Indian Journal of Chemistry Vol. 42B, December 2003, pp. 3 13 1-3 138

Note

Synthesis of 4, 5-dihydro-3-(1'-naphthyl)-2H­pyrazolino[3, 4-a]carbazoles and 3-(1'­naphthyl )isooxazolo[3,4 -a]carbazoles

Vandana T & K J Rajendra Prasad '"

Departmelll of Chemistry , Bharathiar University , Coimbatore - 641046, lndia

Receil'ed 10 January 200 I .. accepted (revised) 20 November 2002

Mixed aldol condensation of l -oxo-l,2,3,4-tetrahydro­carbazolc ] with I-naphthaldehyde yields 2-naphthylidene- l -oxo-1,2 ,3,4-tetrahydrocarbazole 2 which on treatment with hydrazine hydrate affords 4,S .. di hydro-3 -( 1'-naphthyl )-2H-pyrazolino[3,4 -a lcarbazolc 3 and 3-( l'-naphthyl) isoxazolof3,4-a ]carbazole 4 respcctively. A plausib le mechani sm for its fo rmation has been proposed.

Carbazol e alka loids have attracted much interest as ~ylllhetic targels since many of their derivatives ex ­hibit wide range of potent ial biological acti vities 1.4.

These components are considered to represent poten­tial therapeut ic agents against a variety of diseases in itiated by oxygen deri ved free radicals like myocar­dial and cerebral schema, arteriosclerosis, inllamma­llon, rheumatism, senility, cancer and autoimmune diseases5

-7. Although a large number of reports8

.12 are

available in literature describing the synthetic meth­ods directed towards e llipticine, olivacine and related tetracyclic compounds, the replacement of the pyri­dine ring in the natural structure by other heteroaro­matic systems has been reported in scant l.l·16. Based on the above said fac ts and using the reacti vity of 1-oxo- I.2.3.4-tetrahydrocarbazole, we have buil t up pvrazolino an nelated ri ngs on the carbazole moiety.

In achieving o ll r target 1-oxo-l.2,\4-tetra­hydrocarbazole was opted as a precursor. Mi xed aldol reaction 17 of 6-methyl- I-oxo-I,2,3,4-tetrahydro­carbazole la with I-naphthaldehyde under basic con­dit ion gave 6-methyl-2-naphthylidene-l-oxo- 1,2,3,4-tetrahydrocarbazole 2a, the structure of 2a was estab­li shed on the bas is of elemental analysis and spectral data. The IR spectrum exhibited a sharp and strong absorption band at 1645 cm·1 characteristic of ex, ~­unsaturated carbonyl group and a band at 3250 cm·1

ascribable to NH group. The disappearance of C2 pro­ton signal and appearance of naphthyllic proton signal as a singlet at 8 8.28 in its IH-NMR spectrum proved

mixed aldol reaction of la with naphthaldehyde to give 2a. The protons C3 and C4 resonated as multi­plets at 8 3.05 and 8 3.12 while that of methyl group and carbazole NH as a singlet at 8 2.45 and as a broad singlet at 8 8.94 respectively. Further it exhibited a multiplet at 8 7 .22-8.05 which was accounted as resonance of ten aromatic protons. The elemental analysis was compatible with the molecular formul a C24HI9NO. A series of similar compounds were real­ized with lb, Ie, ld and Ie (Scheme I and Table I).

When 2a was treated with hydrazine hydrate in ethanol it afforded the expected 7-methyl-4,5-dihydro-3-naphthyl-2H-pyrazolino[3,4-a]carbazole 3a in 78% yield. Its IR spectrum revealed the formation of C=N (1622 cm· l

) thereby indicating the absence of carbonyl absorption . The IH-NMR spectrum of 3a in

CDCh showed multiplets at 8 2.34, 8 2.75 . 8 3.0 I . b 3.44 which were assignable to C4, C3a, Cs and C3 pro­tons respectively , a broad doublet at 8 5.28 account­able for the pyrazoline-N-H proton. the 10 aromatic protons resonated between 8 7.06 - 7.90 a<; a mult i­

plet. Carbazole NH appeared as a broad sin glet at (5

8.84. Further the elemental anaiysis agreed weil Wllh

the moiecular formula C24H21N3. On the basis of the aforesaid data, the product was establ ised as 7-meth yl -4,5-di hydro-3-naphthy 1-2H -pyrazol i nof3,4-a J­carbazole 3a. Extension of the above reaction to 2b, 2e, 2d and 2e yielded the correspondll1g pyra­zo'lino[3,4-a]carbazole deri vatives 3b, 3e, 3d and 3e (Scheme I and Table II).

In another experiment 2a was treated with hydro­xylamine hydrochloride in dry pyrid ine to yie ld a single product which was puri fied by column chro­matography . The IR: spectrum recorded two absorp­tions at 3465 cm·1 and 1600 cm·1 which are asc rib­able for - NH and -C=N stretch ing vibrat ions respec­tively . The 'H-NMR spectrum registered a three pro­ton singlet at 8 2.18 for methyl group and a mul tipl et at 8 2.84 - 8 2.88 corresponding to C4 and Cs pro­ton s, an aromatic cluster between 87.24 -8 8.06 for ten protons and a broad s inglet at 89.93 for the - H proton . The elemental analysis agreed well with the molecul ar formula C24H1 8N20. Based on the above mentioned spectral data the stucture of the product was assigned to be 7-methyl-3(l '-naphthyl)isoxa

3132

1

Compd

2a

2b

2c

2d

2e

INDIAN J. CHEM., SEC B, DECEMBER 2003

+(if1 ~

alc KOH

3

CHO

8~

~ /; 4'

5

I 3' N-NH 2'

2

1-4 a; R, =C H3, R2=R3=H b; R ,=R3=H, R2=CH3 c; R, =R2=H. R3=CH3 d; R, =R2=R3=H e; R ,=Cl, R2=R3=H

Scheme I

2

NH20H.HCll CsHsN

',::::: 4 R 6 S 8~ 7 I /./ I 3a 3 - , R,~~~4

R3 H N-O 2' 3' , 2

4

Table 1- Physical and mass spectral data of compounds 2a-e

m.p. (OC) Yield (%) MS Mol. formula Found % (Calcd) Solvcnt C H

185 82 337 C24 HI9NO 85.39 05.6 1 04.1 1 PE - EA (85.43 05.68 04.15)

186 79 337 C24 HI'INO 85.38 05.59 04.09 PE - EA (85.43 05.68 04. 15)

190 78 337 C24 HI 'I NO 85.41 05.55 04. 11 PE - EA (85.43 05.68 04. 15)

153 84 323 C23H17 NO 85.40 05.12 04.28 PE-EA (85.42 05.30 04.33)

195 75 357 C23HI6NOCI 72.17 04.4 1 03 .88 PE - EA (72.20 04.50 03.91 )

PE - Petro leum ether 60-80°C, EA - Ethyl acetate

zolor3,4-a]carbazole 4a. Extension of the above re­action on 2b, 2c, 2d and 2e afforded the correspond­ing isoxazolor3,4-a]carbazole derivatives 4b, 4c, 4d and 4e (Scheme I and Table III).

of carbanion intermediate 6,which undergoes 1,3-prototropic shift to y ie ld the expected product 3.

In the formation of product 4 , a lone pair of elec­tron on oxygen of the ketoxime 5 (X=O) obtained from the reaction of 2 with hydroxy lamine hydrochlo­ride in pyridine attacks the naphthylic carbon to af­ford the carbanion intermediate 7 and which subse­quently loses hydride ion to pyridonium ion (which changes into pyridine and hydrogen molecule) (Scheme II). The arieal oxidation phenomenon has been ruled out s ince in nitrogen atmosphere also 2 yielded 4 .

Compound 2a was reacted separately with hydra­zine hydrate in pyrid ine and with hydroxylamine hy­drochloride in ethano l. Starting materials were recov­ered in both the cases .The lo ne pair e lectron on nitro­gen of the hydrazone intermediate 5 (X=NH) obtained from the reaction of 2 with hydrazinehydrate in etha­nol attacks naphthy llic carbon to result the formation

NOTES 3133

Table II - Physical and mass spectral data of compounds 3a-e

Compd m.p. (0C) Yield MS Mol. Found % (Calcd) Solvent (%) formula C H N

3a 174 78 35 1 C24 H21 N.l 81.99 05.93 11 .5 1 PE-EA (82.02 06.02 11 .56)

3b 124 76 351 C24 H2I N) 8 1.98 05.98 11.55 PE-EA (82.02 06.02 I 1.56)

3c 154 79 35 1 C24 H21 NJ 82.01 05.91 11.49 PE-EA (82.02 06.02 11.56)

3d 12 1 78 337 C23 HI 9NJ 8 1.88 05 .67 12.45 PE-EA (8 1.79 05 .65 12.4 1)

3e 169 69 37 1 C2J HIsN.lCl 74.25 04.79 11.22 PE-EA (74.29 04.88 11 .30)

PE - Petroleum ether 60-80°C, EA - Ethyl acetate

Table 111 - Physica l and mass spectral data of compounds 4a-e

Compd m.p. (OC) Yield MS Solvent (%)

4a 143 68 350 PE-EA

4b 109 65 350 PE-EA

4c 139 69 350 PE-EA

4d 11 9 7 1 336 PE-EA

4e 138 6 1 370 PE-EA

PE - Petroleum ether 60-80°C, EA - Ethyl acetate

Experimental Section All melting points were determined in open capil­

lary tubes using mettler FB-S apparatus and are un­corrected. IR spectra were recorded on a Sh imadzu FflR - 820] (PC), spectrometer us ing KBr pelle ts and on ly noteworthy absorption levels are listed. The ' H-NMR spectra were recorded on varian AMX 400

spectrometer, chemical shifts in 8, ppm using TMS as internal standard. Mass spectra were recorded on jeol o 300 spectrometer. Satisfactory m icro analyses were obtained on Carlo Erba 1106 and Perkin Elmer model 240 CHN ana lyzers.

Preparation of 2-naphthylidene-l-oxo-l,2,3,4-tetrahydrocarbazoles 2. A mixture of respective 1-oxo-I,2,3,4-tetrahydrocarbazole (1, 4 mmole) and 1-naphthaldehyde (4 mmole) was treated with 4% ale KOH (15 mL) and the mixture stirred for 6 hr at room temperature. The precipitated crystalline product was

Mol. Found % (Caled) formu la C H

C24 HIX N20 82.24 05 . 16 07 .93 (82.26 05. 18 07.99)

C24HISN20 82.22 05.11 07.93 (82 .26 05. 18 07.99)

C24 HI SN20 82.24 05. 13 07 .92 (82.26 05. 18 07 .99)

Cn HI6N2O 82.09 04.77 08.28 (82 .21 04.79 08.33)

C2J H 15N20CI 74.39 04 .02 07.49 (74.49 04.08 07 .55)

fi ltered off and washed with rectified spirit. A further crop of condensation product was obta ined on neu­trali sa ti on with acetic ac id and dilution with water. The products were recrystallised from methano l (Scheme I and Table I) . The mass fragme ntation pat­tern of co mpound 2c in g iven in Scheme III.

Preparation of 4,S-dihydro-3-(1'-naphthyl)-2H­pyrazoIino[3, 4-a ]carbazoles 3. 2-N aphthy I idene-l­oxo-I,2,3,4-tetrahydrocarbazole (2 , 1 mmol e) was disso lved in abso lute ethano l (20 /TIL) , hydrazine hy­drate (0 .5 mL, 10 mmo le) was added and this mixture was heated at reflux for 4 hr. The so lvent was re­moved under reduced pressure, then the crude reac­tion mixture was pou red into the ice cold water and ex tracted with chloroform, washed wi th water and combined organic layers were dried over anhyd. Na2S04. Evaporation of the solvent followed by crys­tall isation with pet. ether yielded the corresponding

3134

2a

2b

2c

2d

3b

3c

3d

3e

4a

4b 4c 4d 4e

~~ Ar RY~~~ o

2

X=O.N H Ar= I'· naphlhyl

INDIAN J. CHEM., SEC B, DECEMBER 2003

~"" ----__ ::,(h N I ~ Ar R H I

N, .. _ XII ~

~~ P=M: I - Ar

R N H ~-OH

7

j ) 1.3-P,"'""OP" ,h i[,

()irl Ar R~~~ 071- Ar W +

H N- NH

3

RY~~~ N-O

8

N Ii

abstractio n of hydride ion by py ridon iUIll ion

~ I I )<h N' "" Ar

R II I N- O

4

Scheme II

+

Table IV _ ll-l NMR data of compounds 2 a-e, 3a-e and 4a-e

11-1 NMR (8, ppm)

9

"I arie l l' oxidat ior

4

2A5 (s. 31-1. Cc,-C I-I 3 ). 3.05 (m, 21-1 , Cr I-l2), 3.12 (m , 21-1 , C4-1-1 2), 7.22-8 .05 (m, IOH, aromatic H). 8.28 (s, III. l1,l

lic), 8.94 (b s. I H, NH) 2.55 (s , 3H. CrC H), 3.03 (m, 2H, C)- H2), 3.12 (m. 2H, C4-H2), 7.09-8 .04 (m, IOH, aromatic H). 8.28 (s. III . nanhlll\1 lie), 8.95 (b S, IH, NH) 2.49 (s. 3H, Cg-C I-I J ). 3.01 (m, 2H, Cr H2), 3.12 (m, 21-1, C4-H2), 6.89-8.09 (m, lOH, aromatic 1-1). )).3 1 : ~" J II I •• "

lic). 9.15 (bs, 11-1. NH) 3.05 (m. 21-1. C,-Hz), 3. 14 (m, 2H. C4-H2), 7.17-8.04 (m, 11H. aromatic H), 8.32 (s, I H, naphthyllie). 9.36 (h , II i NH ) 2.99 (m. 21-1, C,-H2), 3. 13 (m. 2H, C4-H2), 6.72-8. 19 (m, 9H, aromatic H), 8.3 1 (s, I H, naph thylhc) , 9.32 (b s. 111. 11)

2.34 (m, 2H, C4-H2) , 2.43 (s, 3H, CH 3) , 2.75 (m, I H. C3, -H). 3.0 1 (m, 2H, CS-H2). 3.44 (m, 1 ll , Cr H), S.2ti lao III. pyrazoli ne NH). 7.06-7.90 (m, IOH, aro matic H), 8.84 (b S, I H, carbazole NH) 2.36 (m, 2H, C4 - H2), 2.50 (s, 3H, CH3), 2.76 (m, 11-1 , C3, -H), 3.04 (m, 2H. CS- Hl). 3.46 (m. 1 H. Cr H), 5.28 (d. II! pyrazoline NH). 7.02-7.97 (m, IOH, aromatic H), 8.88 (b S, IH, carbazole NH) 2.26 (m, 2H, C. - H2)' 2.45 (5 , 3H, CH), 2.66 (m, I H, C3.-H), 2.99 (m. 21-1, Cs- 2),3.99 (m, I H, Cr 1-1),5 .24 (d. Il l. pyrazoline NH), 6.70-7.94 (m, 101-1 , aromatic 1-1 ), 9 .1 5 (b s, I H, carbazole NH) 2.27 (m, 2H, C4 - H2), 2.75 (m, IH , C3a-H), 3.03 (m, 2H, Cs- H2), 3.44 (m, IH, C1- H). 5.25 (d, I H. pyrazoline NIl ), 7.11 -7.95 (m, II H, aromatic H), 9.46 (b s, IH, carbazole NH) 2.27 (m. 2H, CC H2), 2.72 (m, IH , C3a-H), 2.97 (m, 2H, Cs- H2), 3.43 (m , I H, Cr H), 5 .26 (d, I H, pyra2.0lin.: NH). 6.99-7 .93 (m, IOH , aromatic H), 9.45 (b s, IH, carbazole NH) 2.18 (s, 2H, CH3), 2.84-2 .88 (m, 4H. C4-H2, CS-H2) , 7.24-8.06 (m, 10H, aromatic H). 9.93 (b s, 11-1, carbazole Nil) 2.1 7 (s , 2H, CI-IJ ) , 2.87-2.90 (m. 4H, C4-H2, CS-H2), 7.12-8.05 (m, IOH, aromatic H), 9.93 (b S, 11-1, carbazole Nil) 2. 17 (s, 2H, CH3) , 2.89-2.96 (m, 4H, C4-H2, CS-H2), 7.03-8.05 (m, lOH, aromatic H), 9.86 (b S, 1 H, carbazole NI-I)

2.89-3.04 (m, 41-1, C4-H2, CS-H2) , 7.11-8.08 (m, 11 H, aromatic H), 9.89 (b s, 1 H, carbazole NH) 2.75-3.04 (m, 4H, C4-1-12, CS-H2), 7.11-8.05 (m, lOH, aromatic H), 9.93 (b s, IH, carbazole NH)

NOTES 3135

mle 157(11.2%)

Qt;A~ ~ 6 I +

~ CH CH3

mle 167( 10.4%)

~.NH ~ mle 282(7.5%)

~I; y-lv 0

CH3

mle 141{17.8%) mle 142(25.2%)

Ar =I'-nnphthyl

Scheme III

3136 INDIAN J. CHEM .. SEC B, DECEM BER 2003

Q=M~

o NH I 0 Ar H2N-NI&CH;"l:" mle44(lOO%)

CH) HN-NH t mle3SI(l4.09%) "-

j.NHZNH '\.. I it 9YQy ..

~ Ar CH) H ~-NH Y'~~ mle3SI(14.09%)

CH) j mle321(9.1 %)

·Ar

·~C·Ar

rI~ It ~f'~~Ar

CH) H ~-NH Y mle349( 12.3%)

.Ar ~~ Y'~~+

CH3 H N-NH

mle211 (S.2%)

Qyq: I N 0

. H H 1+ .C2H../ CH) mleI81(4 .3%) QQQ ' '"'7

~:" ~r-"""II--'I NH Y'N"

CH) H

10 I /'

~H' ~

H)C NH

mleI98(8.3%)

mleI97(2.7S%)

9QQ::l:"

1 0 I + N

H NH "7 mleI83(4,9%)

·HCN

QQQ QjCJ N + H NH

mleI81(4.2%) / + H mleI56(6.1%)

/ ·C2H4

O=:u> . N + H

m/e 128(2.4%) 1'1

+ H mleIS4(8.1%)

~ 0:JCn N . + H mleIS4(8. IS}

Scheme IV

·HCN

\

mleI70(8 ' 1%)

9? ':1:" 1 0 I

N CH) H

mleI43(2.2%)

yp:::l:" 1 . I I

o N CH

J H . mleI69(3.9%)

j .H,

m/eI67(8.S%)

Ar =I'.riaphlhyl

NOTES 3137

11

9:M m/e322(2.1 %)

vrl~ I: N1

A ,Ar QQQ~~~ I 1 1 -Ar ' H I I

A . CH3 N=o+ A A N N .....-Ar

CH) H mle35 1(14.09%) CH3

H

mle292(3.89%) \C,H. j ·NO . / mle318(9.8%)

J

:k \ ()-Y) it / ·H,

Y'~~""'-Ar CH3

-H2

~I~· Y'N~(~Ar

CH3 N-O

mle348( 48. 9%)

~~ I~

I I A N ~ Ar

~I~ ~ CH3 H ~-O

I I mle348(48.9%) A N ~ Ar

CH3 H ~-O ~4 m/e35 1 ( 14.09%)

mle320( 12.04%)

mleI65(35.1 %) j .CH.

eyq~~ I I ~ N A

H .....-Ar

mleI91(3.2%)

mle304(25.2% )

mleI49(25.2%) 0 /1 II I/>+ ~

mle 134( 1.8%)

Ar = I '-naphthyl

mle261 (2.5%)

Scheme V

3138 INDIAN 1. CHEM., SEC B, DECEMBER 2003

4,S-dihydro-3-napthyl-2H-pyrazolino [3,4-a]carba­zole 3 (Scheme I and Table II). The mass fragmenta­tion pattern of compound 3c is given in Scheme IV.

Preparation of 3-(l'-naphthyl)-isoxazolo[3, 4-a]carbazoles 4. 2-Naphthylidene- I-oxo-I,2,3,4-tetra­hydrocarbazole (2, 1 mmole) was treated with hy­droxlylamine hydrochloride(lg, 14 mmole) in pyri­dine (SmL) at 130DC for 10 hr. The reaction mixture then poured into crushed ice, the resulting semi-solid separated was extracted with choroform,subsequently washed with dil.HCI and water. The combined or­ganic layer were dried over anhyd. Na2S04 . Removal of solvent yielded the crude product which was puri­fied by column chromatography using pet. ether -ethyl acetate as a solvent system over silica gel col­umn. The product was recrystalised from the solvent system (Scheme I and Table III) . The mass fragmen­tation pattern of compound 4c is given in Scheme V.

Acknowledgement We acknowledge SIF, IISc Bangalore and RSIC,

CDRI Lucknow for providing spectral and analytical data.

References: I Kapil R S, in The Alkaloids, Vol. 13, edited by R H F Man­

ske, (Academic Press, New York), 1971, 273.

2 Chakraborty D P, in Prog Chem Org Nat Prod, Vo1.34, edited by W Herz, H Gri sebach & G W Kirby, (Springer Verlag, Wien), 1977, 299.

3 Husson H P, in The Alkaloids, Vol.26, edited by A Brossi, (Academic Press, New York,) 1985, I.

4 Chakraborty D P & Roy S, in Prog Chem Org Nat Prod, Vol. 57, edi ted by W Herz, H Grisebach G W Kirby & C Tamm, (Springer Verlag, Wien), 1991, 71.

5 Hammond B, Kantos H A & Hess M L, Can J Physiol Phar­macal, 63 , 1985 173.

6 Cerutti P A, Science, 227 , 1985 375.

7 Halliwell B & Gutteridge J M C, Method in En zymology, 186, 1990 I.

8 Gribble G W, in The Alkaloids, Vol. 39, edited by A Brossi, (Academic Press, New York), 1990, I.

9 Kansal V K & Potier P, Tetrah edron , 42, 19862389.

10 Ducrocq C, Bisagni E, Ri valle C & Lhoste J M, J Chelll Soc, Perkin Trans 1,1979 142.

11 Rastogi S N, Bindra J S, Rai S N & Anand N, Indian J Chern , 10, 1972 673.

12 Schmutz J & Wittwer H, Helv Chilli ACTa, 431960793.

13 Agarwal A, Agarwal S K & Bhakuni D S, Indian J Chem, 3 1 B 199244.

14 Mahboobi S, Kuhr S & Koller M, Tetrah edron, 52, 1996 6373.

15 Peixoto FMC, Queiroz M J R P & Kirsch G, J Chel1l Res (M), 1998 801.

16 Chunchatprasert L & Shannon P V R, J Chel1l Soc Perkin Trans I, 1994 1765.

17 Fateen A K & Ali M M, Indian J Chel1l , 10, 1972 968.