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Novel syntheses of the methoxy isoquinolines and isocoumarins
Tetrahedron
Letters
NOVEL
No.39, pp. 4159-4162, 1968.
Pergamon Press.
Printed in Great Britain.
SYNTHESES OF T9B NETHOXY ISOQlJINOLINZSAKD ISOCOLJKARINS N.S.Narasimhan
Department
and B.H.Bhide
of Chemistry, University
of Poona, Foona-7,Indi.a
(Receivedin UK 19 June 1968; acceptedfor publication1
July
1968)
A recent publication by Hauaer and coworkers (1) on the lithiation of a
few ring substituted N-N dimethyl benzyl amines prompts us We
publish our own results in this field.
to
have been studying (2) the
lithiation of the parent compound and its methoxy derivatives, to obtain the corresponding isoquinolines. Our resulte briefly are
as
followa. Ortho, meta and para methoxy N-N-dimethyl benzylamines wers lithiated with n-butyl lithium in ether. In the first instance, tofix up the position of lithiation, the metelation mixture was treated w'ith benzophenone. In the case of the ortho compound, the reaction took complex course and no useful result was obtained. However in the
a
case
of the meta and pars compounds the corresponding benzhydrols C25H2502N*,I- m.p. 106@ (lit. m.p. 1O4-1O4.5o(1)) and II - m.p. 130° (lit. m.p. 129-129.5o(1)) were obtained in good yields, indicating that lithintion occured ortho to the aimethyl amino methyl side chain.
In
order to obtain the isoquinolines then, the metalation mixture, in the above cases, was treated with ethylene oxide. Further work up,accoraing to the procedure of Naresimhan and Ranade (2) then furnished
*
the
The compounds reported in this communication have sntisfnctory
elemental analysis and spectral (I.R.
and K.K.R.)
4159
data.
4160
No.39
N-N dimethyl tetrahydro isoquinolinium iodides C12H180NI, III m.p. 234-235O (lit. m.p. 229' (3a) and 239' (3b)) and IV - m.p. MO0 (lit. m.p. 174O (4)).
I II
R=OhIe, RPH
R'=H R' I OMe
III R = Ch'Ie,R' = H IV R = H,
RI = OKe
It may be mentioned that the former (III) ie indeed not readily available by the acid catalysed methods. In a related work i.e. syntheses of methoxy isocoumarins,.we have also studied the lithiation of ortho, meta and para methoxy X-methyl benzamides. Hauser and coworkers (5) have observed that in lithiation of N-methyl benzamide, metnlation proceeded positicn.
the
at the ortho
In our com;ounde there were LL\J~Lroups, mcthoxy and amide,
vrhichwere both capnblc of controlling the position cf lithiation. In the first instance, to fix up the position of lithiation, the metalation mixture wae treated with benzoghcnonc. In the caee of the meta and para methoxy comy;ounds,the lactonee C21111603,V - m.p. 22%O formed through the and VI - m.p. 1540 (vIhichwere obviol?.zl;; corrcssondin: bcnzhydrola) were ob+:ainedconsistently in ;;ocdyields. In th? case of i;hcortho methoxy compound, couplicaticns were encountered, althos,h the lactone " J21ii16C3,VII - m.p. 171° in compnrn-tivel:; ~001 yield. obtained, in ’ a few erpcriii!cnts, ” A-
v:af 'Ihe
4161
No.39
results however clearly indicated that in the meta and para methoxy N-methyl benzamides, the metalation was occurring predominantly at the ortho position with respect to the amide group.
In order
to
get the methoxy isocoumarins then, the corresponding metalation mixture, from the lithiation of meta and pare methoxy compounds, was treated with ethylene oxide. Working up the reaction mixture, 5-
methoxy dihydro isocoumarin C10H1003, m.p. 82O, and 6-methoxy
dihydro isocoumarin CIOHIOOJ, m.p. 68O (lit. m.p. 68O (6)), were obtained in good yields.
Bromination with N-bromc-succinimide,
followed by dehydrohelogenation with triethylamine furnished methoxy isocoumarins C10H803, VIII - m.p. 107-108°
the
and
IX - m.p. 95-96O (lit. m.p. 98O (6). 0
/ -0s 0
0
R'
R
VR=OMe,R' VI R*= OMe, R VII RI% OYe, R
ER~'sH w R" = H
VIII
R P OMe,R' P H
IX
R'= OMe, R = H
I RI = H
Again it may be noted that 5 - methoxy isocoumarin (VIII) is not available by the usual procedures and has indeed been obtained for the first time. ACKNOWLEDGEMENT: We are grateful to Prof. H.J.Arnikar for
his
interest in this work, and to C.S.I.R., New Delhi, for a fellowship to B.H.B.
We also thank Mesrs Dai Ichi Karkaria Priv. Ltd. Poona,
for a gift of ethylene oxide.
4162
No.39
REPRRENCES
(1) K.P.Klein and C.R.Hauser, J.OrR. Chem., 2, 1479 (1967) (2) N..S.Waraeimhanand A.C.Hanade, Chemistry and Induetrx, 120 (1967) see also the foot-note. (3s)Simone Durand, Xavier Lueinchi and Robert C. Xoreau., 3111.
sot..
chim. France,
270 (1961)
(3b)Simone Durand, Xavier Lusinchi and R:Delaby, Comet. Rend., 248,
426 (1959)
(4) Robert E. Davie-, R.D.Haworthy, Brymmor Jones and Alex fI.Lacberton, J.Chem. Sot., 191 (1947) (5) Walter Ii.Puterbaugh and C.R.Haueer, J.Orp. Chem., a, (6) Dnyanandr 1;ukhopdhgay and D.K.Chaudhary, J. Indian Chem.Soc., s -
433 (1963)
853 (1964)
Letters
NOVEL
No.39, pp. 4159-4162, 1968.
Pergamon Press.
Printed in Great Britain.
SYNTHESES OF T9B NETHOXY ISOQlJINOLINZSAKD ISOCOLJKARINS N.S.Narasimhan
Department
and B.H.Bhide
of Chemistry, University
of Poona, Foona-7,Indi.a
(Receivedin UK 19 June 1968; acceptedfor publication1
July
1968)
A recent publication by Hauaer and coworkers (1) on the lithiation of a
few ring substituted N-N dimethyl benzyl amines prompts us We
publish our own results in this field.
to
have been studying (2) the
lithiation of the parent compound and its methoxy derivatives, to obtain the corresponding isoquinolines. Our resulte briefly are
as
followa. Ortho, meta and para methoxy N-N-dimethyl benzylamines wers lithiated with n-butyl lithium in ether. In the first instance, tofix up the position of lithiation, the metelation mixture was treated w'ith benzophenone. In the case of the ortho compound, the reaction took complex course and no useful result was obtained. However in the
a
case
of the meta and pars compounds the corresponding benzhydrols C25H2502N*,I- m.p. 106@ (lit. m.p. 1O4-1O4.5o(1)) and II - m.p. 130° (lit. m.p. 129-129.5o(1)) were obtained in good yields, indicating that lithintion occured ortho to the aimethyl amino methyl side chain.
In
order to obtain the isoquinolines then, the metalation mixture, in the above cases, was treated with ethylene oxide. Further work up,accoraing to the procedure of Naresimhan and Ranade (2) then furnished
*
the
The compounds reported in this communication have sntisfnctory
elemental analysis and spectral (I.R.
and K.K.R.)
4159
data.
4160
No.39
N-N dimethyl tetrahydro isoquinolinium iodides C12H180NI, III m.p. 234-235O (lit. m.p. 229' (3a) and 239' (3b)) and IV - m.p. MO0 (lit. m.p. 174O (4)).
I II
R=OhIe, RPH
R'=H R' I OMe
III R = Ch'Ie,R' = H IV R = H,
RI = OKe
It may be mentioned that the former (III) ie indeed not readily available by the acid catalysed methods. In a related work i.e. syntheses of methoxy isocoumarins,.we have also studied the lithiation of ortho, meta and para methoxy X-methyl benzamides. Hauser and coworkers (5) have observed that in lithiation of N-methyl benzamide, metnlation proceeded positicn.
the
at the ortho
In our com;ounde there were LL\J~Lroups, mcthoxy and amide,
vrhichwere both capnblc of controlling the position cf lithiation. In the first instance, to fix up the position of lithiation, the metalation mixture wae treated with benzoghcnonc. In the caee of the meta and para methoxy comy;ounds,the lactonee C21111603,V - m.p. 22%O formed through the and VI - m.p. 1540 (vIhichwere obviol?.zl;; corrcssondin: bcnzhydrola) were ob+:ainedconsistently in ;;ocdyields. In th? case of i;hcortho methoxy compound, couplicaticns were encountered, althos,h the lactone " J21ii16C3,VII - m.p. 171° in compnrn-tivel:; ~001 yield. obtained, in ’ a few erpcriii!cnts, ” A-
v:af 'Ihe
4161
No.39
results however clearly indicated that in the meta and para methoxy N-methyl benzamides, the metalation was occurring predominantly at the ortho position with respect to the amide group.
In order
to
get the methoxy isocoumarins then, the corresponding metalation mixture, from the lithiation of meta and pare methoxy compounds, was treated with ethylene oxide. Working up the reaction mixture, 5-
methoxy dihydro isocoumarin C10H1003, m.p. 82O, and 6-methoxy
dihydro isocoumarin CIOHIOOJ, m.p. 68O (lit. m.p. 68O (6)), were obtained in good yields.
Bromination with N-bromc-succinimide,
followed by dehydrohelogenation with triethylamine furnished methoxy isocoumarins C10H803, VIII - m.p. 107-108°
the
and
IX - m.p. 95-96O (lit. m.p. 98O (6). 0
/ -0s 0
0
R'
R
VR=OMe,R' VI R*= OMe, R VII RI% OYe, R
ER~'sH w R" = H
VIII
R P OMe,R' P H
IX
R'= OMe, R = H
I RI = H
Again it may be noted that 5 - methoxy isocoumarin (VIII) is not available by the usual procedures and has indeed been obtained for the first time. ACKNOWLEDGEMENT: We are grateful to Prof. H.J.Arnikar for
his
interest in this work, and to C.S.I.R., New Delhi, for a fellowship to B.H.B.
We also thank Mesrs Dai Ichi Karkaria Priv. Ltd. Poona,
for a gift of ethylene oxide.
4162
No.39
REPRRENCES
(1) K.P.Klein and C.R.Hauser, J.OrR. Chem., 2, 1479 (1967) (2) N..S.Waraeimhanand A.C.Hanade, Chemistry and Induetrx, 120 (1967) see also the foot-note. (3s)Simone Durand, Xavier Lueinchi and Robert C. Xoreau., 3111.
sot..
chim. France,
270 (1961)
(3b)Simone Durand, Xavier Lusinchi and R:Delaby, Comet. Rend., 248,
426 (1959)
(4) Robert E. Davie-, R.D.Haworthy, Brymmor Jones and Alex fI.Lacberton, J.Chem. Sot., 191 (1947) (5) Walter Ii.Puterbaugh and C.R.Haueer, J.Orp. Chem., a, (6) Dnyanandr 1;ukhopdhgay and D.K.Chaudhary, J. Indian Chem.Soc., s -
433 (1963)
853 (1964)