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Dihydroisobenzofurans and isoindolines by intramolecular inverse Diels-Alder reactions of pyridines
co@-awo s3.00+.00
Tdr&&m VoL 46. No. 2, pp. 607414.19!90 RiIllOdillOrutBIihill
81990PC!Z@lllOORarplc
DIBYDBOISOBENZOFUBAlUB
ANDISOBUDO~BY
DIEISAT.DEItREACl’IOXWOFPYIUDlNES
IDmBAMoLBcuLABMarek Biednyckia
, Dick A. de Bie and Henk C. van der Plas*
Laboratory of Organic Chemistry, Agricultural University Wageningen, Dreijenplein 8,6703 HB Wageningen, The Netherlands (Received in UK 23 August 1989)
Pyridinee bein substituted at oeition 2 or 3 with a ailylated side-c Eain under o a t ermolytic intramolecular Dielspropynyloxymethyl K Alder reaction with formation of dl*Eydroisobenzofurans. The 3-subetituted p ‘dines are found to be more reactive than the 2-substituted ones. Substitution up at the a-position of this side-chain by oYboth hydrogena in the methylene stituent leads to a considerable increase of one methyl as well as one phenyl su%ro* the reaction rate. of 3-trimethylsilylIn a similar way, from the N-acet 1 derivative propynylaminomethyl yridine, the isoindo Pme system ia formed. The rate of the reaction is considerab Qy lower than that of the corresponding propynyloxymethyl derivative.
Abstract:
In our ongoing thermolytically
research
on ring transformations
induced intramolecular
Diels-Alder
of pyrimidines cycloaddition
and pyrazines
by a
reaction we extended this
study to reactions with appropriately substituted pyridine derivatives. We already found that by thermolysis of the 2-substituted
3(5)-nitropyridine
1 nitroindenes
3 are obtained’.
This result
strongly suggests the intermediacy of the cycloadduct 2, being obtained by cycloaddition of the triple bond across the Q-C5 position of the pyridine ring.
Two
3
2
1
questions can be raised: first, is the presence of the electron withdrawing nitro substituent in
the pyridine
ring,
which
lowers
the LUMO energy
level
and therefore
promotes
the
cycloaddition, necessary? and secondly is it possible that the cycloaddition over the Q-C5 position also takes place when the side-chain is present at C-5 and not, as in 1,on position 2. Indications a Research and Development
Department,
Tarchomin Pharmaceutical
607
Works, Fleminga Str. 2,03-176 Warsaw, Poland
M. BWRZYCK~er al.
608
that both
questions
conversion
can positively
of the pyridine
be answered
derivatives
can be taken
from the recently
4 and 6 into the s-indacene
derivative
reported2r3
5 and indolinone
7
respectively.
7
6
We have found
before4 that heating
group at the terminal decomposition,
instead of nitrobenzene
is considerably
of pyridines,
lower.
in which
trimethylsilylpropynyl-X-methyl reactivities
In this paper
on position
gives cleaner
is used as solvent, we deal with
2 or on position
(X=O,N) side chain is present.
of these respective
more substituents
which show the presence
atom of the triple bond usually
when undecane
rate in undecane thermolysis
carbon
of pyrazines,
6h
compounds
and studied
in the side chain on their thermolysis
of a trimethylsilyl reactions
although
the synthesis
and
3 of the pyridine
Furthermore
the influence
with less
the reaction ring
we compared
of the presence
the a the
of one or
rates.
8
a) X = H; b) X = si(c~3)~; C) x = si(m)#a~ Compounds
8a and 9a, being prepared
3-bromopropyne, However,
obtained
on heating
the corresponding
9a by lithiation on heating
gave
from 2- and 3-pyridylcarbinol only
trimethylsilyl
with phenyllithium
at 195’ in undecane
respectively
material
derivatives
8b and 9b, being synthesized
and subsequent
treatment
together
with trimethylsilyl
4trimethylsilyL1,3-dihydroisobenzofuran(lOb1.
from 9b after 154 hours of heating
amounted
with
by reaction with
polymeric
some
carbinol.
from 8a and chloride,
gave
The yield of lob
to 40%; the yield oflOb after 216 hrs of
Dihydroisobcnzofuransand isoindolines
609
heating of 8b was 27%. These results indicate that the internal cycloaddition over the C2-C5 position in 8b occurs less easily than that over the C3-Q position in 9b. The attack of the terminal triple bond carbon, trimethylsilyl
being negatively
charged due to the electron
group, on C5 in 8b apparently
donating
effect of the
occurs less easily than addition to the more
positively charged Q position in 9b. &placement of the trimethylsilyl group in 9b by the more bulky t-butyldiphenylsilyl group i.e. 9c leads to a considerable
increase of reaction time. Only after thermolysis
for 440 hrs (!) in
undecane the starting material 9c was disappeared; product 1Ocwas obtained in only 22% yield. Considerable steric hindrance seems to be the retarding factor in the reaction. In a previous paper4 we proved that the presence of a phenyl group in the a-position
of an w-
alkyne side chain attached to a pyrazine ring leads to a strong enhancement of the rate of the intramolecular Diels-Alder reaction. In order to establish whether this phenomenon could also be observed in pyridine systems we synthesized Treatment of 2(3)-pyridylphenylmethylcarbinol5s6
the 2- and 3-substituted
pyridines 11,12.
with 3-bromopropyne in basic medium gave
the compounds lla,12a.Silylation and germanylation according to described procedures gave llb and I2b,c respectively.
a) X=H, b) X=Si (CH&, c) x-Ge(a-& From the results given in Table 1 it can be seen that the compounds llb,12band 12ccaneasily be converted into the corresponding
dihydroisobenzofurans
13b,c in reasonable-to-good
Moreover it can be concluded that the rate of the intramolecular D&-Alder
yields.
reaction in llb and
12b,c is considerably higher than in case of the compounds 8b and 9b. This rate increase due to the presence of the methyl and phenyl group in the a-position
of the side-chain is considerable
as can be deduced from the fact that the difference in rate, as observedbetweenthe compound 8b and 9b, is nearly equalized between llband 12b.Similar effects have been observed before’flt9 in related systems and can be ascribed to either the Thorpe-Ingold effect10 and/or a more favoured orientation of the alkynyl side-chain towards the pyridine ring, making overlap between the HOMO and LUMO orbitals more effective. In extension of this study we also investigated aminomethylpyridine
14~.
the trimethylsilyl
This compound was prepared
alkynylation with 3-bromopropyne
3-(N-acetyl-N-2-propynyll
from 3-aminomethylpyridine
by
and subsequent treatment of the secondary amino group
M. Btttntuvm et al.
610
with acetyl chloride. The trimethylsilyl derivative was obtained according to known procedures. Thermolysis of 14c bee table 1) gave the isoindoline 15 in low yield. The rate of the reaction is lower than that of the corresponding oxygen compound 9b.
._ 14 a) Y=H, X-H b) Y-CCXXJ,
X-H
cl y-cocH3, xIS(cH&
Table 1. Reaction conditions, products and ‘elds in the Diels-Alder cyclisations of silylated (germanylated) ropynyloxymethy lyr pyridines and propynylaminomethylpyridme in undecane as a soPvent. Starting material
t: 119: l2b lZC
14c
Reaction time (hrs) at 195OC 216 z z 3z
Yield of product % ;:::z 10 c (22) 13 b (60) :z !?z; 15 (19)
EXPERIMENTAL SECHON
Chemie (Brussels, Belgium).
recorded on a Varian EM 390 pm.). Mass spectral data were obtained console. Column chromatograph gg 00 mesh ASTM). Undecane was purchased from A!*
2-(2-nrouvnvloxvmethvl)Dvridine (8a) and 3-(2-nropvnvloxymethvl)pvridine (9& in 150 ml of dry tetrahydrofuran were
M. BIEDRZYCKIet al.
614
ACKNOWLEDGEMENTS The authors
are indebted
microanalyses
to Mr. G. Geurtsen
and for mass spectroscopic
Mr. A. van Veldhuizen
for discussion
and advice, Mr. H. Jongejan
data, Mr. C.J. Teunis for mass spectroscopic
for the data and
for his advice on *H NMR spectra. REFERENCES
1.
A.E. Frissen, A.T.M. Marcelis, G. Geurtsen,
D.A. de Bie, H.C. van der Plas. Reel. Trav. Chim.,
1987.106,547.
H.C. van der Plas. Tetrahedron, 1988,44,2977.
2.
D.A. de Bie, A. Ostrowicz,
3.
L.S. Trifonov,
A.S. Orahovats.
4.
M. Biedrzycki,
D.A. de Bie, H.C. van der Plas. Tetrahedron , in press.
G. Geurtsen,
Helv. Chim. Acta, 1987,70,
1732.
A. Bieniek. 1. Ckem. Sue. Perkin I, 1985, 213.
5.
J. Epsztain,
6.
G.A. Olah, M. Calin. 1. Amer. Ckem. Sot., 1968,90,
7.
M.E. Jung, J. Gervay. Tetrahedron
8.
E.C. Taylor, J.E. Macor. Tetrahedron Lett., 1986,27,
9.
E.C. Taylor, J.L. Pont. J. Org. Ckem. 1987,52,4287.
Lett, 1988,29
943.
, 2429. 2107.
10. R.M. Beesley, C.K. Ingold, J.F. Thorpe. 1. Ckem. Sot., 1915,107,
1080.
Tdr&&m VoL 46. No. 2, pp. 607414.19!90 RiIllOdillOrutBIihill
81990PC!Z@lllOORarplc
DIBYDBOISOBENZOFUBAlUB
ANDISOBUDO~BY
DIEISAT.DEItREACl’IOXWOFPYIUDlNES
IDmBAMoLBcuLABMarek Biednyckia
, Dick A. de Bie and Henk C. van der Plas*
Laboratory of Organic Chemistry, Agricultural University Wageningen, Dreijenplein 8,6703 HB Wageningen, The Netherlands (Received in UK 23 August 1989)
Pyridinee bein substituted at oeition 2 or 3 with a ailylated side-c Eain under o a t ermolytic intramolecular Dielspropynyloxymethyl K Alder reaction with formation of dl*Eydroisobenzofurans. The 3-subetituted p ‘dines are found to be more reactive than the 2-substituted ones. Substitution up at the a-position of this side-chain by oYboth hydrogena in the methylene stituent leads to a considerable increase of one methyl as well as one phenyl su%ro* the reaction rate. of 3-trimethylsilylIn a similar way, from the N-acet 1 derivative propynylaminomethyl yridine, the isoindo Pme system ia formed. The rate of the reaction is considerab Qy lower than that of the corresponding propynyloxymethyl derivative.
Abstract:
In our ongoing thermolytically
research
on ring transformations
induced intramolecular
Diels-Alder
of pyrimidines cycloaddition
and pyrazines
by a
reaction we extended this
study to reactions with appropriately substituted pyridine derivatives. We already found that by thermolysis of the 2-substituted
3(5)-nitropyridine
1 nitroindenes
3 are obtained’.
This result
strongly suggests the intermediacy of the cycloadduct 2, being obtained by cycloaddition of the triple bond across the Q-C5 position of the pyridine ring.
Two
3
2
1
questions can be raised: first, is the presence of the electron withdrawing nitro substituent in
the pyridine
ring,
which
lowers
the LUMO energy
level
and therefore
promotes
the
cycloaddition, necessary? and secondly is it possible that the cycloaddition over the Q-C5 position also takes place when the side-chain is present at C-5 and not, as in 1,on position 2. Indications a Research and Development
Department,
Tarchomin Pharmaceutical
607
Works, Fleminga Str. 2,03-176 Warsaw, Poland
M. BWRZYCK~er al.
608
that both
questions
conversion
can positively
of the pyridine
be answered
derivatives
can be taken
from the recently
4 and 6 into the s-indacene
derivative
reported2r3
5 and indolinone
7
respectively.
7
6
We have found
before4 that heating
group at the terminal decomposition,
instead of nitrobenzene
is considerably
of pyridines,
lower.
in which
trimethylsilylpropynyl-X-methyl reactivities
In this paper
on position
gives cleaner
is used as solvent, we deal with
2 or on position
(X=O,N) side chain is present.
of these respective
more substituents
which show the presence
atom of the triple bond usually
when undecane
rate in undecane thermolysis
carbon
of pyrazines,
6h
compounds
and studied
in the side chain on their thermolysis
of a trimethylsilyl reactions
although
the synthesis
and
3 of the pyridine
Furthermore
the influence
with less
the reaction ring
we compared
of the presence
the a the
of one or
rates.
8
a) X = H; b) X = si(c~3)~; C) x = si(m)#a~ Compounds
8a and 9a, being prepared
3-bromopropyne, However,
obtained
on heating
the corresponding
9a by lithiation on heating
gave
from 2- and 3-pyridylcarbinol only
trimethylsilyl
with phenyllithium
at 195’ in undecane
respectively
material
derivatives
8b and 9b, being synthesized
and subsequent
treatment
together
with trimethylsilyl
4trimethylsilyL1,3-dihydroisobenzofuran(lOb1.
from 9b after 154 hours of heating
amounted
with
by reaction with
polymeric
some
carbinol.
from 8a and chloride,
gave
The yield of lob
to 40%; the yield oflOb after 216 hrs of
Dihydroisobcnzofuransand isoindolines
609
heating of 8b was 27%. These results indicate that the internal cycloaddition over the C2-C5 position in 8b occurs less easily than that over the C3-Q position in 9b. The attack of the terminal triple bond carbon, trimethylsilyl
being negatively
charged due to the electron
group, on C5 in 8b apparently
donating
effect of the
occurs less easily than addition to the more
positively charged Q position in 9b. &placement of the trimethylsilyl group in 9b by the more bulky t-butyldiphenylsilyl group i.e. 9c leads to a considerable
increase of reaction time. Only after thermolysis
for 440 hrs (!) in
undecane the starting material 9c was disappeared; product 1Ocwas obtained in only 22% yield. Considerable steric hindrance seems to be the retarding factor in the reaction. In a previous paper4 we proved that the presence of a phenyl group in the a-position
of an w-
alkyne side chain attached to a pyrazine ring leads to a strong enhancement of the rate of the intramolecular Diels-Alder reaction. In order to establish whether this phenomenon could also be observed in pyridine systems we synthesized Treatment of 2(3)-pyridylphenylmethylcarbinol5s6
the 2- and 3-substituted
pyridines 11,12.
with 3-bromopropyne in basic medium gave
the compounds lla,12a.Silylation and germanylation according to described procedures gave llb and I2b,c respectively.
a) X=H, b) X=Si (CH&, c) x-Ge(a-& From the results given in Table 1 it can be seen that the compounds llb,12band 12ccaneasily be converted into the corresponding
dihydroisobenzofurans
13b,c in reasonable-to-good
Moreover it can be concluded that the rate of the intramolecular D&-Alder
yields.
reaction in llb and
12b,c is considerably higher than in case of the compounds 8b and 9b. This rate increase due to the presence of the methyl and phenyl group in the a-position
of the side-chain is considerable
as can be deduced from the fact that the difference in rate, as observedbetweenthe compound 8b and 9b, is nearly equalized between llband 12b.Similar effects have been observed before’flt9 in related systems and can be ascribed to either the Thorpe-Ingold effect10 and/or a more favoured orientation of the alkynyl side-chain towards the pyridine ring, making overlap between the HOMO and LUMO orbitals more effective. In extension of this study we also investigated aminomethylpyridine
14~.
the trimethylsilyl
This compound was prepared
alkynylation with 3-bromopropyne
3-(N-acetyl-N-2-propynyll
from 3-aminomethylpyridine
by
and subsequent treatment of the secondary amino group
M. Btttntuvm et al.
610
with acetyl chloride. The trimethylsilyl derivative was obtained according to known procedures. Thermolysis of 14c bee table 1) gave the isoindoline 15 in low yield. The rate of the reaction is lower than that of the corresponding oxygen compound 9b.
._ 14 a) Y=H, X-H b) Y-CCXXJ,
X-H
cl y-cocH3, xIS(cH&
Table 1. Reaction conditions, products and ‘elds in the Diels-Alder cyclisations of silylated (germanylated) ropynyloxymethy lyr pyridines and propynylaminomethylpyridme in undecane as a soPvent. Starting material
t: 119: l2b lZC
14c
Reaction time (hrs) at 195OC 216 z z 3z
Yield of product % ;:::z 10 c (22) 13 b (60) :z !?z; 15 (19)
EXPERIMENTAL SECHON
Chemie (Brussels, Belgium).
recorded on a Varian EM 390 pm.). Mass spectral data were obtained console. Column chromatograph gg 00 mesh ASTM). Undecane was purchased from A!*
2-(2-nrouvnvloxvmethvl)Dvridine (8a) and 3-(2-nropvnvloxymethvl)pvridine (9& in 150 ml of dry tetrahydrofuran were
M. BIEDRZYCKIet al.
614
ACKNOWLEDGEMENTS The authors
are indebted
microanalyses
to Mr. G. Geurtsen
and for mass spectroscopic
Mr. A. van Veldhuizen
for discussion
and advice, Mr. H. Jongejan
data, Mr. C.J. Teunis for mass spectroscopic
for the data and
for his advice on *H NMR spectra. REFERENCES
1.
A.E. Frissen, A.T.M. Marcelis, G. Geurtsen,
D.A. de Bie, H.C. van der Plas. Reel. Trav. Chim.,
1987.106,547.
H.C. van der Plas. Tetrahedron, 1988,44,2977.
2.
D.A. de Bie, A. Ostrowicz,
3.
L.S. Trifonov,
A.S. Orahovats.
4.
M. Biedrzycki,
D.A. de Bie, H.C. van der Plas. Tetrahedron , in press.
G. Geurtsen,
Helv. Chim. Acta, 1987,70,
1732.
A. Bieniek. 1. Ckem. Sue. Perkin I, 1985, 213.
5.
J. Epsztain,
6.
G.A. Olah, M. Calin. 1. Amer. Ckem. Sot., 1968,90,
7.
M.E. Jung, J. Gervay. Tetrahedron
8.
E.C. Taylor, J.E. Macor. Tetrahedron Lett., 1986,27,
9.
E.C. Taylor, J.L. Pont. J. Org. Ckem. 1987,52,4287.
Lett, 1988,29
943.
, 2429. 2107.
10. R.M. Beesley, C.K. Ingold, J.F. Thorpe. 1. Ckem. Sot., 1915,107,
1080.