Unexpected Behaviors of Catechols with 2,3-Diaminonaphthalene

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provided by Elsevier - Publisher Connector Journal of Saudi Chemical Society (2016) 20, 201–206

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ORIGINAL ARTICLE Unexpected behaviors of catechols with 2,3-diaminonaphthalene

Davood Habibi *, Fatemeh Aarezi, Parisa Abolfathi

Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran

Received 28 June 2013; revised 5 October 2013; accepted 19 October 2013 Available online 8 November 2013

KEYWORDS Abstract Different behaviors of catechol, 3-methylcatechol, 3-methoxycatechol, 3,4-dihydroxy- Catechols; benz-aldehyde and 3,4-dihydroxybenzoic acid were studied in the presence of 2,3-diaminonaphtha- 2,3-Diaminonaphthalene; lene in the phosphate buffer/acetonitrile solution at room temperature. Potassium hexacyanoferrate; ª 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Room temperature; Phosphate buffer/acetonitrile solution

1. Introduction spectrum of antimicrobial activities and was particularly active against gram-positive pathogens (Giddens et al., 2007) [2]. Phenazine derivatives are an important class of nitrogen-con- Synthesized different phenazinedione derivatives and evalu- taining heterocycles which exhibit a wide range of biological ated the cytotoxicity of the prepared compounds by a SRB as- activities. They can be used as anticancer drugs [10], as antimy- say versus doxorubicin. The phenazinedione derivatives cobacterial agents [11], as promising bioreductive antitumor exhibited excellent cytotoxicity toward almost all the human agents [9], as potential sensitizers in organic photochemistry tumor cell lines tested [10]. [17] and as drugs for the treatment of tuberculosis [19]. They In addition, many phenazine compounds are found in nat- are also active against many other mycobacterial infections, ure and are produced by bacteria [12]. For example Vibrio, particularly those caused by Mycobacterium leprae [20]. Re- Pelagiobacter, Streptomyces and Pseudomonas produce a cently, novel phenazines were developed as promising new range of phenazine compounds which are different in antibi- anti-tumor agents [13]. Also, phenazine is an interesting com- otic properties, depending on the nature and position of side pound and its different properties have been extensively stud- groups attached to a phenazine nucleus [8]. ied [3]. For example the susceptibility tests against a range of In continuation of our previous studies on the synthesis of microbes were carried out by Giddens and his co-worker and new heterocyclic and nitrogen-containing compounds ([15] and they showed that D-alanylgriseoluteic acid had a broad 2005; [4–7] and 2012), we would like to report the synthesis of some phenazine derivatives (3a–b) and other products (3c–f) * Corresponding author. Tel.: +98 811 8227668. from the reaction of different catechols (1a–e) with 2,3-diami- E-mail address: [email protected] (D. Habibi). nonaphthalene (2)byK3Fe(CN)6 [14] in the phosphate buffer/ Peer review under responsibility of King Saud University. acetonitrile (buffer) solution (50:50) at room temperature (Scheme 1).

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2 2. Experimental 3 3 2 3 6 All reagents were purchased from Merck and Aldrich chemical companies and used without further puriﬁcation. 1H NMR 3 spectra were recorded on a Bruker Avance DRX 300 MHz 3 instrument in DMSO. The chemical shifts (d) are reported in 2 3 ppm relative to TMS as an internal standard. Mass spectra 3 6 were recorded on a Shimadzu GC–MS QP 1100 EX mass spec- 2 trometer. FT-IR (KBr) spectra were recorded on a Perkin-El- mer 781 spectrophotometer. Melting points were taken in open capillary tubes with a BUCHI 510 melting point apparatus and Scheme 1 Synthesis of 3a–f from 1a–c with 2.

Table 1 Synthesis of 3a–f from the reaction of 1a–e with 2 by K3Fe(CN)6 in buffer solution at room temperature. Entry Substrate Product 1a–e:2 ratio Yielda (%)

1 OH O OH 1:1 31

OH O OH 1a 3a

H OH N O OH 2 1:2 53 OH N O OH 1a H 3b

CH3 H CH3 3 OH N OH 1:1 46

N OH OH H 1b 3c

OCH3 NH2 4 OH OCH3 1:1 35 NH OH OH 1c HN OH

NH2 3d

OHC OH OHC OH 5 1:1 62 OH HN OH 1d NH OH

OHC OH 3e

HOOC OH NH2 6 1:1 36 OH NH 1e HOOC OH

NH OH

HOOC OH 3f

a Isolated yield. Unexpected Behaviors of Catechols with 2,3-Diaminonaphthalene 203 were uncorrected. TLC was performed on silica gel polygram SIL G/UV 254 plates.

2.1. Typical procedure for the synthesis of 1-methyl-5,12- dihydrobenzo[b]phenazine-2,3-diol (3c)

To a stirred buffer solution (c = 0.15 M, pH = 7, 60 mL), were added 2 (1.0 mM) and K3Fe(CN)6 (6.0 mM) [14]. A solution of 1b (1 mmol) dissolved in buffer (40 mL) was added dropwise during the period of 15 min at room temperature after which the solution became dark and precipitated. AcOH was added to the reaction mixture, the mixture was ﬁltered after 24 h and the ﬁltrate was extracted with CH2Cl2. The solvent was evaporated and the precipitate was crystallized in ace- tone and characterized (3c) by IR, 1H NMR and MS. The residue was not dissolved in any solvent which could be attributed to the oligomers or polymers of catechols. The other products were synthesized with the same method and characterized by the above mentioned techniques. Scheme 3 Proposed mechanism for the synthesis of 3a. 3. Results and discussion of 1a has dominated the nucleophilicity of 2. The reaction Different phenazine derivatives (3a–b) and other products (3c– mechanism is illustrated in Scheme 3 which consists of a dou- f) were synthesized from the reaction of different catechols ble nucleophilic attack of one molecule of 1a on the oxidative (1a–e) with 2,3-diaminonaphthalene (2) in the presence of K3- form of 1a (stages 2 & 4) [7]. Fe(CN)6 as an oxidant catalyst [14] in the phosphate buffer/ M.p. 157 C; IR (Nujol): 3334, 3083, 1726, 1603, 1270, 1 1 acetonitrile solution (buffer, 50:50) at room temperature 1124, 1012, 743 cm ; H NMR (300 MHz, DMSO-d6): 7.25 (Table 1): (6H, aromatic), 4.92 (2H, broad, 2OH); mass: 220 (M + 4) [1,14,16,18]. 3.1. Different products were synthesized as below 3.1.2. 7,14-Dihydrobenzo[2,3-b][1,4]benzodioxino[2,3-

3.1.1. Dibenzo[b,e][1,4]dioxine-2,3-diol, C12H8O4 (3a) i]phenazine-2,3-diol, C22H14N2O4 (3b) Formation of 5,12-dihydrobenzo[b]phenazine-2,3-diol (A, Since we wanted to prepare 5,12-dihydrobenzo[b]phenazine- Scheme 2) was expected from the reaction of the equimolar 2,3-diol (A in Scheme 2) and we knew that 3a was obtained amounts of 1a and 2, but formation of 3a showed that one from the reaction of equimolar amounts of 1a and 2, we in- molecule of 1a reacted as a nucleophile and the other 1a mol- creased the concentration of 2 (2 mmol) in reaction with 1a ecule reacted as an electrophile. Apparently the nucleophilicity (1 mmol) in the presence of K3Fe(CN)6 in the buffer solution

Scheme 2 Expected compounds from the reaction of 1a–c with 2. 204 D. Habibi et al.

Scheme 4 Proposed mechanism for the synthesis of 3b. at room temperature (Table 1). Despite our expectation, 3b at room temperature (Table 1). 3c was the only product which was obtained instead of A. Apparently the nucleophilic power was in concordance with our expectations. The reaction was of A is more than 2 in the reaction condition and the reaction carried out via the attack of 2 on the oxidative form of 1b which preferred to take place via the attack of A on the other oxida- is roughly similar to mechanisms illustrated in Scheme 2. tive form of 1a molecule. M.p. 162.5 C; IR (Nujol): 3373, 3334, 2954, 2852, 1680, The reaction mechanism consists of a nucleophilic attack of 1600, 1465, 1260, 1140, 840, 780 cm1; 1H NMR (300 MHz, one molecule of 2 on the oxidative form of 1a (Scheme 4) with DMSO-d6): 6.69 (7H, aromatic), 4.11 (4H, broad, NH & the subsequent nucleophilic addition of the obtained product OH), 1.25 (3H, CH3); Mass: 281 (M + 3) [1,14,16,18]. (stage 6) to another oxidative form of 1a molecule (stage 7) [7]. M.p. 152 C; IR (Nujol): 3390, 3198, 1602, 1524, 1462, 3.1.4. 4,5-Bis(3-aminonaphthalen-2-ylamino)-3- 1409, 1377, 1304, 1280, 1185, 1108, 917, 813, 722 cm1; 1H methoxybenzene-1,2-diol, C27H24N4O3 (3d) NMR (300 MHz, DMSO-d6): 7.24 (2H, aromatic), 6.97 (2H, 3d was prepared from the reaction of 1c (1 mmol) with 2 aromatic), 6.38 (6H, aromatic), 4.10 (4H, broad, NH & OH); (1 mmol) in the presence of K3Fe(CN)6 in the buffer solution mass: 379 (M + 9). at room temperature (Table 1). Since the mole ratio of 1c to The M+ peaks of nitrogen- or oxygen-containing com- 2 was 1:1, we expected to obtain 1-methoxy-5,12-dihydro- pounds usually show some extra mass units which are more benzo[b]phenazine-2,3-diol (B in Scheme 2). Nevertheless for- than the exact molecular masses. It usually depends on the mation of 3d shows the simultaneous attack of two number of the nitrogen or oxygen in the molecule and is re- molecules of 2 on one molecule of 1c. The mechanism is lated to protonation of the quinonic moiety or/and the amino roughly similar to the mechanisms illustrated in Scheme 2. group [1,14,16,18]. Despite the fact that the 3f molecule does M.p. 254 C; IR (Nujol): 3425, 3380, 2966, 1720, 1631, + 1 1 not have any nitrogen (C12H8O4), its M peak is four units 1600, 1512, 1504, 1454, 1288, 1265, 880, 730 cm ; H NMR more than the expected peak which it probably related to the (300 MHz, DMSO-d6): 7.69 (8H, aromatic), 6.54 (5H, aro- extra four hydrogen bonded to four oxygen of the molecule matic), 6.2 (4H, 2NH2), 4.11 (4H, broad, NH & OH), 3.85 (M + 4H). (3H, OCH3); Mass: 452 (M).

3.1.3. 1-Methyl-5,12-dihydrobenzo[b]phenazine-2,3-diol, 3.1.5. 6,60-(Naphthalene-2,3-diylbis(azanediyl))bis(3,4- C17H14N2O2 (3c) dihydroxybenzaldehyde), C24H18N2O6 (3e) 3c was prepared from the reaction of 1b (1 mmol) with 2 3e was prepared from the reaction of 1d (1 mmol) with 2 (1 mmol) in the presence of K3Fe(CN)6 in the buffer solution (1 mmol) in the presence of K3Fe(CN)6 in the buffer solution Unexpected Behaviors of Catechols with 2,3-Diaminonaphthalene 205

Scheme 5 A plausible mechanism for formation of 3f.

at room temperature (Table 1). Since 1d has only one active 4. Conclusion position in its oxidative form (position 6, Scheme 2), 2 attacked simultaneously on two molecules of 1d. The mechanism We were able to synthesize some phenazine derivatives (3a–b) is roughly similar to those explained before. and other products (3c–f) from the reaction of different cate- M.p. 165 C; IR (Nujol): 3360, 3320, 2864, 1728, 1594, 1 1 chols (1a–e) with 2,3-diaminonaphthalene (2)byK3Fe(CN)6 1570, 1463, 1275, 1122, 1072, 762 cm ; H NMR (300 MHz, in the buffer solution (50:50) at room temperature. DMSO-d6): 9.99 (2H, aldehyde), 6.83–7.35 (10H, aromatic), 4.21–4.23 (4H, broad, 4OH), 3.22 (2H, broad, 2NH); mass: 430 (M) [1,14,16,18]. Acknowledgement

3.1.6. 2-(3-Aminonaphthalen-2-ylamino)-3-(3-(5-carboxy-2,3- The authors gratefully acknowledge the ﬁnancial support from dihydroxyphenylamino)naphthalene-2-ylamino)-4,5- the Bu-Ali Sina University, Hamedan 6517838683, Iran. dihydroxybenzoic acid, C34H26N4O8 (3f) 3f was prepared from the reaction of 1e (1 mmol) with 2 References (1 mmol) in the presence of K3Fe(CN)6 in the buffer solution at room temperature (Table 1). Similar to 1d, also 1e has only [1] S. Bittner, C. Meenakshi, G. Temtsin, Tetrahedron 57 (2001) one active position in its oxidative form (position 6, Scheme 2), 7423. so 2 attacked simultaneously on two molecules of 1e, with the [2] S.R. Giddens, D.C. Bean, Int. J. Antimicrob. Agents 29 (2007) an extra attack of another molecule of 2 on the position 2 of 93. 6,60-(naphthalene-2,3-diylbis(azanediyl)bis(3,4-dihydroxyben- [3] H. Gorner, D. Dopp, A. Dittmann, J. Chem. Soc. Perkin. Trans. zoic acid) (Scheme 5). 2 (2000) 1723. [4] D. Habibi, M. Nasrollahzadeh, A.R. Faraji, Y. Bayat, M.p. 180 C; IR (Nujol): 3370, 3360, 2920, 1724, 1432, 1 1 Tetrahedron 66 (2010) 3866. 1260, 1087, 1074, 1002, 802, 744 cm ; H NMR (300 MHz, [5] D. Habibi, M. Nasrollahzadeh, Monatsh. fur Chem. 143 (2012) DMSO-d6): 9.98 (2H, acid), 6.60–7.30 (14H, aromatic & 2H, 925. NH2), 4.29 (4H, broad, 4OH), 3.25 (3H, broad, 3NH); mass: [6] D. Habibi, M. Nasrollahzadeh, T.A. Kamali, Green Chem. 13 622 (M + 4) [1,14,16,18]. (2011) 3499. 206 D. Habibi et al.

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