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Diels-alder cycloaddition reactions of αβ-unsaturated aldehyde acylhydrazones
Tetrahedron Lcttcm, W32. Priired in Great Britain
00404039/91
No.1.p~ 125-128.1991
DIELS-ALDER
$3.00 + .oo
Pcrgamal Press plc
CYCLOADDITION REACTIONS OF al%UNSATURATED ACYLHYDRAZONRS
ALDEIIYDE
Sylvia J. Allcock,~ Thomas L Gil&r&~ and Prank D. Xi& a Robert Robinson Laboratories,University of Liverpool, P.O. Box 147. Liverpool L69 3BX b SmithXline Beecham Phatmaceuticals, Medicinal Reseamh Centte, C!ok%rbourRoad, The Pinnacles, Hat-low, Essex CM19 SAD, U.K.
Sum-: Acylhydrazones &rived from ~-met~l-~-~~~-enorrhydrarine or &nethyl-&pent4 ynoylhydrazine and &u~~ahuateA akiehydes undergo intramolecular DiebAlder reactions at elevated teqwtwures. An intermolecular counterpar, the &don qfmethacrolein benzoylh~drawne to & phenybnaleimi&, has also been carried out. Among the multitude of methods available for constructing the pyridine ring system, Diels-Alder cycloaddition reactions of I-azabutadienes to dienophiles have had some limited success.* In particular,inmunolecular DielsAkler reactions of this type have proved useful for the rapid comaucdon of polycyclic ring systems, and several naturalpmducts have been syndxsized. 2 One ofthe barriersto applying the methodology mom widely is the lack of simple, isolable I-amdienes of suftlcient mactivity. Ghosez and his co-workers found that NN-dimethylhydrazones 1 of methacmlein and some related unsaturated aldehydes were capable of acting as l-azadienes; they were shown to react with electron deficient alkenes at moderate temperatums.~ This naction has since been used by several others as a mute to pyridine~ and intramoleculsr q&additions
have been mportedwith dinx%hylhydrazonessuch as 2.5 Reactions of oxime
ethers of unsaturatedaldehydes were much less successful and the success with the dimethylhydrazones was ascribed to electron donation fmm the dimethylamino substituent.3 The dimethylhydramno function is thus apparentlycapable of pmmoting addition to electton deficient dienophiles, whereas the parentu&msaturated aldehydes participatein Diels-Akler reactions as hetemdienes only with electron rich dienophiles.
125
126
wehaveanuqedtoizarryoutintramolecularDiels-Aldernactioasof aldehydes and have isolated products of q&addition
severalacylhydrazonesofllnsammted
in sevexal instances. The acylhydrazones 4 were prepared
fmm methacrolein and the terminally unsaturated hydmzides 3 (Scheme 1). Compound 4a could not be induced to undergo intrau~lecuhu cycloaddition by heating in solution up to 200X!, but cumpound 4b gave the cycloadduct 5 in good yield when heated in xylene or in 1,2-dichlombenzene (b.p. 180~).6
0
3a; n =l b; n =2 i, methacmlti,
0 5
4 ii, 1,2dichlombenzene,
heat,
Scheme 1
The addition to a terminal allqne function was also obsaved when the acylhydrazones 6 were heatedz these compounds gave the pyridines 7 (Scheme 2) by aromatization of the initially formed cycloadducts, which.were not detected.’
RrNI
$
Meti
s
6 a; R=Me b; R=Et
R
-_ 91 I
I
"GNHMe
N
Meh
0
0
.
7
Scheme 2
Having observed the successful cycloaddition to these 1-azadienes. in which the nitrogen substituent is clearly a much poorer electron donor than the dimethylamino gmup used in earlier work, we attempted an intexmokxular analogue of the reaction. The benz~ylhydrazone 8 of ux%hacmlein was prepared as a model compound and it was heated in mesitylene (hp. 162oC) with N-phenylmaleimide. The reaction gave the known& pyridine 9a in 91% yield,8 this presumably being formed by elimination of benzamide from the initially formed cycloadduct followed by oxidation. ‘Ihe intermolecular addition to this electron deficient dienophile is more favourable than intramolecular addition to an unactivated triple bond. This was established by heating the acylhyd.raz.ones6 in mesitylene with one equivalent of N-phenylmaleimide. Compound 6a gave the pyridine 9a as the only product; none of the intramolecular adduct 7a was detected. Similarly 6b gave the pyridine 9b4c as the only pmduct.9
127
IiHCOPh 8
9
a;R=Me b;R=Et
These results show that the range of hydrazones capable of acting as 1-azadienes in the Diels-Alder reaction is
wider than previously thought. We are currently attempting to extend the reaction to other hydzazones.10 This innamolecular reaction appears to be rathex limited in scope, however: we have been unable to cyclize the acylhydrazone 10orthecarbamate 11. Compound 11didundergo intermolecular q&addition phenylmaleimide, to give the adduct 9b (92%) as expected
to N-
An attempt to carry out an intramolecular
cycloaddition with a related oxime 12 has so far also proved unsuccessful, in accoxl with earlier observations on oxime ethers.3
12
Grigg and his co-workers have shown that benzaldehyde phenylhydrazone reacts with N-phenylmaleimide in a different way.11 It undergoes q&addition
by way of its 13dipolar tautomer which is produced by a proton
shift f&n the terminal to the central nitrogen atom (Scheme 3). We have not observed analogous reactiolls with hydrazones of unsaturated aldehydes, evidently these hydtazones react prefuenti~ly as azadienes.
phhN
.NHPh
2
ph/$NPh
-
H H
Scheme3
Acknowledgements We thank the SERC for a Studentship (to S.J.A.) and SmithKline Beecham ph arnlaceuticals for support.
128
References
1
and notes
Boger, D. L.; Weinreb, S. N. “Hetero Diels-Alder Methodology in organic Synthesis”, Academic Press, San Diego, 1987, Chapter 9; Boger, D. L; Corbett, W. L.. Wiggans, J. M. J. Org. Chem., 1990,55, 2999-3ooO. Uyehara, T., Suzuki, I., Yamamo to, Y. Tetrahedron Lat., 1990,31,3753-3756..
2 3
Kametani, T.; Hibino, S. Adv. Heterocycl. Chem., 1987,42.245-333. Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez. L. Tetruhedron Lett., 1982,23,3X1-3264;
Ghosez,
L.; Serckx-Poncin, B.; Rivera, M, Bayard. P.; Sainte, F.; Demoulin, A.; Frisque-Hesbain, A.-M.; Mockel. A.; Munoz. L.; BernardHenriet, C. J. Heterocyc. Chem., 1985.22, Suppl. Issue (Lat. Heterocycl.
Chem., 8). 69-78. 4
(a) Tamura. Y.; Tsugoshi. T.; Nakajima, Y.; Rim, Y. Synzhesis. 1984.930-933; Bhattachaqjee,D, Walsh, E.B. J. Chem. Sot. Chem. Comma,
1984,114-l 16; (c) Potts, IC.T.; Walsh,
E.B.; Bhattachajee, D. J. Org. Chem., 1987.52.2285-2292; 3 707 530 (1987) (Chem. Abstr., 1988.108.37663);
(b) Potts, K. T.;
(d) Astles. D. P.; Flood A. Ger. Patent
(e) Waldner. A. Helv. Chim. Acta, 1988,71,486-
492; (f) Waldner, A. Helv. Chim. Acta, 1988,71,493-497;
1989,72,1435-1443;
Fillion, H.; Rougny. A. Tetrahedron L.ett., 1988,29,5913-5916;
(g) Chigr, M.;
(h) Waldner, A. Tetrahedron Lett.,
1989.30, 3061-3064. 5
Dolle, R. E.; Armstrong, W.P.; Shaw, A.N.; Novelli, R. Tetrahedron Lett., 1988.29.6349-6352.
6
Compound 5 was isolated (69%) after 48 h in l&dichlombenzene togetherwith the startinghydrazone 4b (24%).
5 had lap. 58-6ooc and SB (CDCl3) 1.61 (3 H). 1.75-1.89 (3 H, m), 2.00-2.17 (3 H, m), 2.38-
2.46 (2 H, m, CGC&),
3.11 (3 H. NC&), 3.45-3.56 (1 H, m), and 5.74 (1 H, C=qF).
This and other
new compounds gave correct C. H, and N analyses. 1
Pyridine 7a was isolated (44%) after 48 h in 1,2-dichlorobenzene togetherwith the startinghydrarone 6a
(40%). 7a had lap. 66-67oC and SB 2.31 (3 H), 2.65 (2 H. t, J 7.1 Hz), 2.77 (3 H. d, J 4.8 Hz, NC&),
3.08 (2 H, t, 37.1 Hz), 6.5 (1 H, NH). 7.10 (1 H, d, J7.9 Hz, pyridine u-3). 7.42 (1 H, dd, J
7.9 and 2.2 Hz, pyridine H-4). and 8.34 (1 H, d, J 2.2 Hz, pyridine H-6). Compound 7b was isolated (64%) together with 6b (27%) under the same conditions. 7b is an oil (picrate m.p. 104105oC). 8
M.p. 245~246oC (lit.,“= 244246OC).
9
Pyridine 9b was isolated in 92% yield and had np. 189-19fPC (lit.,‘te 1W19loC).
10
The phenylhydmzone. 2,4dinitrophenylhydrszone and tosylhydrazoneof methacroleinalso react with Nphenylmaleimide as 1-azadienes(experimentsby S. J. Shuttlewotth).
11
Chigg, R; Dowling, M.; Jordan, M.W.; Sridharan.V. Tetrahedron, 1987,43,5873-5886.
(Received in UK
30 October 1990)
00404039/91
No.1.p~ 125-128.1991
DIELS-ALDER
$3.00 + .oo
Pcrgamal Press plc
CYCLOADDITION REACTIONS OF al%UNSATURATED ACYLHYDRAZONRS
ALDEIIYDE
Sylvia J. Allcock,~ Thomas L Gil&r&~ and Prank D. Xi& a Robert Robinson Laboratories,University of Liverpool, P.O. Box 147. Liverpool L69 3BX b SmithXline Beecham Phatmaceuticals, Medicinal Reseamh Centte, C!ok%rbourRoad, The Pinnacles, Hat-low, Essex CM19 SAD, U.K.
Sum-: Acylhydrazones &rived from ~-met~l-~-~~~-enorrhydrarine or &nethyl-&pent4 ynoylhydrazine and &u~~ahuateA akiehydes undergo intramolecular DiebAlder reactions at elevated teqwtwures. An intermolecular counterpar, the &don qfmethacrolein benzoylh~drawne to & phenybnaleimi&, has also been carried out. Among the multitude of methods available for constructing the pyridine ring system, Diels-Alder cycloaddition reactions of I-azabutadienes to dienophiles have had some limited success.* In particular,inmunolecular DielsAkler reactions of this type have proved useful for the rapid comaucdon of polycyclic ring systems, and several naturalpmducts have been syndxsized. 2 One ofthe barriersto applying the methodology mom widely is the lack of simple, isolable I-amdienes of suftlcient mactivity. Ghosez and his co-workers found that NN-dimethylhydrazones 1 of methacmlein and some related unsaturated aldehydes were capable of acting as l-azadienes; they were shown to react with electron deficient alkenes at moderate temperatums.~ This naction has since been used by several others as a mute to pyridine~ and intramoleculsr q&additions
have been mportedwith dinx%hylhydrazonessuch as 2.5 Reactions of oxime
ethers of unsaturatedaldehydes were much less successful and the success with the dimethylhydrazones was ascribed to electron donation fmm the dimethylamino substituent.3 The dimethylhydramno function is thus apparentlycapable of pmmoting addition to electton deficient dienophiles, whereas the parentu&msaturated aldehydes participatein Diels-Akler reactions as hetemdienes only with electron rich dienophiles.
125
126
wehaveanuqedtoizarryoutintramolecularDiels-Aldernactioasof aldehydes and have isolated products of q&addition
severalacylhydrazonesofllnsammted
in sevexal instances. The acylhydrazones 4 were prepared
fmm methacrolein and the terminally unsaturated hydmzides 3 (Scheme 1). Compound 4a could not be induced to undergo intrau~lecuhu cycloaddition by heating in solution up to 200X!, but cumpound 4b gave the cycloadduct 5 in good yield when heated in xylene or in 1,2-dichlombenzene (b.p. 180~).6
0
3a; n =l b; n =2 i, methacmlti,
0 5
4 ii, 1,2dichlombenzene,
heat,
Scheme 1
The addition to a terminal allqne function was also obsaved when the acylhydrazones 6 were heatedz these compounds gave the pyridines 7 (Scheme 2) by aromatization of the initially formed cycloadducts, which.were not detected.’
RrNI
$
Meti
s
6 a; R=Me b; R=Et
R
-_ 91 I
I
"GNHMe
N
Meh
0
0
.
7
Scheme 2
Having observed the successful cycloaddition to these 1-azadienes. in which the nitrogen substituent is clearly a much poorer electron donor than the dimethylamino gmup used in earlier work, we attempted an intexmokxular analogue of the reaction. The benz~ylhydrazone 8 of ux%hacmlein was prepared as a model compound and it was heated in mesitylene (hp. 162oC) with N-phenylmaleimide. The reaction gave the known& pyridine 9a in 91% yield,8 this presumably being formed by elimination of benzamide from the initially formed cycloadduct followed by oxidation. ‘Ihe intermolecular addition to this electron deficient dienophile is more favourable than intramolecular addition to an unactivated triple bond. This was established by heating the acylhyd.raz.ones6 in mesitylene with one equivalent of N-phenylmaleimide. Compound 6a gave the pyridine 9a as the only product; none of the intramolecular adduct 7a was detected. Similarly 6b gave the pyridine 9b4c as the only pmduct.9
127
IiHCOPh 8
9
a;R=Me b;R=Et
These results show that the range of hydrazones capable of acting as 1-azadienes in the Diels-Alder reaction is
wider than previously thought. We are currently attempting to extend the reaction to other hydzazones.10 This innamolecular reaction appears to be rathex limited in scope, however: we have been unable to cyclize the acylhydrazone 10orthecarbamate 11. Compound 11didundergo intermolecular q&addition phenylmaleimide, to give the adduct 9b (92%) as expected
to N-
An attempt to carry out an intramolecular
cycloaddition with a related oxime 12 has so far also proved unsuccessful, in accoxl with earlier observations on oxime ethers.3
12
Grigg and his co-workers have shown that benzaldehyde phenylhydrazone reacts with N-phenylmaleimide in a different way.11 It undergoes q&addition
by way of its 13dipolar tautomer which is produced by a proton
shift f&n the terminal to the central nitrogen atom (Scheme 3). We have not observed analogous reactiolls with hydrazones of unsaturated aldehydes, evidently these hydtazones react prefuenti~ly as azadienes.
phhN
.NHPh
2
ph/$NPh
-
H H
Scheme3
Acknowledgements We thank the SERC for a Studentship (to S.J.A.) and SmithKline Beecham ph arnlaceuticals for support.
128
References
1
and notes
Boger, D. L.; Weinreb, S. N. “Hetero Diels-Alder Methodology in organic Synthesis”, Academic Press, San Diego, 1987, Chapter 9; Boger, D. L; Corbett, W. L.. Wiggans, J. M. J. Org. Chem., 1990,55, 2999-3ooO. Uyehara, T., Suzuki, I., Yamamo to, Y. Tetrahedron Lat., 1990,31,3753-3756..
2 3
Kametani, T.; Hibino, S. Adv. Heterocycl. Chem., 1987,42.245-333. Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez. L. Tetruhedron Lett., 1982,23,3X1-3264;
Ghosez,
L.; Serckx-Poncin, B.; Rivera, M, Bayard. P.; Sainte, F.; Demoulin, A.; Frisque-Hesbain, A.-M.; Mockel. A.; Munoz. L.; BernardHenriet, C. J. Heterocyc. Chem., 1985.22, Suppl. Issue (Lat. Heterocycl.
Chem., 8). 69-78. 4
(a) Tamura. Y.; Tsugoshi. T.; Nakajima, Y.; Rim, Y. Synzhesis. 1984.930-933; Bhattachaqjee,D, Walsh, E.B. J. Chem. Sot. Chem. Comma,
1984,114-l 16; (c) Potts, IC.T.; Walsh,
E.B.; Bhattachajee, D. J. Org. Chem., 1987.52.2285-2292; 3 707 530 (1987) (Chem. Abstr., 1988.108.37663);
(b) Potts, K. T.;
(d) Astles. D. P.; Flood A. Ger. Patent
(e) Waldner. A. Helv. Chim. Acta, 1988,71,486-
492; (f) Waldner, A. Helv. Chim. Acta, 1988,71,493-497;
1989,72,1435-1443;
Fillion, H.; Rougny. A. Tetrahedron L.ett., 1988,29,5913-5916;
(g) Chigr, M.;
(h) Waldner, A. Tetrahedron Lett.,
1989.30, 3061-3064. 5
Dolle, R. E.; Armstrong, W.P.; Shaw, A.N.; Novelli, R. Tetrahedron Lett., 1988.29.6349-6352.
6
Compound 5 was isolated (69%) after 48 h in l&dichlombenzene togetherwith the startinghydrazone 4b (24%).
5 had lap. 58-6ooc and SB (CDCl3) 1.61 (3 H). 1.75-1.89 (3 H, m), 2.00-2.17 (3 H, m), 2.38-
2.46 (2 H, m, CGC&),
3.11 (3 H. NC&), 3.45-3.56 (1 H, m), and 5.74 (1 H, C=qF).
This and other
new compounds gave correct C. H, and N analyses. 1
Pyridine 7a was isolated (44%) after 48 h in 1,2-dichlorobenzene togetherwith the startinghydrarone 6a
(40%). 7a had lap. 66-67oC and SB 2.31 (3 H), 2.65 (2 H. t, J 7.1 Hz), 2.77 (3 H. d, J 4.8 Hz, NC&),
3.08 (2 H, t, 37.1 Hz), 6.5 (1 H, NH). 7.10 (1 H, d, J7.9 Hz, pyridine u-3). 7.42 (1 H, dd, J
7.9 and 2.2 Hz, pyridine H-4). and 8.34 (1 H, d, J 2.2 Hz, pyridine H-6). Compound 7b was isolated (64%) together with 6b (27%) under the same conditions. 7b is an oil (picrate m.p. 104105oC). 8
M.p. 245~246oC (lit.,“= 244246OC).
9
Pyridine 9b was isolated in 92% yield and had np. 189-19fPC (lit.,‘te 1W19loC).
10
The phenylhydmzone. 2,4dinitrophenylhydrszone and tosylhydrazoneof methacroleinalso react with Nphenylmaleimide as 1-azadienes(experimentsby S. J. Shuttlewotth).
11
Chigg, R; Dowling, M.; Jordan, M.W.; Sridharan.V. Tetrahedron, 1987,43,5873-5886.
(Received in UK
30 October 1990)