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Retro Diels-Alder reactions of heterocyclic compounds under mild conditions
TetrahedronLetters No. 25, pp 2163 - 2166,1974. PergamonPreS8.
FWT’RO
printed
in
Great Britdn.
DIFXS-ALIERREACTIONSOF KETERCCYCLIC CMPOUNDS UNIER MILD CONDITIONS
D.N. Reinhoudt and Mrs. C.G. Kouwenhoven KONINKLIJKE/SHELL-LABOKAT0RIDM,AMSTKFlDAM (ShellResearch_B.V.)
(Reoeived in UK 17 April 1974; aooeptedfor ptblicatfonS HEY 1974)
The retro Diels-Alderreaction 0r-[~2s+,,2,+,2,] cycloreversion has been used in carbocompoundsl.In cyclic chemistryPorthe synthesisof numerous, otherwisediPPlcultlyaccesslble, general, this reaction is unsuitablefor the preparationof heterocycliccompoundssince very often rather high temperaturesare required,at which most heterocyclesdecompose2.'Iheonly exceptionreported is the eliminationof nitrogen from the adducts of 1,4-disubstitutedtrlor tetrazlneswith ynamines7.We attributethe fast ellmlnationfrom these adducts to the fact that both the diene and the dienophiliccomponentare stabilizedby resonanceIn the transitionstate. We have now investigatedwhether this type of reactioncan be more generallyapplied to the synthesisof heterocycliccompounds.As startingmaterialswe used 'I-oxa-and 7-azabicyclo[2.2.1] hepta-2,5-dienes(J_a,b), which were preparedby Diels-Alderreactionsof furan and N-ethoxycarbonylpyrrole, respectively,with dimethylacetylenedicarboxylate8. Reaction of J,awith one equivalentof 2,4,6-trimethylbenzonltrile oxide In various solvents at 20 "C gave, instead of the expected 1,3-dlpolaradduct @ or J), a mixture of four products. Two of these were identifiedas the furans $aand $,a, and the others as 3-(2',4',6'-trimethylphenyl)isoxazole(5) and 4,5-bis(methoxycarborUT1)-3-(2',4',6'-trimethylphenyl)isoxazole (I). N-ethoxycarbonylpyrrole (Lb)reacted with 2,4,6-trimethylbenzonitrile oxide under the same conditionsto yield two N-ethoxycarborylpyrroles (4_band6-b) togetherwith 5 and z. Other 1,3-dipolarreagentssuch as diphenylnitrllimine and phenylazidereacted similarlyalthough In some cases only two differentproductswere formed; the results of these reactionsare summarizedin the Table. We explain these results in terms of a two-stepprocess,namely, 1,3-dipolaradditionat one of the two double bonds to give &
&
which subsequentlyundergo a fast retro Diels-Alder
reaction.An alternativepathway to the observedproductsmight have been a retro Diels-Alder reaction of l_to yield either & and acetyleneor fiand dimethylacetylenedicarboxylate, followed by 1,3-dipolaraddition to the acetylenes,yielding e.g. 5 and z. Conclusiveevidenceagainst this pathwaywas providedby the followingobservations: (i) In a separateexperimentacetylene,in contrastto dimethylacetylenedicarbomlate,did not react with the 1,3-dipolarreagents at 20 OC. This eliminatesthe possibilitythat sand 2 are 2163
No. 25
2164
R
R
H
H
I H
+
\ X
ti
H
OIN/ i?,
R
Ar
R
6
(a) x=0 (b)
X = NCOOClH8
R = COOCH, Ar=2,4,6-TRIhlETHYLPHENYL SCHEME
-
TABLE
a
1,3-Dipolara reagent
Substrate
Ratio A/Hb (See scheme)
Products (yields)C
La
~,~,~-(cH~)~c~H~cNo
1.17
fta, 2 (54 Z)
Lb
ditta
1.20
kb, 2 (55 $)
I?
C6H5C=N-N-C6H5
0
tia,E(lOOd)
Lb
ditto
0
&b,i! (100%)
c@5N3 ditto
0
La Lb
8
0.51
6-a, z (46 %) 6_ba X'(45 %)
!i,a,g (100%) ftb, l,o(36 $) ab, 2 (64 $)
a. Molar ratio substrate/l,3-dipolar reagent=1/1.05.
b. The conversion
of substra'cewasquantltative (TIC)after16hat25"Cindiethylether.
C. Yields were determinedby PMH spectroscopy(CDC13). formed by a retro Diels-Alderreactionof J.. (ii) Reaction of La,b with one equivalentof N-methyl-p-chlorophenylnitrone gave 1:l cycloadducts 1J in quantitativeyieldsq,although in a competitiveexperimentthe nitrone was
Rb. 25
2165
I
N!,
NQ+C,H,,
9
-CA
10
9
found to react much faster with dimethylacetylenedicarboxylate than with La, b. Therefore we are tempted to concludethat compoundslaandb,at
20 OC, are not In equilibrium
with their Diels-Aldercomponentsand this leaves the formationof the reaction products via reverse Diels-Alderreaction of 2 and 2 as the only pathway.
X = O,NCOOC,H, R = COOCH,
The reason why 2 and 2 (or the adducts with the other l,+dipolar reagentsgiver!in the Table) undergo retro Diels-Aldercleavageunder such mild conditionsmight be due to the stabilizationof the transitionstate (e.g. 13)"'12. ThiSShOeXpblnS
the
relativelyhighther-
ma1 stabilityof the nitrone adduct (1_1), which eliminatesfuran only upon heating at 150 "C.
REFERENCESAND FOOTNOTES 1. For reviews on the retro Diels-Alderreaction,see e.g., H. Kwart and K. King, Chem. Rev., Georg 'Ihieme Verlag, Stuttgart 68, 415 (1968),and H. Wollweber,"Diels-Alder-Fteaktion", = 1972, p.152. 2. Recently,however, vapour-phaseflash pyrolysis 3 (400-500"C) has been applied to prevent this decomposition,e.g. in the synthesesof isobensofuran4,isoindole5and benzazete6via retro Diels-Alderreactions. 3. H.J. Hageman and U.E. Wiersum, Chem. In Britain, 2, 206 (1973). 4. R.N. Warrener,J. Am. Chem. Sot., s, -
236
(1971):
2166
Ao. 25
1972, 5. J. Bornstein,D.E. Remy and J.E. Shields,J.C.S. Chem. COIIXU., 6. B.M. Adger, M. Keating, C.W. Rees and R.C. Storr, J.C.S. Chem.G.,
1149.
m,
19.
1970, 3357. 7. A. Steigel and J. Sauer,TetrahedronLetters, 8. R.C. Bansal, A.W. McCullochand A.G. McInnes, Can. J. Chem. 2,
2391 (1969).
9. Compounds J.lconsistedof mixtures of two isomers (endo and exo) which were separatedby chromatography;all novel compoundsafforded satisfactoryanalyticaland spectroscopical data. 10.
In contrastto the fast Diels-Alderreactionof 2 and 2 Huisgen and Christl"found that the 1,3-dipolaradducts of nitrlle oxides or diphenylnitrilimine with cyclopentadiene decomposedonly upon heating at 140-160 'C.
11.
R. Huisgen and M. Christl,Angew. Chem. Intern.Ed. Engl. 5, 456 (1967).
12. It is well known that acetylenedoes not enter into cycloadditionreactionswith 1,3-dlpolarreagentsunder mild conditions.However, using L as "activated"acetylene, in some cases 1,3-dipolaradducts of acetylenecan be obtained (e.g.2 and 12).
FWT’RO
printed
in
Great Britdn.
DIFXS-ALIERREACTIONSOF KETERCCYCLIC CMPOUNDS UNIER MILD CONDITIONS
D.N. Reinhoudt and Mrs. C.G. Kouwenhoven KONINKLIJKE/SHELL-LABOKAT0RIDM,AMSTKFlDAM (ShellResearch_B.V.)
(Reoeived in UK 17 April 1974; aooeptedfor ptblicatfonS HEY 1974)
The retro Diels-Alderreaction 0r-[~2s+,,2,+,2,] cycloreversion has been used in carbocompoundsl.In cyclic chemistryPorthe synthesisof numerous, otherwisediPPlcultlyaccesslble, general, this reaction is unsuitablefor the preparationof heterocycliccompoundssince very often rather high temperaturesare required,at which most heterocyclesdecompose2.'Iheonly exceptionreported is the eliminationof nitrogen from the adducts of 1,4-disubstitutedtrlor tetrazlneswith ynamines7.We attributethe fast ellmlnationfrom these adducts to the fact that both the diene and the dienophiliccomponentare stabilizedby resonanceIn the transitionstate. We have now investigatedwhether this type of reactioncan be more generallyapplied to the synthesisof heterocycliccompounds.As startingmaterialswe used 'I-oxa-and 7-azabicyclo[2.2.1] hepta-2,5-dienes(J_a,b), which were preparedby Diels-Alderreactionsof furan and N-ethoxycarbonylpyrrole, respectively,with dimethylacetylenedicarboxylate8. Reaction of J,awith one equivalentof 2,4,6-trimethylbenzonltrile oxide In various solvents at 20 "C gave, instead of the expected 1,3-dlpolaradduct @ or J), a mixture of four products. Two of these were identifiedas the furans $aand $,a, and the others as 3-(2',4',6'-trimethylphenyl)isoxazole(5) and 4,5-bis(methoxycarborUT1)-3-(2',4',6'-trimethylphenyl)isoxazole (I). N-ethoxycarbonylpyrrole (Lb)reacted with 2,4,6-trimethylbenzonitrile oxide under the same conditionsto yield two N-ethoxycarborylpyrroles (4_band6-b) togetherwith 5 and z. Other 1,3-dipolarreagentssuch as diphenylnitrllimine and phenylazidereacted similarlyalthough In some cases only two differentproductswere formed; the results of these reactionsare summarizedin the Table. We explain these results in terms of a two-stepprocess,namely, 1,3-dipolaradditionat one of the two double bonds to give &
&
which subsequentlyundergo a fast retro Diels-Alder
reaction.An alternativepathway to the observedproductsmight have been a retro Diels-Alder reaction of l_to yield either & and acetyleneor fiand dimethylacetylenedicarboxylate, followed by 1,3-dipolaraddition to the acetylenes,yielding e.g. 5 and z. Conclusiveevidenceagainst this pathwaywas providedby the followingobservations: (i) In a separateexperimentacetylene,in contrastto dimethylacetylenedicarbomlate,did not react with the 1,3-dipolarreagents at 20 OC. This eliminatesthe possibilitythat sand 2 are 2163
No. 25
2164
R
R
H
H
I H
+
\ X
ti
H
OIN/ i?,
R
Ar
R
6
(a) x=0 (b)
X = NCOOClH8
R = COOCH, Ar=2,4,6-TRIhlETHYLPHENYL SCHEME
-
TABLE
a
1,3-Dipolara reagent
Substrate
Ratio A/Hb (See scheme)
Products (yields)C
La
~,~,~-(cH~)~c~H~cNo
1.17
fta, 2 (54 Z)
Lb
ditta
1.20
kb, 2 (55 $)
I?
C6H5C=N-N-C6H5
0
tia,E(lOOd)
Lb
ditto
0
&b,i! (100%)
c@5N3 ditto
0
La Lb
8
0.51
6-a, z (46 %) 6_ba X'(45 %)
!i,a,g (100%) ftb, l,o(36 $) ab, 2 (64 $)
a. Molar ratio substrate/l,3-dipolar reagent=1/1.05.
b. The conversion
of substra'cewasquantltative (TIC)after16hat25"Cindiethylether.
C. Yields were determinedby PMH spectroscopy(CDC13). formed by a retro Diels-Alderreactionof J.. (ii) Reaction of La,b with one equivalentof N-methyl-p-chlorophenylnitrone gave 1:l cycloadducts 1J in quantitativeyieldsq,although in a competitiveexperimentthe nitrone was
Rb. 25
2165
I
N!,
NQ+C,H,,
9
-CA
10
9
found to react much faster with dimethylacetylenedicarboxylate than with La, b. Therefore we are tempted to concludethat compoundslaandb,at
20 OC, are not In equilibrium
with their Diels-Aldercomponentsand this leaves the formationof the reaction products via reverse Diels-Alderreaction of 2 and 2 as the only pathway.
X = O,NCOOC,H, R = COOCH,
The reason why 2 and 2 (or the adducts with the other l,+dipolar reagentsgiver!in the Table) undergo retro Diels-Aldercleavageunder such mild conditionsmight be due to the stabilizationof the transitionstate (e.g. 13)"'12. ThiSShOeXpblnS
the
relativelyhighther-
ma1 stabilityof the nitrone adduct (1_1), which eliminatesfuran only upon heating at 150 "C.
REFERENCESAND FOOTNOTES 1. For reviews on the retro Diels-Alderreaction,see e.g., H. Kwart and K. King, Chem. Rev., Georg 'Ihieme Verlag, Stuttgart 68, 415 (1968),and H. Wollweber,"Diels-Alder-Fteaktion", = 1972, p.152. 2. Recently,however, vapour-phaseflash pyrolysis 3 (400-500"C) has been applied to prevent this decomposition,e.g. in the synthesesof isobensofuran4,isoindole5and benzazete6via retro Diels-Alderreactions. 3. H.J. Hageman and U.E. Wiersum, Chem. In Britain, 2, 206 (1973). 4. R.N. Warrener,J. Am. Chem. Sot., s, -
236
(1971):
2166
Ao. 25
1972, 5. J. Bornstein,D.E. Remy and J.E. Shields,J.C.S. Chem. COIIXU., 6. B.M. Adger, M. Keating, C.W. Rees and R.C. Storr, J.C.S. Chem.G.,
1149.
m,
19.
1970, 3357. 7. A. Steigel and J. Sauer,TetrahedronLetters, 8. R.C. Bansal, A.W. McCullochand A.G. McInnes, Can. J. Chem. 2,
2391 (1969).
9. Compounds J.lconsistedof mixtures of two isomers (endo and exo) which were separatedby chromatography;all novel compoundsafforded satisfactoryanalyticaland spectroscopical data. 10.
In contrastto the fast Diels-Alderreactionof 2 and 2 Huisgen and Christl"found that the 1,3-dipolaradducts of nitrlle oxides or diphenylnitrilimine with cyclopentadiene decomposedonly upon heating at 140-160 'C.
11.
R. Huisgen and M. Christl,Angew. Chem. Intern.Ed. Engl. 5, 456 (1967).
12. It is well known that acetylenedoes not enter into cycloadditionreactionswith 1,3-dlpolarreagentsunder mild conditions.However, using L as "activated"acetylene, in some cases 1,3-dipolaradducts of acetylenecan be obtained (e.g.2 and 12).