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A new indazole ring synthesis
TetrahedronLetters N0.38, pp. 3375-3376,1970. PergamonPress. Printed in Great Britain.
ANEW INDAZOLERING SYNTHESIS A.L. Patey and N.M. Waldron ChemistryDept., Chelsea College of Scienceand Technology,Manresa Rd., London, S.W.3. (Receivedin UK 14 July 1970; accepted for publication19 July 1970) 4-Nitrobenzyldimethylamine(I) was nitratedwith fuming nitric acid/fuming sulphuricacid, in good yield, to an unstable red oil which was the expected2,4-dinitrobenzyl dimethylsmine(II) T(no solvent)7.68
(6H,s,2Me),6.12
(2H,s,CH2),1.93
(lH,d,H6),1.53 (lH,q,H5),1.39 (lH,d,H3),(J3_52.5c/s,J3_6 Oc/s, J5_6 8.8c/s); y(cm-1) 3110, 2980, 2955, 2870, 2830, 2780, 1610, 1540. The six absorptionsin the C-H stretchingregion of the i.r. spectrumof II were very similar to absorptionsin the same region of the i.r. spectrumof I. When first isolated,the unstable red oil (II) containeda few yellow crystalsand, after several days, the oil was transformed into a mass of yellow crystals,m.p.158.5-160'after crystallisationfrom ethanol. The yellow crystalswere 2-methyl-6-nitroindazo1e (III) (litlY2m.p.160')as indicatedby correct analysis; mass spectrum (molecularion) 177; similarn.m.r. spectrumto the publisheddata2; Y (cm-') 3150, 3060, 2940, 1525; A (y) 265 (E,6410),293 @2950), and it confirms 355 (E295). This is an unequivocalsynthesisof 2-methyl-6-nitroindazole the original structuralassignmentof Auwers3.
cH$JHe,
-
(1)
m
00
&+z (=I
OJJ
Another reaction,intendedto yield II, in fact produced the indazole (III). When an ether solutionof dimethylsminewas slowly added to an ice-coldether solution of 2,4_dinitrobenayl chloride (IV) a vigorous exothermicreaction ensued and a 75% yield of the indazole (III) m.p.l60-161'was obtained,which was identicalwith the previously obtained sampk? by all the above physicalmeasurements. The indazole (III) was further
3375
3376
No.38
characterisedby stannouschloridereductionto 6-amino-2-methylindaaole m.p.l54-6' (lit3m.p.156-7').t(CCl3)5.85 (JH,s,Me),3.37 (H,), 3.16 (I$), 2.52 (H4) ~c/s), 2.25 (~3);v(Cm') 3460, 3200, 3100, 1632. The (J4-5 SC/s, J4_7 1c/s, J5_7 amino compoundwas benzoylatedto give white crystalsof 6-benzsmido-2-methylindazole, m.p. 22f5', U(cm-1) 5260, 5140,,1660,1570. In both methods of preparationof III, it is reasonableto assume that the intermediateis II and, since II survivedthe strong acid nitratingmixture in one case but not the alkaline dimethylaminein the other, the cyclisationto form an indazolering clearlyneeds basic conditions. The mechanismof formationmay involve the N-oxide (V) as intermediate,as this requires the loss of the elementsof methanol from II. Several slightlysimilsralkaline cyclisations,of benzyl compounds with g-nitro substituents,to form indazolerings are known415, the most similarbeing the reaction of 2,4-dinitrobenzalanilines (VI) with sodium carbonateto yield the N-oxide (VII) and the substitutedindazole (VIII)4.
QNak
CZMa>
00
YN@>R
!=I
+%Q>R
t=jno
(m)
The scope and limitationof the reactionare being investigated. We thank A.W. Ellis for useful n.m.r. discussionsand ScienceResearch Council for a research grant to A.L. Pa-key. References 1.
O.N. Witt, E. Nobelting, and E. Grandmougin,~.,18YO,~, - 3638. E.Noelting,E., lYO4,57,2584.I.M.Barclay,N.Campbell,and G.Dodds,J.,lY41,117. R.R.Davies,J.,lY55, 2412.
2. J.Elguero,A.Fruchier,and R.Jacquier,Bull.Soc.Chim.,lY66,20'74. 3. LAuwers and X.Schwegler,~.,1920,~,1211. 4. S.Secareanuand I.Lupas,Bull.Soo.Chim.,[4],lYjj,~,l4j6;[5],l9~4,fr37);[5],l975r~,69; 1936,~,1161;J.Brakt.Chem.,1954,~,90. 5. T.Naito, R.Domori,and M.Sano,J.l?harm.Soc.Jaaan,lY54,&596. I.Tsranescuand E.Tsnanescu,Bull.Soc.Chim.,[5],lYjj,&1016.
ANEW INDAZOLERING SYNTHESIS A.L. Patey and N.M. Waldron ChemistryDept., Chelsea College of Scienceand Technology,Manresa Rd., London, S.W.3. (Receivedin UK 14 July 1970; accepted for publication19 July 1970) 4-Nitrobenzyldimethylamine(I) was nitratedwith fuming nitric acid/fuming sulphuricacid, in good yield, to an unstable red oil which was the expected2,4-dinitrobenzyl dimethylsmine(II) T(no solvent)7.68
(6H,s,2Me),6.12
(2H,s,CH2),1.93
(lH,d,H6),1.53 (lH,q,H5),1.39 (lH,d,H3),(J3_52.5c/s,J3_6 Oc/s, J5_6 8.8c/s); y(cm-1) 3110, 2980, 2955, 2870, 2830, 2780, 1610, 1540. The six absorptionsin the C-H stretchingregion of the i.r. spectrumof II were very similar to absorptionsin the same region of the i.r. spectrumof I. When first isolated,the unstable red oil (II) containeda few yellow crystalsand, after several days, the oil was transformed into a mass of yellow crystals,m.p.158.5-160'after crystallisationfrom ethanol. The yellow crystalswere 2-methyl-6-nitroindazo1e (III) (litlY2m.p.160')as indicatedby correct analysis; mass spectrum (molecularion) 177; similarn.m.r. spectrumto the publisheddata2; Y (cm-') 3150, 3060, 2940, 1525; A (y) 265 (E,6410),293 @2950), and it confirms 355 (E295). This is an unequivocalsynthesisof 2-methyl-6-nitroindazole the original structuralassignmentof Auwers3.
cH$JHe,
-
(1)
m
00
&+z (=I
OJJ
Another reaction,intendedto yield II, in fact produced the indazole (III). When an ether solutionof dimethylsminewas slowly added to an ice-coldether solution of 2,4_dinitrobenayl chloride (IV) a vigorous exothermicreaction ensued and a 75% yield of the indazole (III) m.p.l60-161'was obtained,which was identicalwith the previously obtained sampk? by all the above physicalmeasurements. The indazole (III) was further
3375
3376
No.38
characterisedby stannouschloridereductionto 6-amino-2-methylindaaole m.p.l54-6' (lit3m.p.156-7').t(CCl3)5.85 (JH,s,Me),3.37 (H,), 3.16 (I$), 2.52 (H4) ~c/s), 2.25 (~3);v(Cm') 3460, 3200, 3100, 1632. The (J4-5 SC/s, J4_7 1c/s, J5_7 amino compoundwas benzoylatedto give white crystalsof 6-benzsmido-2-methylindazole, m.p. 22f5', U(cm-1) 5260, 5140,,1660,1570. In both methods of preparationof III, it is reasonableto assume that the intermediateis II and, since II survivedthe strong acid nitratingmixture in one case but not the alkaline dimethylaminein the other, the cyclisationto form an indazolering clearlyneeds basic conditions. The mechanismof formationmay involve the N-oxide (V) as intermediate,as this requires the loss of the elementsof methanol from II. Several slightlysimilsralkaline cyclisations,of benzyl compounds with g-nitro substituents,to form indazolerings are known415, the most similarbeing the reaction of 2,4-dinitrobenzalanilines (VI) with sodium carbonateto yield the N-oxide (VII) and the substitutedindazole (VIII)4.
QNak
CZMa>
00
YN@>R
!=I
+%Q>R
t=jno
(m)
The scope and limitationof the reactionare being investigated. We thank A.W. Ellis for useful n.m.r. discussionsand ScienceResearch Council for a research grant to A.L. Pa-key. References 1.
O.N. Witt, E. Nobelting, and E. Grandmougin,~.,18YO,~, - 3638. E.Noelting,E., lYO4,57,2584.I.M.Barclay,N.Campbell,and G.Dodds,J.,lY41,117. R.R.Davies,J.,lY55, 2412.
2. J.Elguero,A.Fruchier,and R.Jacquier,Bull.Soc.Chim.,lY66,20'74. 3. LAuwers and X.Schwegler,~.,1920,~,1211. 4. S.Secareanuand I.Lupas,Bull.Soo.Chim.,[4],lYjj,~,l4j6;[5],l9~4,fr37);[5],l975r~,69; 1936,~,1161;J.Brakt.Chem.,1954,~,90. 5. T.Naito, R.Domori,and M.Sano,J.l?harm.Soc.Jaaan,lY54,&596. I.Tsranescuand E.Tsnanescu,Bull.Soc.Chim.,[5],lYjj,&1016.