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First cycloaddition of 2-vinylindoles with dimethyl, 1,2,4,5-tetrazine-3,6-dicarboxylate: Diels-Alder reactions with inverse electron demand to new substituted and annelated pyridazines
Tetrahedron Letters,Vol.29,No.32,pp Printed in Great Britain
3927-3928,1988
0040-4039188 $3.00 -f .oo Perqamon Press plc
FIRST CYCLOADDITIOBS OF 2-VIBYLIBDOLES YITE DIHBTEYL 1,2,4,5-TETBAZIBE-3,6DIBLS-ALDER PEACTIOUS WITH IBVEPSB BLECTBOU DEMABD TO UEU DICABBOXYLATB: SUBSTITUTED ABD ABBELATED PYPIDAXIBES Ulf Pindurf and Myung-Eva Kim Institut fiirPharmaxie im Fachbereich Chemie und Pharmaaie der Universitgt, Saarstrasse 21, D-6500 Bainz, Federal Republic of Germany SLMARY: 2-Vinylindole la and its donor-/acceptor-substituted @-derivatives lb-le reactwith dimethyl 1,2,4,5-tetraxine-3,6-dicarboqlate to form new indolyl-1,4-dihydropyridaaines 3a, 7 and annslated pyridazinas3b-d, 5, 6. The reactionsproceedunder stericcontrolwith Ngh locoselectivities. The 2- and 3-vinylindoles are synthetically attractp2s building blocks for the regioand stereocontrolled [blannelationof the indole skeleton 9 . Because of their outstandingxdonor reactivity, 2- z 3-vinylindoles (ERoBo ca. -7 to -8 eV)3 should also participate in [4 + 2)-cycloadditionswith inverse electron demand4-8. We report here the first [4 + 2]cycloadditionsof some 2-vinylindoles1 with dimethyl 1,2,4,5-tetrazine-3,6_dicarboxylate. The Z-vinylindole parent compound la reacts selectively with the tetrazine (1:l mmol, CB2C12, 5 h, -75 'C to RT) to furnish the 1,4-dihydropyridaxine-dicarboxylate 3a. The tetrazine undergoes addition to the sterically less hindered 2-vinyl functional group more rapidly. However, the dimethylated 2-vinylindole lb reacts with the tetrazine (1:l mmol, CH2C12, - 75 to -10 "C) to yield the dihydropyridazinoindole3b exclusively.
E 1. (4 + 2~eycloaddltlon 2. [4+2~cyclomasion -N2
la
R’ H
R2 H
lb lc Id
Me Me me
Me E OMe
3b IW.)
-I---
2b-2d
3b-3d
R2=E.t&0
E=co2Mc
I
1. [4*2] -cydoaddit&n
t
-Nz
R',R2=H
5
(8%)
L
bc.bii
‘I-enda-trig
F?=MUJ
1
I
E
6 19%)
In the cases of lc and Id, further transformations of 3 take place during the reactions with the tetrazine.The unstable primary cycloadducts 3c and 3d formed in the reactions of lc (1:l.l mmol, dioxane, 100 OC, 81 h) and Id (1:l.l mmol, CH2C12, -75 OC to RT, 21 h) with the tetraxine can only be characterized as crude products and, in the further course of the 39.27
3928
reaction, undergo an initial oxidative heterolysis at the N/C-4a bondsa to give the intermediates 4c and 4d. When R = CO2Me, a Michael-type addition to give the pyridazino[~]-annelated dihydroquinoline5 occurs and, when R = OMe, the new bensaaepine derivative 6 is formed from 4d. The orientations of the two cyclizations of 4 are plautible in terms of the electrostatic concept and allowed processes according to Baldwin's rules . Like la, the vinylindole le also reacted (1:l.l mmol, CH2C12, 40 'C, 7 h) selectively at the 2-vinyl moiety to yield the indolyldihydropyridasine 7
I le
II
(PSI
I REFERENCES
@ISI
and central chiralitv and exists as a mixture of atropisomers (dynamic NMR spectroscopy)11~12*13.
AND NOTES
1. L. Pfeuffer,U. Pindur, Helv.Chim.Acta 70, 1419 (1987)and 71, 467 (1988). 2. U. Pindur,Heterocycles, in press. 3. U. Pindur,L. Peuffer,Monatsh.C&em.,in press. 4. J. Sauer, R. Suetmann, Angew. Chem. 92, 733 (1980);Angew. Chem., Int. Ed. Engl. 19, 770 (1980); D.L.Boger, M.D.Mullican, Tetrahedron Lett. 23, 4556 (1982);J. Sauer, A. Mielert, D. Lang, D. Peter, Chem.Ber. 98, 1435 (1965). 5. U. Pindur,L. Pfeuffer,Chimia 41, 125 (1987). 6. I. Fleming,FrontierOrbital8and OrganicChemicalReactions,John Wiley & Sons,New York, 1976. 7. SC. Benson, CA. Palabrica,JR. Snyder,J. Org.Chem. 52, 4610 (1987). 8. a) G. Seitz, T. Kiimpchen, Arch.Pharm.(Weinheim,Ger.)309, 679 (1976);G. Seitz, R Mohr, Chem.sill, 81 (1987);b) T. RRmpchen,Thesis,MarburgUniversity(PRG),1978. 9. J.E. Baldwin, J. Chem.Sot.,Chem.Commun. 1976, 734. 10. M. Eitel, U. Pindur,Helv.(him.Acta, in press. 11. of Ia with Dimmtbyl 1,2,4,Hetrazhz-3,6-d.icarboxylatel Tgpical Proc&mw 2-Vinylin429 mg, 3 mmol) in dry dichloromethane (30 ml) was treatedportionwisewith the tetrazinc (594mg, 3 mmol) with stirringunder argon at -75 'C for 1 h and 20 'C for 4 h. The solvent was evaporatedand the residueseparatedby flash chromatography [silicagel, Merck 60, grain size 0.043-0.040mm, 1:l petroleumether (b.p. 4C+60 "C)/diethyl ether] t yield 3a. 12. SelectmdPhysical Data of the Products. Compound3a: mp. 152 'C.PH-NMR (400 MHs, (DMSO-dd): 63.68 (8, 3H, CCCCH3),3.76 (s, 3H, COGCH3),4.89(d, 3J - 5.9 Hz, lH, pyridazineH-4), 6.OU (8, lH, indoleH-3), 6.05 (dd, 3J - 5.9 Hz, 4J = 2.2 Hz, pyridkne H-5) 6.92 (t, 3J - 7.2 Hz and 7.6 Ha, lH, indoleH-6), 7.12(ty 3J = 7.3 ti< 1H. indoleH-5), 7.35(d,'3 J = 8.0 HsTlH, indoleH-7), 7.40 (d, 35 = 7.8 Hz, lH, indoleH-4), 10.78(d, 'J - 2.2 Hz,1 yridazine NH), 10.92 (8, la, Indole‘NH). compo;hd3b: m.p. 131 'C. k+MR (CDC13):6 -1.58 (dd, J = 6.5Hx, 4J = 1.6Ha, 3H, =CHCZll), 3.13 (8,3H, COOCH3),3.85 (8, 3H, NCH3), 3.96 (8, 3H, COOCH3),4.74(dd, 3r= 15.4Hz, 4J = 1.6 Hz, 18, e=CHCH ), 5.31 (m, 3J - 6.5 Hz and 15.4 Hz, lH, CH=CHCH3),6.69 (d, 3J = 8 Hs,iH, H-6), 6.80 (ddd,3;= 8 Hz, 4J 1.8 Hz, lH, H-8), 7.30 (ddd, 3J =: Hz, 4J = 1.2Hz: 18, 7-H), 8.34 (d, 3J = 8 HZ, lH, H-9) 9.74 (8, 18, NH).Product 5: m.p.235 'C (acetone).'H-NMR (CDC13):6 - 3.52 (Td, 25 = 17.4 Hz, 1J = 12.6 Hz, lH, CH2), 3.63 (dd, 2J - 17.4 Hz, 3J = 5 Hz, lH, CH2), 3.69 (8, 3H, G3 or NCH3),3.74 (8, 3H, 0CH3 or NCH3), 3.80 (s,3H, OCH3 or %l3), 3.91 (8, 38, OCH3 or NCH3), 4.15 (dd, 3L= 12.6Hz and 5 Hz, H-5), 7.11 (dt, 3J - 7.3 Hz, 4J - 1.1 He, lH, H-9), 7.20 (mc, 3H. H-7, H-8, H-10).Compound6: m.p. 145 OC. 'H-NMR&X3): 6 - z91 (8, 3H, H3CC at C-6), 3.30 (dd, 25 = 16 Hz, 3J = 1.5 Hz, lH, H-5), 3.50 (8, 3H, COOCH3),3.65 (dd, 2J = 16 Hz, 3J - 4.2 Hz, LH, H57, 3.71 (8, %, NCH3), 4.01 (8, 3H, COOCH3),5.73 (q, 3J = 1.5Hz and 4.2 Hz, li, H-6), 7.29 (mc, 3H, H-8, H-9, H-lo),8.16 (d, 3J = 8.9Ha, lH, H-11).l&MR (CDC13):6 = 29.67(NCH3),52.79and 53.24 (COO~H,),56.07 (OCH,),28.30 (C-5). 90.66 (C-6); sp2-CH: 109.45,120.31,121.07,122.19; quaternaryC: 102.14,124.04,132.06,137.94,145.55,166.94;193.03and 199.26(2 x CO).Compound 7: m.p.141 Y. lH-NMR (CD2Cl2,20 OC, mixtureof atropisomers): 6 - 1.06(dd,3J = 6.9Rz, 3H, CH3 at C-5),2.10and 2.24 2 x s, 3H, indole 3-(.X3), 3.51and 3.64 (2 x s, 3H, ind~e 1-0X3),3.60 (a, 3H, COOCH3), 3.69 (q, 4J - 6.9 Hz, lH, H-5), 3.84 (8, 3H, COOCH3),7.08 (2 x t, lH, indole H-6), 7.19 (2 x t, lH,$1dole%5), 7.28(m, lH, indoleH-7), 7.52 (m, lR, iudole lf-4), 8.8: (a, lH, NH). 13.MNDO calculations~" performedfor la do predicta UJMOdieneflDMOdie,_p~le-coutrolledo reaction
(Received
in Germany
4 May
1988)
3927-3928,1988
0040-4039188 $3.00 -f .oo Perqamon Press plc
FIRST CYCLOADDITIOBS OF 2-VIBYLIBDOLES YITE DIHBTEYL 1,2,4,5-TETBAZIBE-3,6DIBLS-ALDER PEACTIOUS WITH IBVEPSB BLECTBOU DEMABD TO UEU DICABBOXYLATB: SUBSTITUTED ABD ABBELATED PYPIDAXIBES Ulf Pindurf and Myung-Eva Kim Institut fiirPharmaxie im Fachbereich Chemie und Pharmaaie der Universitgt, Saarstrasse 21, D-6500 Bainz, Federal Republic of Germany SLMARY: 2-Vinylindole la and its donor-/acceptor-substituted @-derivatives lb-le reactwith dimethyl 1,2,4,5-tetraxine-3,6-dicarboqlate to form new indolyl-1,4-dihydropyridaaines 3a, 7 and annslated pyridazinas3b-d, 5, 6. The reactionsproceedunder stericcontrolwith Ngh locoselectivities. The 2- and 3-vinylindoles are synthetically attractp2s building blocks for the regioand stereocontrolled [blannelationof the indole skeleton 9 . Because of their outstandingxdonor reactivity, 2- z 3-vinylindoles (ERoBo ca. -7 to -8 eV)3 should also participate in [4 + 2)-cycloadditionswith inverse electron demand4-8. We report here the first [4 + 2]cycloadditionsof some 2-vinylindoles1 with dimethyl 1,2,4,5-tetrazine-3,6_dicarboxylate. The Z-vinylindole parent compound la reacts selectively with the tetrazine (1:l mmol, CB2C12, 5 h, -75 'C to RT) to furnish the 1,4-dihydropyridaxine-dicarboxylate 3a. The tetrazine undergoes addition to the sterically less hindered 2-vinyl functional group more rapidly. However, the dimethylated 2-vinylindole lb reacts with the tetrazine (1:l mmol, CH2C12, - 75 to -10 "C) to yield the dihydropyridazinoindole3b exclusively.
E 1. (4 + 2~eycloaddltlon 2. [4+2~cyclomasion -N2
la
R’ H
R2 H
lb lc Id
Me Me me
Me E OMe
3b IW.)
-I---
2b-2d
3b-3d
R2=E.t&0
E=co2Mc
I
1. [4*2] -cydoaddit&n
t
-Nz
R',R2=H
5
(8%)
L
bc.bii
‘I-enda-trig
F?=MUJ
1
I
E
6 19%)
In the cases of lc and Id, further transformations of 3 take place during the reactions with the tetrazine.The unstable primary cycloadducts 3c and 3d formed in the reactions of lc (1:l.l mmol, dioxane, 100 OC, 81 h) and Id (1:l.l mmol, CH2C12, -75 OC to RT, 21 h) with the tetraxine can only be characterized as crude products and, in the further course of the 39.27
3928
reaction, undergo an initial oxidative heterolysis at the N/C-4a bondsa to give the intermediates 4c and 4d. When R = CO2Me, a Michael-type addition to give the pyridazino[~]-annelated dihydroquinoline5 occurs and, when R = OMe, the new bensaaepine derivative 6 is formed from 4d. The orientations of the two cyclizations of 4 are plautible in terms of the electrostatic concept and allowed processes according to Baldwin's rules . Like la, the vinylindole le also reacted (1:l.l mmol, CH2C12, 40 'C, 7 h) selectively at the 2-vinyl moiety to yield the indolyldihydropyridasine 7
I le
II
(PSI
I REFERENCES
@ISI
and central chiralitv and exists as a mixture of atropisomers (dynamic NMR spectroscopy)11~12*13.
AND NOTES
1. L. Pfeuffer,U. Pindur, Helv.Chim.Acta 70, 1419 (1987)and 71, 467 (1988). 2. U. Pindur,Heterocycles, in press. 3. U. Pindur,L. Peuffer,Monatsh.C&em.,in press. 4. J. Sauer, R. Suetmann, Angew. Chem. 92, 733 (1980);Angew. Chem., Int. Ed. Engl. 19, 770 (1980); D.L.Boger, M.D.Mullican, Tetrahedron Lett. 23, 4556 (1982);J. Sauer, A. Mielert, D. Lang, D. Peter, Chem.Ber. 98, 1435 (1965). 5. U. Pindur,L. Pfeuffer,Chimia 41, 125 (1987). 6. I. Fleming,FrontierOrbital8and OrganicChemicalReactions,John Wiley & Sons,New York, 1976. 7. SC. Benson, CA. Palabrica,JR. Snyder,J. Org.Chem. 52, 4610 (1987). 8. a) G. Seitz, T. Kiimpchen, Arch.Pharm.(Weinheim,Ger.)309, 679 (1976);G. Seitz, R Mohr, Chem.sill, 81 (1987);b) T. RRmpchen,Thesis,MarburgUniversity(PRG),1978. 9. J.E. Baldwin, J. Chem.Sot.,Chem.Commun. 1976, 734. 10. M. Eitel, U. Pindur,Helv.(him.Acta, in press. 11. of Ia with Dimmtbyl 1,2,4,Hetrazhz-3,6-d.icarboxylatel Tgpical Proc&mw 2-Vinylin429 mg, 3 mmol) in dry dichloromethane (30 ml) was treatedportionwisewith the tetrazinc (594mg, 3 mmol) with stirringunder argon at -75 'C for 1 h and 20 'C for 4 h. The solvent was evaporatedand the residueseparatedby flash chromatography [silicagel, Merck 60, grain size 0.043-0.040mm, 1:l petroleumether (b.p. 4C+60 "C)/diethyl ether] t yield 3a. 12. SelectmdPhysical Data of the Products. Compound3a: mp. 152 'C.PH-NMR (400 MHs, (DMSO-dd): 63.68 (8, 3H, CCCCH3),3.76 (s, 3H, COGCH3),4.89(d, 3J - 5.9 Hz, lH, pyridazineH-4), 6.OU (8, lH, indoleH-3), 6.05 (dd, 3J - 5.9 Hz, 4J = 2.2 Hz, pyridkne H-5) 6.92 (t, 3J - 7.2 Hz and 7.6 Ha, lH, indoleH-6), 7.12(ty 3J = 7.3 ti< 1H. indoleH-5), 7.35(d,'3 J = 8.0 HsTlH, indoleH-7), 7.40 (d, 35 = 7.8 Hz, lH, indoleH-4), 10.78(d, 'J - 2.2 Hz,1 yridazine NH), 10.92 (8, la, Indole‘NH). compo;hd3b: m.p. 131 'C. k+MR (CDC13):6 -1.58 (dd, J = 6.5Hx, 4J = 1.6Ha, 3H, =CHCZll), 3.13 (8,3H, COOCH3),3.85 (8, 3H, NCH3), 3.96 (8, 3H, COOCH3),4.74(dd, 3r= 15.4Hz, 4J = 1.6 Hz, 18, e=CHCH ), 5.31 (m, 3J - 6.5 Hz and 15.4 Hz, lH, CH=CHCH3),6.69 (d, 3J = 8 Hs,iH, H-6), 6.80 (ddd,3;= 8 Hz, 4J 1.8 Hz, lH, H-8), 7.30 (ddd, 3J =: Hz, 4J = 1.2Hz: 18, 7-H), 8.34 (d, 3J = 8 HZ, lH, H-9) 9.74 (8, 18, NH).Product 5: m.p.235 'C (acetone).'H-NMR (CDC13):6 - 3.52 (Td, 25 = 17.4 Hz, 1J = 12.6 Hz, lH, CH2), 3.63 (dd, 2J - 17.4 Hz, 3J = 5 Hz, lH, CH2), 3.69 (8, 3H, G3 or NCH3),3.74 (8, 3H, 0CH3 or NCH3), 3.80 (s,3H, OCH3 or %l3), 3.91 (8, 38, OCH3 or NCH3), 4.15 (dd, 3L= 12.6Hz and 5 Hz, H-5), 7.11 (dt, 3J - 7.3 Hz, 4J - 1.1 He, lH, H-9), 7.20 (mc, 3H. H-7, H-8, H-10).Compound6: m.p. 145 OC. 'H-NMR&X3): 6 - z91 (8, 3H, H3CC at C-6), 3.30 (dd, 25 = 16 Hz, 3J = 1.5 Hz, lH, H-5), 3.50 (8, 3H, COOCH3),3.65 (dd, 2J = 16 Hz, 3J - 4.2 Hz, LH, H57, 3.71 (8, %, NCH3), 4.01 (8, 3H, COOCH3),5.73 (q, 3J = 1.5Hz and 4.2 Hz, li, H-6), 7.29 (mc, 3H, H-8, H-9, H-lo),8.16 (d, 3J = 8.9Ha, lH, H-11).l&MR (CDC13):6 = 29.67(NCH3),52.79and 53.24 (COO~H,),56.07 (OCH,),28.30 (C-5). 90.66 (C-6); sp2-CH: 109.45,120.31,121.07,122.19; quaternaryC: 102.14,124.04,132.06,137.94,145.55,166.94;193.03and 199.26(2 x CO).Compound 7: m.p.141 Y. lH-NMR (CD2Cl2,20 OC, mixtureof atropisomers): 6 - 1.06(dd,3J = 6.9Rz, 3H, CH3 at C-5),2.10and 2.24 2 x s, 3H, indole 3-(.X3), 3.51and 3.64 (2 x s, 3H, ind~e 1-0X3),3.60 (a, 3H, COOCH3), 3.69 (q, 4J - 6.9 Hz, lH, H-5), 3.84 (8, 3H, COOCH3),7.08 (2 x t, lH, indole H-6), 7.19 (2 x t, lH,$1dole%5), 7.28(m, lH, indoleH-7), 7.52 (m, lR, iudole lf-4), 8.8: (a, lH, NH). 13.MNDO calculations~" performedfor la do predicta UJMOdieneflDMOdie,_p~le-coutrolledo reaction
(Received
in Germany
4 May
1988)