Indian Journal of ChemistryVol. 458, January 2006, pp. 292-296

. i .

Pyrazolo-fused quinoline analogues: Synthesis of IH-pyrazolo [3, 4-bJ quinolinesand 3-amino-lH-pyrazolo [3, 4-b] quinolines from 3-formyl and 3-cyano-2-

chloroquinolines

Ambika Srivastava, Mrityunjay K Singh & R M Singh*Department of Chemistry, Banaras Hindu University, Varanasi 221 005, India

E-mail: rmohan@bhu.ac.in

Received /6 December 2004: accepted (revised) 26 JUlie 2005

Stepwise synthesis of IH-pyrazolo [3, 4-b] quinolines 6 has been described from the reactions of 2-chloro-3-formylquinolines I with cthyleneglycol and hydrazine hydrate reagents in sequence followed by hydrolysis with BiCI1.However, 3-amino-1 H-pyrazolo[3, 4-b]quinolines 7 have been synthesized from 2-chloro-3-cyanoquinolines 2 with excessof hydrazine hydrate in one step. The functional group manipulation of amino group in compounds 7 has also been studied.

Keywords: IH-pyrazolo [3, 4-b 1 quinolines, 3-amino-1 H-pyrazolo [3, 4-b] quinolines

IPC: Int.CI7 C 070215/00

The fused guinolines are known to bind DNA wi;':high affinity, inhibit DNA topoisomerase and displaycytotoxic and antitumour activities'. In particular,pyrazolo-fused guinoline derivatives exhibit variousbiological activities such as antiviral, antimalarial,lowering of serum cholesterol and display pHdependent fluorescent properties'. Although numberof methods are available for pyrazolo-fusedquinolines ', it is still attracting considerable interesttowards the synthesis of number of other relatedcompounds.

As a part of our studies concerning the synthesis ofVilsmeier-Haack reagent aided synthesis of guinolinebased fused heterocyclic compounds, we wereinterested in pyrazolo-fuscd quinoline derivatives.Wehave previously described the number of thiophene-fused quinolines". In this paper we wish to report thesynthesis of some unsubstituted/substituted 1l l-pyrazolo [3, 4-b] guoinolines 6 and 3-amino-lJ-/-pyrazolo [3, 4-b] guinolines 7.

The key intermediates for the synthesis of desiredpyrazolo-fused quinoline derivatives were 2-chloro-3-formylquinolines 1 and 2-chloro-3-cyanoquinolines 2,respectively which were prepared by the routesummarised in the Scheme I.

The reaction of acetanilides with Vilsmeier reagentgave 2-chloro-3-formylguinolines 1, which upontreatment with CAN (cerric ammonium nitrate) in

agueous NH3 afforded the 2-chloro-3-cyanoquinolines2 in good yield (Scheme I).

The 2-chloro-3-formylquinolines having~-chlorovinylaldehyde moiety were presumed toundergo facile cyclisation with hydrazine hydrate inethanol to afford 1H-pyrazolo [3 ,4-b] quinol inederivatives]. Thus, the reaction of 2-chloro-3-fonnylguinolines 1 with excess of hydrazine hydratein ethanol afforded the hydrazones 3 in quantitativeyield, which failed to undergo cyclisation to yield IH-pyrazolo [3,4-b] guinolines 6 even after prolongedrefluxing, was presumably owing to the unfavourableE-configuration. However, similar systems werereadily accessible if the aldehydic group is protectedto prevent the preferential attack by nitrogennucleophiles":". The protection of aldehydic group inthe present system was achieved with ethyleneglycolto afford dioxolan deri vatives, 2-chloro-3-[ I ,3-dioxolan-2-yl] quinolines 4. Thus the dioxolanderivatives 4, prepared from the reaction of 2-chloro-3-fonnylguinolines 1 with ethyleneglycol in thepresence of p-toluenesulphonic acid and molecularsieves in toluene, were refluxed with excess ofhydrazine hydrate to give the 2-hydrazino-3-[ I, 3-dioxolan-2-yl] guinolines 5. The subsequent de-acetalisation and cyclisation reactions of compounds5 with BiCl3 in methanol, in one-step, at roomtemperature afforded IJ-/-pyrazolo [3,4-b] quinol ines

SRIVASTAVA et al.: PYRAZOLO-FUSED QUINOLINE ANALOGUES 293

12 R

a Hb 6-Mec -7.oMe

Scheme I

-ocx~CHOR 1~ N~ CI

1

b

_4.;:..• .:.:.5 • .::.J6I-'-'R'--_--HOM.

.p'1~ N CI

'+~

~ ~ -Bim3

1<: ~ I ~ ./ ...~----M-.-O-H-----

N NH

H

6

6 in good yield (Scheme II). The structures ofcompounds 6 were characterised from their spectral, .

data. The H NMR spectrum of compound 6a showeda broad singlet at 0 11.6 for the NH proton and asinglet at 08.73 for the azomethine proton along withthe signals of other aromatic protons.

However, in contrast, 2-chloro-3-cyanoquinolines 2upon reaction with excess of hydrazine hydrate inDMF in a short time afforded products in aquantitative yield which were characterized as 3-amino-IH-pyrazolo [3,4-b] quinolines 7 from theirspectral data (Scheme III). The IH NM R spectrum ofcompound 7a showed a singlet at 0 11.8 for the NHproton and another singlet at 0 6.0 for the NHz protonsalong with the signals for the aromatic protons. Its IRspectrum showed absorptions at 3294, 3125 and 3184em" for the NH and NHz stretchings and the massspectrum showed the M++ I peak at 185.

Finally, the scope of the functional group mani-pulation in 3-amino-1H-pyrazolo [3,4-b] quinolines 7was further investigated. Recently, a facile trans-formation of functional groups in a similar compoundsuch as 3-amino-4-hydrazino-1 H-pyrazolo [3,4-b]

h

4

Scheme II

quinoline has been reported to afford 2,4-diazido-quinoline-3-carbonitrile upon reaction with nitrous acidin strong acidic conditions". Thus, the similar reactionof compound 7a was carried out with sodium nitrite in70% H2S04 to give 2-azidoquinoline-3-carbonitrile 10.In contrast to the rearranged product 2-azidoquinoline-3-carbonitrile 10, the isolated product wascharacterized as 3-diazo-l H-pyrazolo [3,4-b] quinoline8a from its spectral and analytical data (Scheme III),showing that a simple diazotization reaction was takingplace at the amino group. The IR spectrum of 8bshowed a very strong absorption at 2094 em" for thediazo group. The structure of the products 8 was furtherchemically evidenced by performing the couplingreaction with ~-naphthol which yielded 3-(2-hydroxy-1-naphthyl) azo-l H-pyrazolo [3, 4-b] quinolines 9. The'H NMR spectrum of 9a in DMSO-d6 exhibited DzOexchangeable signals at 0 14.91 and 14.37 for thephenolic proton of 9a and NH proton of 9a',respectively suggesting the existence of both keto andenol tautorners in solution. Its IR spectrum showedabsorptions at 3410 and 1570 crn' for the OH/NH andN=N groups, respectively.

1I294 INDIAN J. CHEM., SEC B, JANUARY 2006

R

~N/

N NH

I HN~; H,SO.,oOc

R

H

b 6-Me

7-OMe

t ~'ccc~cI :r=-',9 R~ # • HN N3 b 6-Me

10o8

+ ,H:XOallc , 2-nephlhol

-~N ~ I -

R/ R

NH

9

In summary we have described a general stepwiseand one-step synthesis of IH-pyrazolo [3, 4-b]quinolines and 3-amino-1H-pyrazolo [3, 4-b]quinolines, respectively. The 3-amino-l H-pyrazolo[3, 4-b] quinolines are valuable synthone for thesynthesis of the variety of pyrimidino condensedheterocycl ic compounds.

Experimental SectionMelting points were determined in an open

capillary tube with a Buchi melting point apparatusand are uncorrected. Elemental analysis was obtainedusing Perkin-Elmer 240C CHN-analyzer. IR spectrawere recorded on a FT IR-5300 (JASCO) spectro-photometer; IH NM R spectra in CDCI3 at 300 MHzon a Jeol AL-300 spectrometer (chemical shifts in 8,ppm) relative to TMS as an internal standard; massspectra were recorded on a Firming MAT 1020B.Reactions were monitored by TLC, using silica gelrF254+366as an adsorbent and ethyl acetate-hexane indifferent ratios as eluent. Reagent quality solventswere used as such. The acetanilides used as startingmaterial were synthesised from anilines upon reactionwith acetic anhydride under aqueous conditions atroom temperature or upon refluxation for 20-30 minin almost quantitative yield.

Preparation of 2-chloro-3-formylquinolines la-c.To a solution of acetanilides (5 mmoles) in dry DMF

H\N-N

9'

Scheme III

(15 mrnoles) at 0-5°C rOCl, (60 mmoles) was addeddropwise with stirring and the mixture was thenstirred at 80-90 °C for time ranging between 4-16 hr.The mixture was poured onto crushed ice, stirred for 5min and the resulting solid filtered, washed well withwater and dried. The compounds were recrystallisedfrom ethyl acetate (Table I).

Preparation of 2-chloro-3-cyanoquinolines 2a-c.A suspension of 2-chloro-3-formylquinolines 1 (Immole) in 30% aq. ammonia (3 mL) was stirred for 5min at room temperature, resulting in the formation ofa turbid solution. To this CAN (I mmole) was addedwith constant stirring at One. After completion of thereaction (monitored byTLC, disappearance of reddishbrown colour of reaction mixture in 10-15 min) thereaction mixture was extracted with chloroform-ethylacetate (5:3 ml.), dried (Na2S04) and evaporatedunder vacuum to obtain the solid product which wasrecrystallised from ethanol (Table I).

Preparation of dioxolan derivatives of 2-chloro-3-formylquinolines 4a, b. A solution of 2-chloro-3-formylquinolines (2 mmoles) in toluene (20 mL)containing ethyleneglycol (6 mmoles) and a fewcrystals of p-toluenesulfonic acid were heated underreflux for 4-5 hr in the presence of molecular sieveusing a Dean-Stark trap. The cooled solution wastreated with saturated aqueous sodium carbonate(lO ml.), dried (Na2S04) and evaporated under

SRIVASTAVA et al.: PYRAZOLO-FUSED QUINOLINE ANALOGUES 295

Table 1- Characterization data of compounds I, 2, 4, 5, 6, 7, 8 and 9

Compd R Mol.formula m.p Yield Found (Calcd) % IH NMR (CDCI3)(Mol. wt) °c (%) H C N (8, ppm)

la H C1oH6NOCI 149 82 3.16 62.68 7.31 10.5 (s, IH, CHO), 8.8 (s, IH, H-4), 8.1 (d,(191) (3.14 62.72 7.29) IH, H-5), 8.0 (d, IH, H-8), 7.9 (dt, IH, H-6),

7.7 (dt, IH, H-7).

Ib 6-Me CIIHgNOCI 123 80 3.92 64.25 6.81 10.6 (s, IH, CHO), 8.5 (s, IH, H-4), 8.0 (d,(205) (3.93 64.28 6.82) IH, H-8), 7.75 (dd, I H, H-7), 7.65 (s, IH, H-• 5), 2.6 (s, 3H, CH3).

Ie 7-0Me CIIHgN02C1 (221) 196 89 3.64 59.61 6.32 10.5 (s, I H, CHO), 8.6 (s, IH, H-4), 7.78 (d,(3.62 59.62 6.29) I H, H-5), 7.5 (s, IH, H-8), 7.3 (dd, IH, H-

6),4.0 (s, 3H, OCH3).

2a H CIOHsN2CI 162 86 2.67 63.68 14.85 8.7 (s, IH, H-4), 8.2 (d, IH, H-5), 8.0 (d,( 188.5) (2.63 63.56 14.90) I H, H-8), 7.8 (dt, I H, H-6), 7.7 (dt, IH, H-

7).

2b 6-Me CIIH7N2CI 172 89 3.48 65.20 13.82 8.5 (s, IH, H-4), 8.0 (d, IH, H-8), 7.75 (dd,(202.5) (3.42 65.21 13.81 ) IH, H-7), 7.65 (s, IH, H-5), 2.6 (s, 3H, CH3)

2e 7-0Me CIIH7N2CI 198-01 75 3.23 60.23 12.81 8.5 (s, IH, H-4), 7.78 (d, I H, H-5), 7.4 (s,(218.5) (3.23 60.42 12.80) I H, H-8), 7.3 (dd, I H, H-6), 4.0 (s, 3H,

OCH3)

4a H CI2HION02CI 48-51 92 4.28 61.16 5.94 8.4 (s, IH, H-4), 8.1 (d, IH, H-5), 7.82 (d,(235.5) (4.27 61.15 5.95) 1H, H-8), 7.73 (dt, IH, H-6), 7.6 (dt, IH, H-

7),6.25 (s, IH, CH), 4.2 (rn, 4H, (CH2h)

4b 7-0Me C13HI2NOJCI 115-17 96 4.55 58.77 5.27 8.34 (s, IH, H-4), 7.7 (d, IH, H-5), 7.37 (s,(265.5) (4.54 58.76 5.27) IH, H-8), 7.25-7.21 (dd, IH, H-6), 6.24 (s,

I H, CH), 4.21-4.15 (m, 4H, (CH2h), 3.96 (s,3H,OCH3)

Sa H CI2H13NJ02 68 83 5.67 62.31 18.17 9.3 (s, IH, H-4), 8.5 (d, IH, H-5), 8.2 (d,(231) (5.69 62.31 18.19) IH, H-8), 7.9 (t, IH, H-6), 7.7 (t, IH, H-7),

6.2 (s, I H, NH), 5.8 (s, IH, CH), 4.2 (m, 4H,(CH2h), 1.6 (brs, 2H, NH2).

5b 7-0Me C13H!sNJO,(l61 ) 153 82 5.79 59.76 16.08 12.0 (s, I H, NH), 8.3 (s, IH, H-4), 7.9 (d,(5.77 59.78 16.09) IH, H-5), 7.4 (s, IH, H-8), 7.2 (d, IH, H-6),

5.6 (s, IH, CH), 4.2 (m, 4H, (CH2h), 1.7(brs, 2H, NH2).

6a H C1OH7NJ 159-61 78 4.17 70.99 24.84 11.61 (brs, 1H, NH, D20 exchangeable), 9.1(169) (4.18 71.00 24.86) (s, IH, 1-1-4),8.73, IH, HC=N), 8.49 (d, IH,

;": H-5), 8.3 (d, IH, H-8), 7.81 (t, IH, H-6), 7.7(t, IH, H-7)

6b 7-0Me CIIH9NJO . 221-23 83 4.55 66.32 21.09- 't2.01 (brs, IH, NH, D20 exchangeable),(199) (4.53 66.30 21.11 ) 8.57 (s, I H, H-4), 8.27 (s, IH, HC=N), 7.85

(d, IH, H-5), 7.42 (s IH, H-8), 7.15 (d, IH,H-6), 4.0 (s, 3H, OCH3)

f!:

7a* H GIOHSN4 305 92 4.38 65.21 30.43 11.8 (s, 1H, NH, D20 exchangeable), 8.8 (s,(184) (4.36 65.19 30.43) I H, H-4), 8.0 (d, 11-1,H-5), 7.8 (d, 1H, H-8),

7.6 (dt, IH, H-6), 7.4 (dt, IH, H-7), 6.0 (s,2H, NH2).

7b* 6-Me C\lH1oN4 279·81 88 5.08 66.65 28.26 11.8 (s, 1H, NI-I, D20 exchangeable), 9.2 (s,(198) (5.11 66.64 28.28) I H, H-4), 8.0 (d, 1H, H-8), 7.9 (s, 1H, H-5),

7.6 (dd, IH, H-7), 5.9 (s, 2H, NH2), 2.6 (s,3H, CH3).

7e* 7-0Me C\lH,oN4O 276 81 4.71 61.67 26.15 12.0 (s, IH, NH, D20 exchangeable), 8.5 (s,(214) (4.73 61.65 26.17) IH, H-4), 7.84 (d, I H, H-5), 7.52 (s, IH, H-

8), 7.17 (d, IH, H-6), 6.0 (s, 2H, NH2), 4.0" (s, 3H, OCH3)

- CO/1/d

296 INDIAN J. CHEM., SEC B, JANUARY 2006

Table I - Characterization data of compounds I, 2, 4, 5, 6, 7, 8 and 9 - Contd

Compd R Mol.formula m.p Yield Found (Calcd) % IH NMR (CDCl)(Mol. wt) Uc (%) H C N (8, pprn)

8a* H CIOHsNs 160 62 2.58 61.54 35.88 9.2 (s, IH, H-4), 8.3 (d, IH, H-5), 8.1-7.7(195) (2.63 61.51 35.83) (rn, 3H, H-6, H-7 & H-8).

8b* 6-Me C11H7NS 147 73 3.37 63.15 33.48 8.7 (s, IH, H-8), 8.0 (d, IH, H-8), 7.8 (rn,(209) (3.39 63.23 33.51 ) 2H, H-7 & H-5), 2.6 (s, 3H, CH3).

9a H C2oH13NsO 228 82 3.86 70.79 20.64(339) (3.92 70.59 19.89)

9b 6-Me C21HISNsO 281 88 4.28 71.38 19.82(353) (4.09 71.42 19.75)

* DMSO-d6 solvent was used for IHNMR spectra

vacuum to give 2-chloro-3-( 1 ,3-dioxolan-2-yl)quino-lines 4 as pale yellow solid, pure enough for furtheruse. The crude products were recrystallised from ethylacetate - pet.ether-toluene mixture (Table I).

Preparation of 2-hydrazino-3-(1, 3-dioxolan-2-yl) quinolines Sa, b. To a solution of 4 (I mmole) inexcess of hydrazine monohydrate was refluxed undernitrogen while stirring for 3 hr. The product 5 wasrecovered via filtration and washed well with water,dried and recrystallised from ethanol (Table I).

Preparation of IH-pyrazolo [3, 4-b] quinolines6a, b. To a solution of 5 (I mmole) in methanol (SmL), was added BiCh (O.S mmole) and the mixturestirred at rt for 30 min. On completion of reactionmethanol was removed under reduced pressure andice was added to quench the catalyst. The reactionmixture was extracted with chloroform (3 x S mL.).The combined organic layers were washed with waterand dried over sodium sulphate. The solvent wasremoved under reduced pressure to obtain the solidproduct which was recrystallised from ethanol(Table I).

Preparation of 3-amino-lH-pyrazolo [3, 4-b]quinolines 7a-c. A mixture of 2 (I mmole) andhydrazine hydrate (3 mL) was refluxed for IS minand then left to cool to room temperature, whereuponthe product crystallized out which was filtered andwashed well with water and needed no furtherpurification (Table I).

Formation of 3-diazo-lH-pyrazolo 13, 4-blquinolines 8a, b. To a solution of compounds 7(1 mmole) in 70% H2S04 (3-4 mL) cooled in ice-saltto -SoC, was added dropwise a solution of sodiumnitrite (3 mmoles) in water (1 ml.) and the reactionmixture was maintained at -SoC for 1 hr and then waspoured into ice-water. The precipitated product wasfiltered, washed well with water and dried (Table I).

Coupling reaction of compounds 8 with p-naphthol: Formation of 3-(2-hydroxy-I-naphthyl-azo)-IH-pyrazolo (3, 4-bJ quinolines 9a,b. Asolution of compounds 8 (I mmole) in SO%sulphuricacid (2 mL) cooled to O-S °C, was treated withalkaline ~-naphthol (I mmole) solution and stirred atroom temperature for S min whereupon dark red solidprecipitated which was filtered and washed with waterto get 9.

Acknowledgement

Authors thank the CSIR, New Delhi for financialsupport.

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c-