Indian Journal of Chemistry Vol. 42B, June 2003, pp. 1 456- 1459

Oxidative cyclization of arenecarbaldehyde 4-methylquinolin-2-ylhydrazones to 3-aryl-9-methyl- l ,2,4-triazolo[4,3-a]quinolines using nitrous acid: A reinvestigation

Om V Singh*t, Praveen Kumar Amancharla & G Venkateshwar Rao

Research & Development Centre, EID Parry (I) Ltd., 145, Devanahal l i Road, Off Old Madras Road, Bangalore 560 049, India Received 4 June 2002; accepted (revised) 1 7 October 2002

Arenecarbaldehyde 4-methylquinolin-2-ylhydrazoncs la-f on treatment with sodium nitrite in acetic acid afford 3-aryl-9-methyl- I ,2,4-triazolo[4,3-aJquinolines 3a-f instead of 3-aryl-5-methylquinolino[3,2-eJ- I ,2,4-triazines 2 under microwave ir­radiation as well as thermal conditions. The structure of 3 has been confirmed by NMR eH & 13C), 2D-NMR (COSY, NO­ESY, HMQC & HMBC) and high-resolution mass spectroscopic methods. A most probable mechanistic pathway of this transformation is also proposed.

Recently, Kidwai et ai ' have reported the synthesis of 3-(substituted phenyl)-5-methylquinolino[3,2-e]-1 ,2,4-triazines 2 by nitrosation of arenecarbaldehyde 4-methylquinolin-2-ylhydrazones 1 using sodium nitrite in acetic acid under microwave irradiation as well as thermal conditions. The authors have described that the formation of 2 proceeds by nitrosation of 1 at Cr position of quinoline ring followed by cyclization. However, Crposition of quinoline ring is not highly activated and nitrosation at this position will be difficult especially in the presence of other nucleophilic center present in the molecule such as NH of hydrazone group. Hence, we thought to reinvestigate this reacti.)n and following are the results of our findings.

The treatment of 4-methoxybenzaldehyde 4-methylquinolin-2-ylhydrazone 1b with sodium nitrite in acetic acid under reflux for 2 hr as well as microwave irradiation for 5 min afforded 3-(4-methoxyphenyl)-9-methyl- l ,2,4-triazolo[4,3-a]quinoline 3b instead of 2 (Scheme I) as described by Kidwai et al' . The molecular formula of compound 3b was determined using high-resolution electron impact mass spectrum (mlz 289. 1 2 1 3) and found to be C ' 8H,sN30 (calculated 289. 1 2 1 5 for C'8H,sN30). I 3C NMR and DEPT- 1 35 spectrum showed 1 8 carbon atoms out of which were 7 quaternary, 9 tertiary and 2 primary carbons. The presence of 9 tertiary carbons in DEPT-1 35 spectrum clearly showed that the product is not 2, which should have only 8 tertiary carbon atoms. The methyl group of quinoline ring appeared at 8 2.637 as a doublet

t Present Address: Department of Chemistry, University of Texas at San Antonio, 6900 North Loop 1 604 West, San Antonio, Texas 78249, USA; E-mail : osingh@lItsa.cdll

Scheme I

b) 4-CH30-C6H4; d) 4-CH3-C6H4; f) a-Naphthyl

(J= 1 .26 Hz), which showed the presence of a proton at the nearby carbon and appeared as quartet at 8 7.456 (1= 1 . 16 Hz). Further, the structure of 3b was confirmed by using 2D-NMR experiments (COSY, NOESY, HMQC and HMBC). NOESY spectrum showed the key evidence of NOE correlations (Figure 1) of methyl group (8 2.637) with H- l O (8 7.456) and H-8 (8 7.899). HMBC spectrum showed key shift correlation (Figure 1) of H- lO (8 7.456) to 1 49.45 (C- lOa) and 1 25 .94 (C-8a), H-2' and 6' (8 7.596) to 1 48.49 (C-3). Based on these analyses, complete assignment of 'H and I 3C NMR data of 3b were made for first time and results are presented in Table I .

Kidwai et ai' have assigned the structure 2 based on ' H NMR (90 MHz), mass spectral data and ele­mental analyses. However, mass spectral data as well

SINGH et al. : SYNTHESIS OF 3-ARYL-9-METHYL-I ,2,4-TRIAZOLO[4,3-a)QUINOLINES 1457

�.r-CH� H 8 9 H ( 7'7' , � IO :::::.... 4 H 6 S N '-':N I

�V,{2 H-J 0, H-.J CH3�

NOE Correlations

H '7' , :::::....

" oWil CH3 HMBC Correlations

Figure 1

as elemental analyses seems to be manipulated and NMR data does not show any separation of peaks in aromatic region due to low resolution. Further, identi­ties of compounds 3a-e were confirmed by compari­son of spectral data. co-IR and mixed melting points with those reported by us earlier2 by oxidative cycli­zation of 1 using thallium(III) acetate. It is worth to mention here that our earlier I H NMR assignment for

H-5 and H-8 are not correct due to the lack of 2D NMR data and should be interchanged.

The generality of above transformation was checked by treating other 4-methylquinolin-2-ylhydrazones of aromatic aldehydes la-f with sodium nitrite in acetic acid and in all cases respective 3-aryl-9-methyl- l ,2,4-triazolo[4,3-a]quinolines 3a-f were obtained in 70-80% yields. The characterization data of 3a-f are presented in Tables I and II.

The most probable mechanism of above transfor­mation is depicted in Scheme II. The initial e1ectro­phillic attack of nitrosonium ion, generated from ni­trous acid, at the nitrogen atom of hydrazone 1 gave respective N-nitrosation intermediate 4 that on subse­quent elimination of NO' anion afforded another in­termediate 5. The loss of proton from 5 yielded inter­mediate 'nitrilimine' 6, which subsequently isomer­izes to intermediate 7. The intramolecular nucleophil­lic attack of N atom of quinoline ring of 7 at the car­bon atom of 'nitrilimine' afforded the respective 1 ,2,4-triazolo[ 4,3-a ]quinolines 3.

The formation of 'nitrilimine' as intermediate dur-

Table I_IH, nC, HMQC, NOESY and HMBC data of 3b and I JC NMR data of 3a-e

Position

3 4a

IH NMR (J, Hz)

5 7.659 (8.55 & 0.9) 6 7.357 ( 1 .32, 8.56 &

7.68) 7 7.5 1 8 (0.92, 7.70 &

8. 1 ) 8 7.899 (8. 1 & / .5)

8a 9 10 7.456 ( 1 . l 6) lOa l ' 2' 7.596 (8.97)

3' 7.012 (9.02) 4' 5' 7.0 1 2 (9.02) 6' 7.596 (8.97)

9-Me 2.637 ( 1 .26)

Others 3.936 * vaiues are interchangeable

I JC NMR 1 48.49 1 36.44 1 16.62 1 28.44

1 25.64*

1 25.70*

1 24.94 1 3 1 .64 1 13 .85 1 49.45 1 2 1 .59 1 3 l . l 3

1 14.36 1 60.99 1 14. 1 3 1 3 l . l 3

1 9.44

55.29

3b

HMQC NOESY HMBC

1 16.62 7.357 125.64, 1 24.94 1 28.44 7.659, 125.70

7.5 1 8 1 25.64* 7.899, 1 16.62, 1 25.70

7.357 1 25.70* 7.5 1 8, 1 36.44, 128.44,

2.637 1 3 1 .64

1 1 3 .85 2.637 124.94, 149.45

1 3 1 . 1 3 7.0 12 1 3 1 . 1 3, 148.49, 1 60.99

1 14. 1 3 7.596 1 14.36, 1 2 1 .59

1 14. 1 3 7.596 1 14.36, 1 2 1 .59 1 3 1 . 1 3 7.012 1 3 1 . 1 3, 1 48.49,

1 60.99 1 9.44 7.456, 1 24.94, 1 1 3.85

7.899 55.29 7.0 12 160.99

DC NMR 3a 3c 3d 3e

1 48.59 147.61 148.82 1 48.3 1 1 36.44 1 36.59 1 36.38 1 36.49 1 16.73 1 16.68 1 16.87 1 16.86 128.5 1 128.70 1 28.53 1 28.65

1 25.73* 1 25.98* 125.76* 1 25.82*

1 25.82* 1 26.07* 1 25.82* 1 25.88*

1 24.98 1 25 . 12 125.09 1 25 . 1 2 1 3 1 .56 1 3 1 .49 1 3 1 .78 1 3 1 .69 1 13 .88 1 1 3.95 1 14.03 1 14.01 149.56 149.80 149.62 149.58 1 30.26 1 28. 1 7 1 26.70 1 22.9 1 1 28.94 1 29.36 1 29.7 1 1 08.95

1 29.65 1 3 l . l9 129.7 1 149.39 1 29.76 1 36.73 14049 1 48 . 1 6 1 29.65 1 3 l . l9 1 29.7 1 1 10.86 1 28.94 1 29.36 1 29.7 1 1 24.23

1 9.49 1 9.57 19.57 1 9.57

2 1 .54 1 0 1 .69

1458 INDIAN 1. CHEM., SEC B, JUNE 2003

Table II-Characterization data of compounds 3a-f.

EI-HRMS Yield" Compd m\z (M+) Mol . formula mp Ar Found (Calc.) °C (%)

3a C6HS 259. 1 1 06 C 17H I3N3 1 52-53 ' 72 (259J 1 09)

3b 4-MeO-C6H4 289. 1 2 1 3 C J HHJsN30 1 72-73 70 (289. 1 2 1 5) 3c 4-CI-C6H4 ndb C17HJ2CIN3 2 1 1 - 1 3 80

3d 4-Me-C6H4 273. 1262 CJMHJsN3 2 12- 14 78 (273. 1 266)

3e 3,4(OCH2O)C6H3 303 . 1005 CJRHJ3N302 201 -02 75 (303. 1 007)

3f . : -Naphthyl 309. 1 263 C2 JH JsN3 1 69-70 75 (309. 1266) " Yields are based upon isolated crystall ized products b nd means not determined

CH3 $ c(j""" NO l ,-'l /- -�

N N-N=C-Ar 1 H H

..

Scheme II

ing the above transformation was indirectly supported by the following observation. If nitrilimine is inter­mediate, phenylhydrazones of aromatic aldehydes should give N1-acetyl-N2-aroylphenylhydrazines on treatment with sodium nitrite in acetic acid by the ad­dition of acetic acid to nitri limine. This is found to be true as treatment of 2,4-dinitrophenylhydrazones of aromatic aldehydes 8a-b with sodium nitrite in acetic

H

MN'N�Ar 02N N02 8a-b

Scheme III

acid afforded N1 -acetyl-Nz-aroyl-2,4-dinitrophenyl­hydrazines 12a-b in 70% yields under microwave irradiation as well as thermal conditions (Scheme III). The addition of acetic acid to interme­diate nitrilimine 9, formed from 8, may give respec­tive hydrazonyl acetate 10 which on 1 ,4-acyl migra­tion from 0 to N atom affords 1 1 and finally interme­diate 11 isomerizes to 12. This was further supported by the fact that 4-nitrophenylhydrazone of benzalde­hyde afforded N1 -acetyl-Nz-benzoyl-4-nitrophenyl­hydrazine on treatment with lead tetraacetate in acetic acid via intermediate nitrilirnine and its formation was confirmed by trapping it with acrylonitrile in situ. 3,4

SINGH et al. : SYNTHESIS OF 3-ARYL-9-METHYL-L2,4-TRIAZOLO[4,3-a]QUINOUNES 1 459

Recently, Zolfgol et atS have also utilized nitrous acid for the oxidation of nitrogen heterocycles such as 1 ,4-dihydropyridines were oxidized to respective pyridines in high yields. Further, the application of nitrous acid for the synthesis of other bioactive 1 ,2,4-triazolo-heterocycles is under progress in our laboratory.

Experimental Section

Melting points were taken in open capillaries and are uncorrected. IR spectra (vOlax in cm- I ) were recorded on a Perkin Elmer 283 IR spectrophotometer, IH NMR, 13C NMR, COSY, NOESY, HMQC and HMBC spectra (chemical shifts in 8, ppm) on Brucker DPX-200 (200 MHz) and AMX-400 (400 MHz) using CDCh as sol­vent and mass spectra on JEOL JMS-SX 1 02 mass spectrometer operating at 70 eV. The reactions were callied out in BPL domestic microwave oven (BMC-990T) operating at 2450 Hz.

3-Aryl-9-methyl-l, 2, 4-triazolo[4, 3-a] quinolines 3a-f. General procedure. To a solution of hydrazones (1a-f; 0.01 mole) in acetic acid ( 1 0 mL) was added a solution of sodium nitrite (0.03 mole) in water ( 1 mL) and resulting mixture was refluxed for 2 hr. The reaction was cooled to room temperature and was slowly added to water. The aqueous mixture was extracted with CH2Ch (3 x 50 mL), washed with saturated NaHC03 solution followed by water and dried (Na2S04)' The sol­vent was removed at reduced pressure and the residue was purified by passing through a small column of basic alumina to afford 3a-f.

3-Aryl-9-methyl-l, 2, 4-triazolo[4, 3-a]quinolines 3a-f. General procedure using microwave irradia­tion. To a solution of hydrazones ( la-f; 0.01 mole) in acetic acid ( 10 mL) was added sodium nitrite (0.03 mole) in water ( 1 mL) and reaction mixture was sub­jected to microwave irradiation for 5-7 min. After usual work up as above, the compound was purified as de­scribed above to afford 3a-f and their characterization data are given in Tables I and II.

3-( a-Naphthyl)-9-methyl-l,2,4-triazolo[ 4,3-a ]qui­nolines (30: IH NMR (200 MHz, CDCI3): 8 2.64 1 (d, 3H, 1=1 . l 8 Hz, CH3), 7.00-7.066 (m, 2H, H-6' & H-7'), 7.277-7.372 (m, 3H, H-7, H-4' & H-5'), 7.496 (t, I H, J=6.96 & 6.52 Hz, H-3'), 7.604 (br s, 1 H, H- IO), 7.646 (t, 1 H, 1=7.64 Hz, H-6), 7.755 (d, 1 H, J=6.84 Hz, H-8'), 7.854 (d, lH, J=7.92 Hz, H-8), 7.96 (d, 1 H, 1=8. 1 6 Hz, H-2'), 8 . 104 (d, I H, 1=8. 1 6 Hz, H-5).

Oxidation of 2,4-dinitrophenylhydrazones of aromatic aldehydes Sa-b. General procedure. To a solution of hydrazones (Sa-b; 1 mmole) in acetic acid ( 1 0 mL) was added a solution of sodium nitrite (3 mmole) in water ( 1 mL) and resulting mixture was re­fluxed for 2 hr. After completion (TLC), the reaction was worked as above and product was purified by col­umn chromatography over silica gel using CHCl3 as eluent to afford NI -acetyl-Nraroyl-2,4-dinitrophenyl­hydrazines 12a-b.

N1-Acetyl-Nz-benzoyl-2,4-dinitrophenylhydrazine 12a. Yield 70%, mp 1 62-63°C; IH NMR (200 MHz, DMSO-d6): 8 2. 1 60 (s, 3H, CH3), 7 .547-585 (m, 2H, H-3' & H-5'), 7 .647-7.7 1 4 (m, 2H, H-3 & H-4'), 7.962-7 .98 1 (m, 2H, H-2' & H-6'), 8.524 (dd, IH, J=2.28 & 8 .98 Hz, H-5), 8 .69 1 (d, 1 H, J=2.20 Hz, H-2), 1 1 .978 (brs, 1 H, NH, D20 exchangeable); 13C NMR (50 MHz, DMSO-d6): 8 2 1 .42 (q, CH3), 1 20.95 (d, C3), 1 26.38 (d, Cs), 1 28.29 (2 x d), 1 29. 1 1 (d), 1 29. 1 8 (2 x d), 1 3 1 .25 (s, CI '), 1 33 .34 (d), 1 38.48 (s, C2), 1 43.65 (s, CI ), 145 .08 (s, C4), 1 66.99 (s), 1 72.33 (s).

N l -Acetyl-N 2"( 4' -methoxybenzoyl)-2,4-dinitro­phenylhydrazine 12b. Yield 70%, mp 1 73-74°C; IH NMR (200 MHz, DMSO-d6): 8 2 . 1 35 (s, 3H CH3), 3 .826 (s, 3H, OCH3), 7 .082 (d, 2H, 1=8.58 Hz, H-3' & H-5'), 7.668 (d, 1 H, 1=8.90 Hz, H-6), 7 .958 (d, 2H, J=8.44 Hz, H-2' & H-6'), 8.5 1 9 (dd, I H, J=2.22 & 8 .96 Hz, H-5), 8.68 1 (d, 1 H, 1=2.2 ] Hz, H-2), 1 1 .832 (brs, 1H , NH, D20 exchangeable) ; I 3C NMR (50 MHz, DMSO-d6): 8 2 1 .39 (q, CH3), 55 .90 (q, OCH3), 1 14.4 1 (d, C3' & Cs'), 1 20.89 (d, C3), 1 23.2 1 (s, C6), 1 26.32 (d, Cs), 1 29.05 (s, C I '), 1 30. 1 7 (d, C2' & C6'), 1 38.65 (s, C2), 1 43.59 (s, C I ), 1 44.96 (s, C), ] 63 .27 (s, C4'), 1 66.39 (s) & 1 72 .43 (s).

Acknowledgement Authors are thankful to Dr M C Gopinathan, Gen­

eral Manager (R &D) for providing laboratory facili­ties and encouragement.

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37 8 , 1998, 1 063. 2 Singh 0 Y, Muthukrishnan M & Sundaravadivelu M, Indian J

ehem, 408, 2001, 262. 3 SCOll P L & Butler R N, J ehem Soc (e), 1966, 1 202.

4 Butler R N & O'Danohue A M, Tetrahedron Lell, 20, 1979, 4583. 5 Zolfigol M A, Borazjani M K , Sadeghi M M, Baltork I M &

Memarian H R, SYlltir eommun, 30, 2000, 5 5 1 and references cited therein.