 2-oxide 296, which was N-methylated by diazomethane 297 at the 3-position to produce the compound 298. The 15 N NMR spectrum of the products showed all the signals well to


N


N

N

m-CPBA

N

N

O

N

DCM, r.t., 7-8 h

OR

N

NH3, N2H4 76 83 MeOH, 0 °C, 2 h

N

OR

X 295 (50-59%)

294 (54-60%)

293

N KOH (aq, 20%)

N

CH2N2 297

O

N

NH

MeOH, 20 °C, 17 h O

O

N

N N

MeOH, Et2O (1:1) 0 °C, 1 h

O

N +

O

N

Me

O

OR 299 (11%)

298 (50%)

296 (60%)

N

X= NH2, HNNH2 R= Me, C6H5 Scheme 58. Formation of the 2-oxides 298 and 299 on N-oxidation of 4-alkoxy-[1,2,3]-benzotriazine 293.

N O N

O N N

R/Ar

R

h O

NH2

301

R

302 (80-95%)

MeOH, 2 h H N

N 300

N Ar

R= Me, Et Ar= C6H5, 4-OMeC6H4, 4-ClC6H4

303

NO

N Ar 304 (50-64%)

Scheme 59. Photolysis of 4-substituted [1,2,3]-benzotriazine 3-N-oxides 300.

high field (low frequency) of nitromethane, and so did not contain two adjacent lone pairs. The N-oxide group was therefore at the 2position in each case. A small amount of the 3-oxide was also isolated from the oxidation of the 4-methyl derivative. These 2-oxides proved to be remarkably resistant to deoxygenation by triethylphosphite or phosphorus trichloride. The methoxy group of 4methoxy-[1,2,3]-benzotriazine 2-oxide 299 could be displaced by a variety of nitrogen nucleophiles (Scheme 58) [99]. 2.7. 4-Substituted [1,2,3]-Benzotriazine 3-Oxidederivatives Horspool and coworkers explained that an aromatic N-oxide lost NO upon photolysis through the intermediate N-nitroso compound 301, which gave a positive test for an N-nitroso compound. For instance, aliphatic derivative of 4-alkyl-[1,2,3]-benzotriazine 3N-oxide 300 on irradiation in methanol produced 2-aminophenyl ketone 302 via the unstable oxaziridine intermediate 301. On the other hand, upon irradiation of aromatic derivative of 300 in methanol, 3-arylindazoles 304 were obtained through the loss of NO of 2nitrosoindazole derivatives 303 in 50-64% yield (Scheme 59) [100]. 2.8. Five-Membered Fused [1,2,3]-Benzotriazine Derivatives 2.8.1. Triazolo[4,3-c][1,2,3]-Benzotriazine Derivatives Treatment of 4-chloroquinazolines 305 with hydrazine hydrate 83 at 150ºC in a sealed tube gave 4-amino-3-(2-aminophenyl)-4H[1,2,4]-triazoles 306 and a second product, 3-(2-aminophenyl)-4H[l,2,4]-triazole 307, was also isolated. 4-Amino-3-(2-aminophenyl)-

4H-1,2,4-triazole 306 on reaction with two equivalents of nitrous acid, afforded 308 in good yield. Next, reduction of 308 with sodium borohydride in isopropanol yielded 3-(2-aminophenyl)-4H-1, 2,4-triazole 309. Finally, l, 2,4-triazolo [1,5-c] [1,2,3]-benzotriazine 310 was obtained via diazotization and cyclization of 309 (Scheme 60) [101]. 2.8.2. Triazolo [4,3-c][1,2,3]-Benzotriazine Derivatives 3-(2-Aminophenyl)-s-triazole 311 on reaction with nitrous acid, gave s-triazolo[4,3-c][1,2,3]-benzotriazines 314 through diazotization and ring closure. The same product was also obtained from 4hydrazinyl [1,2,3]-benzotriazine 312 and orthoesters such as triethylorthopropionate 313 in the presence of hot aqueous potassiumcarbonate (Scheme 61) [102]. 2.8.1. Indolo [1,6-a][1,2,3]-Benzotriazine Derivatives Based on the success of ortho-alkenyl anilines in many kinds of C(sp2)–H transformations, the scope of the substituted heterocyclic compounds 315 as a substrate was further investigated. Fortunately, anilines with several ortho-heteroarenes such as indoles 315 in the presence of TBN 90 generated the desired products, indolo[1,6a][1,2,3]-benzotriazine derivatives 316, in moderate to excellent yields under optimized conditions (Scheme 62) [103]. 2.8.2. Imidazo [1,2-c][1,2,3]-Benzotriazine Derivatives Foroumadi and coworkers developed a three-step sequence for the synthesis of imidazo[1,2-c][1,2,3]-benzotriazine derivatives


N2H4 83

N

NH2

Seald glass tube 120-150 °C, 6 h

N

305

H N

+

N

N

N

NH2 H N

i-PrOH, reflux, 6 h

N

N

H N

2) r.t., 12 h N

N

N

308 (70%)

N

1) NaNO2, HCl (aq, 2 N) 0-5 °C, 1 h

N N N

2) r.t., 12 h N

N

307 (22%)

306 (66%)

NaBH4

1) NaNO2, HCl (aq, 2 N) 0-5 °C, 1 h

NH2

NH2

N Cl


N

N

310 (80%)

309 (70%) Scheme 60. Reaction of 4-chloroquinazolines 305 with hydrazine 83.

NH2

1) NaNO2, H2SO4 (aq, 8 N) H3PO2, - 10 °C, 2 h

H N R N

2) 60 °C, 2 h

N

N

311 Et N

O

O O

N

N

Et

R

N

Et

313

N NHNH2 312

N R

N

314 (75-90%)

K2CO3(aq, 2N), 100 °C Reflux, 48 h

R= H, Me, Et, C6H5 Scheme 61. Synthesis of s-triazolo[4,3-c][1,2,3]-benzotriazine 314.

t-BuONO 90

R N H

H2N

R

Reflux, EtOH, 120 °C

N N

315

N

316 (62-80%)

R= 6-Me, 6-i-Pr, 6-t-Bu, 6-OMe, 7-Me, 7-i-Pr, 7-t-Bu, 7-F Scheme 62. Synthetic route of indolo [1,6-a][1,2,3]-benzotriazine derivatives 316.

321. First, the reaction of benzyl 317 with 2-nitrobenzaldehyde derivatives 20 were carried out in the presence of NH4OAc 318 in acetic acid at reflux temperature to yield 319. Reduction of the nitro group with zinc powder in the mixture of MeOH/H2O was happened which resulted in formation of compound 320. This reaction was simply performed in the presence of ammonium chloride. Finally, the diazotation of amine moiety and subsequent cyclization in the presence of sodium nitrite in aqueous acidic solution led to imidazo[1,2-c][1,2,3]-benzotriazines 321 (Scheme 63) [104]. 2-(2-Aminophenyl) benzimidazoles 323 were prepared from the condensation of an o-phenylenediamine 322 with an anthranilic acid 49 in polyphosphoric acid (PPA) at 250ºC. The benzimidazo[l,2-c][1,2,3]-benzotriazine systems 324 were then prepared by

the diazotization and ring closure of 2-(2-aminophenyl)benzimidazole 323. Substituents did not affect the ease of ring closure and all the benzimidazobenzotriazines were obtained in excellent yields (Scheme 64) [105]. Zaika and Joullie found that by heating benzimidazo [l, 2-c][l, 2,3]-benzotriazine derivatives 324 with an excess of sulfuric acid, nitrogen was gently evolved and the compound 324 was hydrolyzed to the corresponding 2-(2-hydroxyphenyl) benzimidazoles 325. In addition, benzimidazo [1,2-c][1,2,3]-benzotriazine derivatives 324 reacted with cuprous chloride to produce the corresponding 2-(2halopheny1) benzimidazoles 327. It is noteworthy to mention that, when benzimidazo [l,2-c][1,2,3]-benzotriazines were subjected to the Sandmeyer reaction [106], when treated with hydrochloric or



R2 R3

O

NO2

R2

R1 R3

NH4OAc, AcOH 318

+ H

R4 O

N

R4

Reflux, 12 h

O

R1

NO2 R1

HN 317

20

319

R2

R1

R3 Zn, NH4Cl

NH2

R2

N

R4

N

1) NaNO2, HCl, H2O 0 °C, 30 min

R1

R3

R1

N N

HN

MeOH, H2O r.t., 2 h

2) r.t., 2 h

R4

320

R1= H, OMe R2= H, OMe R3, R4= H, OCH2O

N

321 (79-89%) R1

R1

Scheme 63. Synthesis of imidazo[1,2-c][1,2,3]-benzotriazine 321. R2

NH2

R3

H2N

PPA

R2

H N

R1

N

H2N R3

+ R1

NH2

250 °C, 1-2 h

R4

HO2C

R4

49

322 1) NaNO2, HCl, H2O 0- 5 ° C, 35 min 2) EtOH, reflux, 1-2 h

323 N

R2

N

O

N R1

R3 N 324 (92-98%)

HO

PPA:

P

O

H

OH

n

R4

R1= H, Me, Cl R2= H, Me, Cl R3= H, Cl R4= H, Me, F, Cl

Scheme 64. Synthesis of benzimidazo [l,2-c][1,2,3]-benzotriazine 324. R4 H2SO4 (aq, 6 N) N

N R2 R1

Reflux, 3.5 h

N

R1

N

R2

N H

R3

R3

N R4 324 R1= H, Me, Cl R2= H, Me, Cl R3= H, Cl R4= H, Me, F, Cl X= Cl, Br

HO

325 (39-97%) 1) CuX2 (aq, 10%), HX 326 r.t., 2 h 2) 100 °C, 15 min

R4 R1

N

R2

N H

R3

327 (39-97%)

X

Scheme 65. Sandmeyer reaction and acidic hydrolysis of benzimidazo[1,2-c][1,2,3]-benzotriazines 324.

hydrobromic acids in the presence of cuprous salt 326 the same yield of the corresponding 2-(2-halophenyl)benzimidazoles 327 was formed (Scheme 65) [107]. Spector and Joullie explored the reaction of benzimidazo[1,2c][1,2,3]-benzotriazine 324 with phenyl isothiocyanate 328 in o-

dichlorobenzene (ODCB). The replacement of the diazo group of 324 by phenyl isothiocyanate 328 was a characteristic reaction of this system to produce a 5-phenylbenzimidazo [1,2-c]quinazoline6(5H)-thione 329. Furthermore, the reaction of 324 with ethanolic potassium hydroxide yielded 2-phenylbenzimidazole 330 based on



S C N

Ph

S N N

328 N

1) ODCB, 170 °C, 2 h 2) HCl, 170 °C, 1 h

N

N

N 329 (36.6%) H N

N Method A-B

324

N 330 (50-77%) Method A: KOH (aq, 15%), EtOH, Reflux, 8 h Method B: 1) N2 (g), EtOH, Quartz vessel, 30 min 2) hu, UV lamp, 450 W, 3 h Scheme 66. Reactions of benzimidazo[1,2-c][1,2,3]-benzotriazine 324.

N N

NH2

H N

H2N

N

N

NH2

PPA 180 °C, 2 h N

NH2 332

N

H N

N

1) H2SO4, 0- 5 °C 2) NaNO2 H2SO4, 0- 5 °C

333

49

NH2

N N

COOH

NH2 331

N

H2N

335 (40%)

3) H3PO4, 10 °C, 1 h N

N

N

N N

N

334 336 (32%)

Scheme 67. Synthetic route of pyridoimidazo[4,5-b][1,2,3]-benzotriazines 335 or [4,5-c][1,2,3]-benzotriazines 336.

the reactions of diazonium salt in basic media (method A). In another procedure, method B, the photolysis of 324 was carried out under UV light irradiation in the presence of nitrogen atmosphere and 2-phenyl benzimidazole 330 was isolated (Scheme 66) [108]. Spector and Joullie found that the internal diazonium salt is a useful approach for the synthesis of pyridoimidazobenzotriazines 335 or 336 from the starting materials, 2-aminophenylimidazo [4,5b]-pyridine 333 or 2-aminophenylimidazo[4,5-c]-pyridine 334. The latter compounds were in turn prepared from the condensation of 2,3-pyridinediamine 331 or 3,4-pyridinediamine 332 with anthranilic acid 49 in the presence of PPA. Interestingly, the compounds 335 and 336 were finally obtained by the ring closure diazotization of their respective precursors with nitrosylsulfuric acid rather than the usual diazotization reagent (sodium nitrite plus hydrochloric acid) (Scheme 67) [109, 110]. 2.8.3. Pyrido [3, 2: 4,5] Pyrrolo [1,2-c][1,2,3]-Benzotriazine Derivatives Derivatives of ring systems pyrido[3',2':4,5]pyrrolo[1,2c][1,2,3]-benzotriazine 344 were prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines 343 in excellent yields. The key intermediates for the synthesis of the benzotriazines 344 were substituted 2-(1H-pyrrolo[2,3-b] pyridin-2-yl) anilines of type 338. These latter compounds were conveniently prepared by

an intramolecular Chichibabin-type reaction [111] between 3methylpyridine 338 and 2-aminobenzonitriles 213 in the presence of lithium diisopropylamide (LDA). The acetylation of compounds 338 gave the corresponding acetamide derivatives 339 in quantitative yields, which were nitrosated with sodium nitrite in acetic acid to give the desired nitroso-acetamides 340 in excellent yields. The subsequent removal of acetyl group using potassium hydroxide led to the amino derivatives 343. Diazotization of intermediates 343 gave the expected nitrosopyrido [3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazines 344 in excellent yields. As in indole and pyrrole series a bromine atom was used in the attempt to lock the 3 position of the pyrrole moiety. The compounds 338 were brominated using N-bromosuccinimide in dimethylformamide to get the corresponding brominated intermediates 341 in very good yields. In this case, differently from the indole and also pyrrole series, in which an unusual Japp-Klingemann reaction [112] occurred affording the corresponding cinnoline derivatives, the diazotization of the bromo derivatives 341 gave 12-bromopyrido [3',2': 4,5]pyrrolo[1,2c][1,2,3]-benzotriazines 342 in excellent yields (Scheme 68). These compounds were screened on about 60 human tumor cell lines derived from nine cancer cell types. Tested compounds exhibited antiproliferative activity against all the human cell lines. A particular efficacy was observed against the leukemia sub-panel. Flow cytometric analysis of cell cycle demonstrated an increase of per-



R1 Me

NC

R1

1) LDA, THF 0 °C, 30 min

H2N

R2

2) THF, 90 °C, 90 min 3) LDA, THF, 0 °C, 30 min 4) 50-60 °C, 4 h

+ N 337

213

R2

R1 Ac2O R1

r.t., 2 h

R2

N H

H2N

338 (45-62%)

R2 N H

N

2) r.t., 1 h O

HN O

340 (94-99%) Me

Me

9 H2N

Br

R1

Br

338 NBS, DMF

R2 r.t., 16 h

N H

N

R1

NO

2) r.t., 1 h

N H

N

O

N H

R1

1) NaNO2, H2O AcOH, 0 °C, 1-2 h 2) r.t., 1 h

N

R2

N N

H2N

N

344 (91-98%)

343

Me

N

NO

R1 R2

HN

340

N

342 (95-99%)

KOH (aq, 15%) EtOH Reflux, 24 h

R2

N

N

H2N

NO R2

R1

1) NaNO2, H2O AcOH, 0 °C

341 (75-91%)

N

R1

NO

1) NaNO2, H2O AcOH, 0 °C, 1-2 h

HN

338

R2 N

N H

N

N H

N

R1= H, Cl R2= H, Me, OMe, Cl Scheme 68. Synthesis of substituted 12-nitrosopyrido [3',2': 4,5]pyrrolo[1,2-c][1,2,3]-benzotriazines 344 and 12-bromopyrido [3',2':4,5] pyrrolo [1,2-c][1,2,3]benzotriazines 342. NO2

N

NH2 NH2

N NH

H2, Raney Ni

NH

EtOH, 70 °C, 3-4 h

X 345

NH2

N

1) NaNO2, HCl (aq, 2 N) 0 °C, 1 h

N N

NH2 N

2) r.t., 2-3 h X

X

347 (70-87%)

346

X= O, NH

Scheme 69. 2-Aminopyrimidin-4 (3H)-ones bearing [1,2,3]-benrotriazinyl group 347.

centage of cells in G2/M phase. They cause apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3, caspase-8 and caspase-9. Moreover, these compounds acted as topoisomerase I inhibitors [113]. 2.9. Six-Membered Fused [1,2,3]-benzotriazine Derivatives 2.9.1. Pyrimido [1,6-c][1,2,3]-benzotriazine Derivatives Brown and Stevens developed a synthetic route to pyrimido [1,6-c][1,2,3]-benzotriazines 347. Reduction of 2-nitrobenzamido-

precursors 345 to 2-aminobenzamido-precursors 346 took place upon treatment with hydrogen and Raney nickel. The pyrimidine derivatives bearing [1,2,3]-benzotriazinyl units 347 were prepared by diazotization and ring closure of the appropriate 2-aminobenzamido-precursors 346 (Scheme 69). Many of the prepared benzotriaiznepyrimidines were screened for tumour-inhibitory activity against lymphoid leukaemia (L1210), P 388 (lymphocytic leukaemia) in mice, and human epidermoid carcinoma of the nasopharynx (cell culture). None of the benzotriaiznepyrimidines 347


NH2

R


N

1) NaNO2, HCl (aq, 5 N) 0 °C, 1-2 h

CN

H2N

2)

R

NH2

213

NC

NH2

N

HN CN

R

N

NC 349B (40-45%)

349A (40-45%)

N 348

NC

N

CN

N

H N

NH2 N

EtO(CH2)2OH, KOH Reflux, 3-4 h N EtOH, piperidine Reflux, 2.5 h

N N N

R NH

NH2 N

EtOH, piperidine

N N

R

Reflux, 2.5 h

N

NH2 N

CN NH

350 (45-55%)

351 (50-65%)

R= H, Me, Br, NO2 Scheme 70. Synthesis of 4-amino-2(2H)-imino-s-triazino[1,2-c][1,2,3]-benzotriazines 351.

NO2 NO2

C H

1) BF3, benzene 23 °C, 20 min

N

Me

+ O

H H N Raney Ni, H2 (g)

H

2) 40 °C, 4 h O

352

353

N 1) NaNO2, HCl, H2O 0- 5 °C, 5- 10 min

H O

Me

MeOH, THF

354 (26%)

NH2 H H N

Me

N N

H

2) H2NSO3H, r.t., 5 min

355 (73%)

O

Me

356 (40%)

Scheme 71. Formation of 1,2,14b, 14c-tetrahydro-3a-methyl-3aH-furo[3', 2': 3,4]quino[1,2-c][1,2,3]-benzotriazine 356.

displayed inhibitory activity against lymphoid leukaemia (L-1210) [114]. 2.9.2. Triazino [1,2-c][1,2,3]-Benzotriazine Mackenzie and Stevens developed a protocol for the synthesis of s-triazino- [1,2-c][1,2,3]-benzotriazine ring-system 351. 2aminobenzonitrile 213 was diazotized and coupled with cyanoguanidine 348 in basic media to give the cistriazenoguanidines 349A and trans isomer 349B. Cyanoguanidine 349B cyclized with piperidine in absolute ethanol to 350 because the amino- and cyanogroups in the proposed intermediates 349B and 350 were in favourable orientation for sequential nucleophilicaminenitrile addition reactions. Finally, heating of 350 with piperidine in absolute ethanol led to s-triazino [1,2-c][1,2,3]-benzotriazine ring-system 351 (Scheme 70) [115]. 2.9.3. Furo [3', 2': 3,4] Quinolino [1,2-c][1,2,3]-Benzotriazine Derivatives The 1,2,14b, 14c-tetrahydro-3a-methyl-3aH-furo[3',2': 3,4]quino[1,2-c][1,2,3]-benzotriazine 356 was prepared via the Povarov-

type reaction [116]. In the first step, the cycloaddition of N-(2nitrobenzylidene) aniline 352 and 2,3-dihydro-5-methyl furan 353 proceeded smoothly to afford 354. Then catalytic hydrogenation over Raney nickel produced 4-(2-aminophenyl)-2,3,3a, 4,5,9bhexahydro-9b-methylfuro[3,2-c]quinoline 355 in good yield. Finally, treatment of 355 with aqueous nitrous acid gave 1,2,14b,14ctetrahydro-3a-methyl-3aH-furo[3',2':3,4]quino[1,2-c][1,2,3]-benzotriazine 356 (Scheme 71) [117]. 2.9.4. Quinoxalino [1,2-c][1,2,3]-benzotriazine Derivatives Quinoxalino [1,2-c][1,2,3]-benzotriazins 360 were synthesized by diazotization of 3-(2-aminophenyl) quinoxaline-2(1H)-one 357, which resulted in 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzenediazonium 358. The latter cyclized to 359 by nucleophile attack of nitrogen atom to diazonium moiety,which led to final products 360 upon treatment with sodium sulphite (Scheme 72) [118]. 2.9.5. Quinazolino [3,2-c][1,2,3]-benzotriazine Derivatives Quinazolino [3,2-c][1,2,3]-benzotriazin-8-one 361 was formed when [1,2,3]-benzotriazin-4 (3H)-one 8 was refluxed in diglyme at



NH2

O

N

N

R2

1) NaNO2, AcOH H2O, 0 °C

N H

R1

2) r.t., 1 h

O

357

N

N

N

R2

N H

R1

358 (89-91%) N

1) H2SO4, H2O, reflux, 1 h 2) r.t., 30 min 3) 0- 5 °C, 1 h

O

N N

R2

N H

R1

359

NH N

R2 R1= H, Me R2= H, Me

O

4) Na2SO3 (aq, 20%), r.t., 30 min 5) Reflux, 2 h 6) r.t., 12 h

N H

R1

360 (37-84%)

Scheme 72. Synthetic route of quinoxalino [1,2-c][1,2,3]-benzotriazins 360.

162-164°C. The reaction probably proceeds by decomposition to an intermediate ketenimine and reaction with a second molecule of [1,2,3]-benzotriazinone 8 (Scheme 73) [119, 120]. N

N

N

Diglyme

N N

NH

O

Reflux, 1 h N

O 8

361 (71%)

Scheme 73. Thermolysis of [1,2,3]-benzotriazin-4 (3H)-one 8.

CONCLUSION In the present review, we highlighted the synthesis, chemical reactivity, biological activity and applications of aromatic derivatives [1,2,3]-benzotriazines. The study offered an extensive description on the synthesis of [1,2,3]-benzotriazine scaffolds from different starting materials by taking advantage of diazoniun chemistry. Wherever possible, the mechanistic aspects were depicted. In addition, the reactions of these [1,2,3]-benzotriazine systems with different reagents were presented. Also, [1,2,3]-benzotriazine scaffolds proved to have significant antitumor activity in various cancer cell lines. Eventually, this review focused on [1,2,3]-benzotriazine moieties that are mainly applied as coupling reagents for the synthesis of polyamides, selective chelating reagents for the ppm levels of Fe (III) ion, and privileged coupling agents and additives in peptide synthesis. LIST OF ABBREVIATIONS Abs Ala AD AEMP AMPAR

= = = = =

BTDP

=

BTC

=

Absolute Alanine Alzheimer’s disease 2-(2-Aminoethyl)-1-methylpyrrolidine Â-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors [([1,2,3]-Benzotriazine-4-one)-3-yl] diphenyl phosphate Bis(trichloromethyl) carbonate

Cod DBD

= =

DCC DCM DEPBT

= = =

DIC DIEA Diglyme DMF DOMP

= = = = =

Dppf EDC

= =

Fmoc Gly GI50 HOAt HOOBt

= = = = =

HOBt HRN Ile Leu LDA m-CPBA Met MVECs NMP Ns ODCB OTS PAM

= = = = = = = = = = = = =

1,5-Cyclooctadiene Dimethoxy ester of benzotriazinedithiophosphoric acid N, N´-Dicyclohexylcarbodiimide Dichloromethane 3-(Diethoxyphosphoryloxy)-[1,2,3]benzotriazine-4(3H)-one N, N´-Diisopropylcarbodiimide N, N´-Diisopropylethylamine Diethylene glycol dimethyl ether Dimethylformamid 5-(3,4-Dihydro-4-oxo-[1,2,3]-benzotriazin3-yloxy)-3,4-dihydro-1-methyl-2H pyrroliumhexachloroantimonate 1,1´-Bis (diphenyl)phosphino)ferrocene 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide N-9-Fluorenyl methyl oxycarbonyl Glycine Growth inhibition of 50% of cells 1-Hydroxy-7-azabenzotriazole 3,4-Dihydro-3-hydroxy-4-oxo-[1,2,3]benzotriazine Hydroxybenzotriazole Hydrazine and Raney Nickel Isoleucine Leucine Lithium diisopropylamide meta-chloroperoxybenzoic acid Methionine Microvascular endothelial cells N-Methyl-2-pyrrolidone Nano second ortho-Dichlorobenzene Tosylate Positive allosteric modulator


PEG Phe PPA TBAI TBAB TBAC TBHP TBN TFA THF Val VEGFR-2

= = = = = = = = = = = =

S 47445

=

Poly (ethylene glycol) Phenylalanine Polyphosphoric acid Tetrabutylammonium iodide Tetrabutylammonium bromide Tetrabutylammonium chloride t-Butylhydroperoxide t-Butyl nitrite Trifluoroacetic acid Tetrahydrofuran Valine Vascular endothelial growth factor receptor2 (8-cyclopropyl-3[2-(3-fluorophenyl) ethyl]-7,8-dihydro-3H- [1,3] oxazino[6,5g][1,2,3]-benzotriazine-4,9-dione

CONSENT FOR PUBLICATION


[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

Not applicable. [20]

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

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ACKNOWLEDGEMENTS

[22]

We are grateful for financial support from the Research Council of Alzahra University and support of National Elites Foundation of Iran, Tehran.

[23]

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