Indian loumal of Chemi stry Vol. 38B, September 1999, pp. 1036-1040

Condensation of 2,3-pyridinediarnines with acetonylacetone

P K Dubey* & R Vinod Kumar

Departme nt of Chemi stry, College of Engineering, J.N.T . Un iversity, Ku katpall y, Hydcrabad A.P. 500 072, India

Received 21 August 1998; accepted (revised) 24 August 1999

The reacrion of 2 ,3 -pyridincd iamine la and its 5-bromo analogue lb, independentl y, with acetonylacetone leads to the fo rmation of I : I condensation products irrespective o f the molar ratios empl oyed. T hc condensation products h ~ l ve been

assigned 2-amino 2a and 5-bromo-2-ami no-'\ (2 ' ,5'-dimethylpyrro lyl)pyri dine 2b structu res. Aut hentic chemi cal evidence is given in support of the claim for these structures ruling out the cquall y probablc alternati ve structure 3 fo r these cOIllPou nds. Attempted studics on the reacti vi ty o f the latter compounds towards elcctrophilic reagents such as acetic anh ydri de , hcnzoyl chl oride, and arylsulphonyl chl orides have been described.

The condensati on of 1,4-diketones wi th aromatic pri mary amines employing we ll known Pall-Icnorr reaction results in the formation of N-substituted-2,S­d imethylpyrroles . Bu u-Hoi reported2 the format ion of N 2 -substituted-2 ,S-dimethylpyrro les by refluxi ng 2-amino-ring-al ky l -substitutedpyridines wi t~. acetony 1-acetone .

In the present work, we report the reacti ons of 2, 3-pyridi ned iamine and its S-bromo analogue with acetonylacetone whi ch results in the fo rmatio n of N 3

_

substituted products . The reacti vity of the two amino groups, which a re not simil a r unl ike in 0 -

phenylened iami ne, has been stud ied in detai l, by attempting condensation o f 2 wi th different e lectrophile <; such as acetic anhydride, benzoyl chloride and ary l sulphony l chlorides etc .

Results and Discussion

Condensation of 2 ,3-pyr id inediamine (la, i e., 1, X = H) with ace tonylacetone in 1: I molar rati o in hot acetic acid for 2 hr fo llowed by simple process ing gave a colourless crystalline compound melting at 129-31 °C . It was found to be homogenous on TLC and anal ysed for a I : I compos it ion.

It dissolved readily in el i!. HC l at RT and could be regenerated by addition of ag . ammoni a . T he IR spectrum of this compound showed absorptions at 3470, 3310 (unequal doub let. m, -NH2) , 3 160 (m), 2940 (w), 1620(vs, C=N), IS96 (w), 1460 (vs), 14 40 (w) , 1400 (m), 1330 (w) , 12S0 (m) c m-I e rc ., indicating the presence of a primary amino group and absence of a carbonyl functionality . Its IH-NMR (CDC 13fTMS) showed signals at 8 2 .0 (s, 6H,

2xCH3) , 4 .S (broad s, 2H, - NH2) , 5 .85 (sharp s, 2 1-1 ,

pyrro ly 1 protons), 6.7 (dd I H, ~-protO t1 of pyri d ine ring), 7 .3 (d, I H, y-pro to n o f pyrid ine ring), 8. 1 (d ,

I H, a-proton of pyri d ine ring) e tc . Its mass spectru m showed peaks at mlz. 187 ( 100%) 186 (30%), 172 (9S%), 171 (1 8%), 170 (28 %), 169 (2S %), 157 (8 3%), 14S ( IS %), 138 (8.3 %), 120 (5%), 104 (~.3%) . 94 ( 16 .6%) , 93 ( 15 .8%) , 92 (S.8%) e tc . It may be menti oned here that the same product was iso lated from any react io n be tween 1a and acetonylacetone irrespecti ve of the molar ratios of the reactants empl oyed.

Based on the above data, the compound may be

considered to ha ve 2-a mino-3-(2' ,S' -di methy l­pyrro ly J )pyridine struc ture (2a , i.e ., 2 , X=H) or 3-

amino-2-(2' ,S' -dime thy l pyrro ly I)pyrid inc st ruc ture (3a , i.e. , X=H) (Scheme I.)

Structure 3a is cons idered to be less prohable in view of the facts that 2-am in o group in 2-am in o pyr id ine is les s basic-' co mpared to th e 3-amin o group in 3-aminopyrid ine and the kno wn tendency o f I : I product fo rmation by 2.3-pyrid i ned iami nes in t he i r reactions with aromatic a lclehydes4

. Furthermo re, treatment of 3-am inopyridine \V ith acclOnylaceto ne in acetic ac id at loooe ro r 4 hr read ily gave a product.

which was identi fied as 3-(2'.:'i '-dimethy l-pyrrol yl)pyridi.ne. S im ilar treatme nt of 2-am inopyridine wi th acetonylacetone under the same cond itions led to the recovery o f start in g mate rial s. Simila rly , the condensatio n of S-bromo-2,3-pyridinediamine (Ib, i.e., 1, X=Br) with acerony l­acetone gave a product, which has been ass igned 2-amino-5-bromo-3-(2' ,S' -d i meth y Ipyrro I y I )pyridi ne

DUBEY el a!. : CONDENSATION OF 2, 3-PYRIDINEDl~MINES WITH ACETONYLACETONE 1037

CH3 - CO-(C~h-CO- CH3

I AoOH

X'OCN~ " I

N~

X = H or Sr 1

2

x'(Xt< N OH

4

I X'((~ X.. "

AcOH ~ CH3-CO- (CH:1)2- CO- CH:3 I P

Brn'r< N N~

2b

3 ""-

Scheme I

BryY't( ~.,~

N OH

4b

1 CH3-CO-(CH2)2-CO-CH3/

AcOH

BrnN02 BrnN02 BrnNH2

" I NaN02 Ni"i4 . H:P / " I .. " I ..

N NH2 H2-'304/ Raney - Nil N OH N OH oce MeOH 5b 6b 7b

Scheme II

structure (2b, i.e., X=Br) on the basis of spectral and analytical data and by analogy with 2a. Further evidence for the structure of 2 came from the following work: 2b (ie., 2, X=Br) on treatment with NaN02 in aq. HCl (50%) at ODC gave S-bromo-2-hydroxy-3-(2',5'-dimethylpyrrolyl)pyridine 4b which could also be prepared alternatively in an authentic manner. Thus, diazotization of 5-bromo-3-nitro-2-aminopyridine5 5b with NaN02 in H2S04 at ODC gave

.the known6 5-bromo-2-hydroxy-3-nitropyridine 6b. ;-The latter on reduction with hydrazine hydrate I Raney-Ni gave 5-bromo-2-hydroxy-3-aminopyridine 7b which on treatment with acetonylacetone in acetic acid gave 4b, identical in m.p., m.m.p., co-TLC and superimposable IR with the product obtained from 2b

above. All these reactions are briefly summari sed in Scheme II.

With a view to study the reactivi ty of the 2-amino group, the condensation of 2 with electrophilic reagents was attempted. Thus, the reaction of 2 with each of the reagents, acetic anhydride, benzoy l chloride, benzenesulphonyl chloride and tosyl chloride independently, under different conditions led to the recovery of starting materials. However, 2-aminopyridine as such reacted with ' the above electrophilic reagents to give the corresponding acylated/sulphonylated products Table I. For comparison purposes studies were conducted on the reactIvIty of carbocyclic analogue of 2,3-pyridinediamine i.e., a-phenylenediamine which are

1038 INDIAN 1. CHEM., SEC B, SEPTEMBER 1999

mentioned here. Thus, condensation of 0 -

phenylenediamine with acetonylacetone in I: I and 1:2 molar ratios respective ly in hot acetic acid gave the known 1-(0-aminophenyl)-2,S-dimethylpyrrrole7 8

and 1, I '-o-phenylene bi s-2,S-dimethylpyrrole8 9. Furtheffi1ore, 4 on treatment with acetic anhydride in

oc'3 8

pyridine gave the corresponding acetyl derivative i.e., amino groups are equally reactive. Furthermore, the l-acetamido-2-(2',S'-dimethylpyrrolyl)benzene. rotation of one pyrryl group around C-N bond

The unreact tvtty of the 2-amino group in (benzene ring carbon and pyrryl ring nitrogen) would compound 2 towards another mole of acetonylacetone have lessened the steric hindrance in the molecule and and those electrophilic reagents mentioned above, can facilitated the formation of a dipyrryl de ri va ti ve. This be explained on the basis of a combination of steric view is supported by the fact that the I : 2 and electronic factors. The 2-amino group of 2 does condensation product· of a-phe nylenediamine with not react with acetonylacetone for reasons of its acetonylacetone is formed in a step wise manner. In poorly basic nature. Furthermore, even if such a case, the J: 1 prod uc t initially fo rmed would condensation occurs under fo rcing condi tions a have attained a conformation suitab le for the second hypothetical 1 2 product [i .e ., 2.3-di(2' ,S'- amino group to react with anot her mole of dimethylpyrrolyl)pyridine] would be formed which acetoylacetone to form the most stable co nformati on will have the two pyrrole rings in out of plane with of d ipyrryl derivative, wherein , the two pyrryl rings each other. The pyrrole rings cannot be co-planar with will be perpendicu la r to each other and one of the the pyridine ring for steric reasons . Thi s is shown by pyrryl rings will be perpendicular to the pl:.lIle of the an accurate construction of the frame-work molecular benzene ring whereas the other wil l be in the same models of the I : ] and 1 : 2 condensation products of plane as the benzene ring. Thi s is shown by an 1 with acetonylacetone. However, the L) rmati on of accurate construction of fra me-work mol ecul ar d ipyrryl derivative in case of a-phenylened iamine models of 1 : 1 and I : 2 condensati on prouucts . could be explained based on the fact that both the The unreactivity of the 2-amino g roup in 2 towards

--------------------~------------~--~----------Table I--Reactions of 2-aminopyridinc wi th electrophilic reagent s.

SI Substrate No used

2-Amino pyrid ine

2 -do-

3 -do-

4 -do-

Reagent used

Acetic anhyd ride

Benzoyl chloride

Benzene sulphonyl chloride

Tosyl chtoride

Product obtained

2-Acetamido pyridine

2-Benzamido pyridine

2-Benzene sulphonamiJo

pyridine

2-Tosylamido pyridine

* %Nitrogen: Found :11.92. C"H ION2S02 requires 11.95 .

•

Yield ('Yo )

74

54

63

20

Rex tn Solvent

Hex:1I1e­benzene

Benzene

Benzene

Benzene­Methanol

m.p. °C

70-71 (Lit~ 7 1 )

85-87 ( Lit~ 87)

174-75'

2 13- 14 (Lit9 216)

IR

3200 ( Ill. LlI1 : harp, - NH) with a shoulder at 3270, 3125, 30 10 ( Ill. -C I-I ), 1670 (vs, C=O), 1(,00, 1590 , 1540, 1470, 1440. 1360. 1300 CIll · ' (series o/" ~lrol1g. sharr absorrtions)

3300 (Ill.-N H) with a shou lder at :n05. 3210, 3160, 3 100 etc. (series or weak absorptions, -CH). 1670 (vs, C=O), 1620, 1580, 1550, 1430, 1350, 1300 cm· ' (series o f strong sh8rp absorpti ons)

2800 (vb .. Ill . bonded- , 'H), 1620, 1585, 1540. 1460. 1395, 1370 cm·' (series o /" strong, sharp absorrtions)

2800 (vb, bondcJ -N H) 1620. 1610, 1540, 14GO, 1395. 1360 Cill- ' (scrics of strong. sharr absorptions)

DUBEY e/ at. : CONDENSATfON OF 2, 3-PYRIDINEDIAMINES WITH ACETONYLACETONE 1039

the electrophilic reagents such as acetic anhydride, benzoyl chloride etc. may once again be explained on the basis of stereo-electronic factors . Under normal conditions the lone pair of electrons on pyrryl nitrogen is probably in resonance with pyridine ring and so the pyrryl ring tends to acquire a planar configuration with the pyridine ring. In such a si tuation , formation of a 2-acetamido or 2-benzamido derivative of 2 is sterically inhibited. However, in the case of o-phenylenediamine, the lone pair of electrons in 4 on pyrrolyl nitrogen is not so strongly in resonance with the benzene ring thereby permitting rotation across C-N bond leading to a configuration in which the pyrryl ring is perpendicular to the benzene ring and subsequent condensation with the amino group of 4 with acetic anhydride giving the corresponding acetyl derivati ve of 4.

Experimental Section

All the melting points are uncolTected and were determined in a sulphuric acid bath. TLC analyses were carried out on glass plates coated with silica gel­G as adsorbant using the C0mmon organic solvents for the elution and spotting was done by iodine/ U.V. light. The starting materi als 1a and Ib were prepared from commercially available 2-amino pyridine using a known procedures . Other chemicals used in this work were of LR grade and were obtained from commercial suppliers.

Condensation of 1 with acetonylacetone : A mixture of 1 (20 mM) and acetonylacetone (2.4 mL, 20 mM) was heated in acetic acid (20 mL) on a steam bath at 100°C. The progress of the reaction was monitored by TLC. After the completion of reaction (2-4 I-,r) a product separated out on pouring the mixtnre into ice-cold water or on subsequent neutralisation with aq. NaHCO}. The separated product was filtered, washed with water (2 x 25 mL) and dried. Yield of 2a was 3.35g (90%) and of 2b was 4.3g (80%). The crude products thus obtained were recrystallised from hot hexane or from hexane­benzene mixture to yield pure products, m.p 129-310 C for 2a and 152-54 °C for 2b. The IR spectrum (KBr) of 2b showed peaks at 3470, 3270 (unequal doublet, m, - NH2), 3120 (m), 1620 (s, C=N), 1530 (w), 1450 (s), 1410 (s), 1350 (w), 1220 (w) cm-I. Its IH NMR(CDCl}ITMS) revealed signals at 8 2 .0 (s, 6H, 2 x CH3) , 4.45 (s, 2H,-NH2), 5.9 (s, 2H, pyrryl protons), 7.5 (s, IH, 'Y- proton of pyridine ring), 8.15 (s, 'H, a-proton of pyridine ring) . The mass spectrum

showed peaks at mlz. 267 and 265 (twin peaks, 83.3%, M+2 and M+), 252 and 250 (twin peaks, 100%), 173 and 171 (twin peaks, 25 %), 94 and 92 (twin peaks, 42%) etc. % Nitrogen of 2a : Found : 22.42 . C 11 H 13N, requires 22.44. % Nitrogen of 2b : Found : 15.73. C 11 H I2 Br N, requires 15 .78.

Diazotization of 2b to obtain 4b. To a soluti on of 2b (1 .325 g, 5 mM) in aq. HCI (50%, 20 mL) was added a cooled solution of sodium nitrite (0.345 g, 5 mM) at O°C for 10 min . At the end of thi s period , the separated solid was filtered , washed with water (2 x 25 mL) and dried . The crude product thus obtained was recrystallised from benzene-methanol (2: I) to get pure 4b, m.p . 216-1 8°C. %Nitrogen : Found: 10.43. CIIHIIBrN20 requires 10.48. IR(KBr) : 3065 (br, m, -NH- stretching vibration) , 2362 (m), 1667 (vs, -CO-), 1602 (s), 1523 (m), 1437 ( ~) , 1406 (m) , 1378 (m), i 319(w), and 12J4 cm- I (m); 'H_ MR

(CDCI}ITMS) : 8 2.0 (s, 6H, 2 x CH.1), 6.0 (s, 2H, pyrryl protons), 6.4 (d, J H, J = 2Hz, y -proton of pyridine ring), 6.6 (d, I H, J = 2Hz, a-proton of pyridine ring), 11.4 (s, IH , -OH) .

Reduction of 6b to obtain 7b. To a solution of fib (0.94 g, 5 mM) in methanol (40 mL) was added Raney-Nickel (catalytic amount) and the reac ti on mixture was heated to 40°C. Then hydrazine hydrate (0.25 mL, 5 mM) was added dropwise for 10 min . Stirring was continued for 2 hr. At the end of thi s period; the reaction mixture was filtered and the filtrate was evaporated to obtain a residue . The latter on recrystallisation with benzene-methanol (2: I) gave pure 7b, m.p. 187-89° C. % Nitrogen: Found : 14.80. CsHsBrN20 requires 14.82. IR(KBr) : 3422 and 3294 (m, unequal doublet, -NH2)' 2928 (br, m, -NH), 1651 (vs, -CO-), 1608 (vs), 1467 (s), 1350 (m); IH-NMR (CDCliDMSO-d6) : 85 .1 (s, 2H, -NH 2), 6.45 (d, 1 H, J = 2Hz, 'Y -proton of pyridine ring), 6.6 (d, 1 H, J =

2Hz, a-proton of pyridine ring) , 11 .4 (s, I H, -OH). Condensation of 7b with acetonylacetone to

obtain 4b. To a solution of 7b (1.33 g, 5mM) in acetic acid (20 mL) was added acetonylacetone (0.6 mL, 5mM) and the reaction mixture was heated on a steam-bath at 100°C for I hr. At the end of this period, the reaction mixture was cooled to RT and poured into cold water. The separated solid was filtered, washed with water (2 x 25 I1lL) and dri ed. The crude product was recrystallised from benzene­methanol (2: 1) to obtain pure 4b, m.p. 216-17°C.

Reaction of 2-aminopyridine with acetic anhydride/acylhalides : General procedure. To a

1040 INDIAN 1. CHEM., SEC B, SEPTEMBER 1999

solution of 2-aminopyridine (20 mM) in pyridine (l0 mL) was added dropwise the respective acid anhydride! acylhaJide (20 mM) taking care to see that the temperature does not rise above RT. The progress of the reaction was monitored by TLC. After the completion of the reaction (15-20 min.) as indicated by the disappearance of 2-aminopyridine, the reaction mixture was poured into water and neutralised if necessary with aq. HCI when a product separated out. The latter was filtered, washed with water (2 x 10 mL) and dried. The m.p., yields and IR data are recorded in Table-I.

Condensation of o-phenylenediamine with acetonylacetone. An equimolar mixture of 0-

phenylenediamine and acetonylacetone (20 mM each) was heated in acetic acid on a steam bath at 100°C for 2 hr. At the end of this period, the reaction mixture was cooled to RT and poured into water. The separated solid was filtered, washed with water (2 x 25 mL) and dried . Yield 3.2g (61 %) . The product thus obtained was recrystallised from hot hexane to yield pure 8, m.p. 76 - 77°C, IR (KBr) : 3400, 3320 (unequal doublet, m, -NH2)' 1620 (m, C=N), 1500 (vs), 1460 (m), 1430 (w), 1400 (s), 1320 (w) cm- I; IH NMR(CDCliTMS) : 8 2.0 (s, 6H, 2 x CH3), 3.4 (broad s, 2H, -NH2), 5.9 (s, 2H, pyrryl protons), 6.7-7.3 (complex m, 4H, benzene ring protons).

Similarly, the 1:2 condensation product 9 was obtained by the same method in an yield of 2.7g (73%), m.p. 151-52°C. IR(KBr) : 2922 (w), 1620 (w), 1495 (vs), 1448 (vs), 1390 (vs), 1314 (s), 1215 (w), 1113 (m) cm-I; IHNMR (CDC1 3ITMS) : 8 1.90 (s, 12H, 4 x CH3), 5 .84 (s, 4H, pyrryl protons), 7.27-7.50 (complex m, 4H, benzene ring protons) .

Reaction of 8 with acetic anhydride. A mixture of 8 (1.86g, 10 mM), acetic anhydride (0.94 mL, 10m M) and pyridine (catalytic amount) was heated on a water bath at 100DC for 4 hr. Then the reaction mixture was cooled to RT and neutrali sed with aq. NaHC03. The separated solid was filtered, washed with water (2 x 10 mL) and dri ed, yield 1.68g (73 %). The crude product was recrystallised from hexane­benzene to obtain pure 1-(0-acetamid ophenyl)-2,5-dimethylpyrrole, m.p. 152-54°C. % Nitrogen of 8 : Found : 12.26. CI 4HI6N20 requires 12.27. IR(KBr) : 3448 (broad, s, -NH) , 1671 (sharp, strong, C=O), 1594 (m), 1524 (m), 1453 (m), 1304 (m) cm-I.

Acknowledgement

Thanks are due to University Grants Commission , Govt. of India, New Delhi and Social Welfare Department, Govt. of Andhra Pradesh, Hyderabad for financial support.

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