Synthesis of fused pyridopyrrolidine dione derivatives using hetero Diels-Alder reactions

Article abstract of DOI:10.1016/S0040-4039(01)02000-7

Hetero Diels-Alder reactions of heteroaromatic amidines and maleimide afforded novel fused pyridopyrrolidine dione scaffolds in moderate to good yields under mild conditions.

Full text of DOI:10.1016/S0040-4039(01)02000-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8931–8934
Synthesis of fused pyridopyrrolidine dione derivatives using
hetero Diels–Alder reactions
Helen J. Mason, Ximao Wu, Rebecca Schmitt, John E. Macor and Guixue Yu*
Hopewell Discovery Chemistry, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 13 August 2001; accepted 24 October 2001
Abstract—Hetero Diels–Alder reactions of heteroaromatic amidines and maleimide afforded novel fused pyridopyrrolidine dione
scaffolds in moderate to good yields under mild conditions. © 2001 Elsevier Science Ltd. All rights reserved.
Hetero Diels–Alder reactions have been extensively uti-
lized in the construction of heterocyclic rings, such as
substituted pyridines. However, use of this methodol-
1 for detailed SAR studies and subsequent compound
3
scale-up.
1
ogy has not been as well established for the synthesis of
fused pyridine derivatives. Several reports have recently
appeared applying hetero Diels–Alder chemistry to the
The use of conjugated amidines as azadienes, or as
1
heterodienophiles is well documented in the literature.
Retrosynthetic analysis from 2 leads to diester 3
(Scheme 1), which we reasoned should be available
from the reaction of the amidine 4 and DMAD (5,
2
synthesis of fused pyridine derivatives. These reports
provided novel entries into highly substituted, fused
pyridine scaffolds. In this communication, we wish to
report our new approaches to fused pyridines using
hetero Diels–Alder reactions under mild conditions
forming versatile substrates.
4
Scheme 1). Hetero Diels–Alder cyclization of 4 and 5
proceeded smoothly in an acetic acid solution at ambi-
ent temperature to generate dihydropyridine 6 (Scheme
2). Instead of eliminating dimethylamine to form 3, 6
persisted in the solution and was observed as its
methanol adduct 7 by LC-MS analysis (methanol in the
eluent) whose regiochemistry was not defined. We
assumed that the elimination was retarded by the cis
geometry of the hydrogen and the dimethylamino
group, thus preventing the 1,4-conjugate elimination
In our studies of the synthesis of pyrazolopyridopyri-
3
dazine PDE5 inhibitors, we required large quantities of
intermediate 1 (Scheme 1). Our original synthesis of 1
took five steps to reach intermediate 2 in 18% overall
yield starting from 5-amino-1-ethylpyrazole. This path-
way failed to supply sufficient amounts of intermediate
5
from occurring. Elevated temperature and/or the addi-
H
N
O
O
OMe
OMe
Cl
N
MeO C
2
NH
N
CO Me
2
O
O
5
Cl
N
N
N
N
Me
N
N
N
N
N
2
N
3
N
1
N
4
N
Et
Et
Et
Et
Me
Scheme 1.
Keywords: hetero Diels–Alder reaction; maleimide; pyridine; pyridopyrrolidine dione.
*
Corresponding author. Fax: 609-818-3450; e-mail: guixue.yu@bms.com
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02000-7

8
932
H. J. Mason et al. / Tetrahedron Letters 42 (2001) 8931–8934
H CO
MeO C
3
2
CO Me
CO Me
2
2
H
H
CO Me
2
CO Me
CO Me
2
2
5
N
N
N
Me
Me
Me
N
N
N
N
4
N
N
N
N
N
Et
Et
Et
Me
Me
Me
6
7
Scheme 2.
tion of oxidizing agents, such as m-CPBA to oxidize
cially available heteroaromatic amines with maleimides
(Table 2). Without optimizing each individual reaction
condition, we examined aminothiophene, aminoisoxa-
zole and aminobenzothiophene using the reaction con-
ditions described in Table 2. All three substrates
afforded the desired pyridopyrrolidine dione products,
albeit in lower yields for the simple thiophenylpyri-
dopyrrolidine dione (23) and isoxazolopyridopyrro-
lidine dione (25). In view of the complexity of the fused
heterocyclic scaffolds formed and the ease of synthesis,
this procedure provides a concise, facile route to the
formation of these complex fused pyridopyrrolidine
the dimethylamino moiety in order to facilitate elimina-
5
tion, also failed to produce 3.
Based on these observations, we hypothesized that by
using a dienophile in a lower oxidation state, such as
maleimide (8), the resultant Diels–Alder product 9
would have a hydrogen anti to the leaving dimethyl-
amino group (Scheme 3). E2 elimination of dimethyl-
amine would afford the intermediate 10. Aromatization
of 10 forming 11 should be accomplished by air oxida-
tion. As anticipated, pyridine 11 was produced in a 50%
yield when 2 equiv. of maleimide was used in acetic acid
at 60°C (Scheme 3).
8
dione derivatives. Further optimization of these reac-
tions is the subject of additional studies.
This successful, novel transformation encouraged us to
examine the effect of solvent on this reaction. We found
that water was a superior solvent for the reaction,
In summary, we have developed a facile methodology
for the synthesis of fused pyridopyrrolidine dione
derivatives. The chemistry described in this report pro-
vides a concise and facile route for rather complicated
fused heterocyclic scaffolds. We are currently investi-
gating the scope of this reaction by extending it to other
heteroaromatic amidines as the diene precursors and by
utilizing other dienophiles. The results of these studies
will be reported in due course.
affording the desired pyrazolopyridopyrrolidine dione
6
1
1, even at room temperature. When 4 equiv. of
maleimide was used with air bubbling through the
aqueous solution for 24 h, 11 was produced in 70–75%
optimized yield. The product gradually precipitated
from the reaction solution and was collected by filtra-
tion. The structure of 11 was subsequently confirmed
7
by X-ray analysis.
To explore the generality of this reaction, we examined
a number of other aminopyrazole analogs, as shown in
Table 1. These reactions afforded moderate to good
yields of the desired pyrazolopyridopyrrolidine diones
9
General procedure
Aminopyrazoles (5.0 mmol) were heated at refluxed in
dimethylformamide dimethylacetal (5.5 mmol) for 5 h.
The resulting mixture was dissolved in water (20 mL),
and maleimide (20.0 mmol) was added. The resulting
solution was stirred at ambient temperature with air
bubbling through the reaction solution. After about 1
h, solid would begin to form. The product was filtered
(
13, 15, 17, 19 and 21). Due to the insolubility of the
diene precursors in water, acetic acid was used at
elevated temperatures.
To extend the application of this hetero Diels–Alder
reaction, we investigated the reaction of other commer-
O
NH
O
O
O
NH
NH
NH
O
O
O
O
8
-Et NH
air
2
N
H
N
N
N
N
Me
Me
N
N
N
N
N
9
N
4
N
N
N
Et
Et
Et
Et
Me
Me
10
11, 50%
Scheme 3.

H. J. Mason et al. / Tetrahedron Letters 42 (2001) 8931–8934
8933
Table 1.
after 24 h and rinsed with ethanol to afford the desired
pyridopyrrolidine dione. For reactions performed in
acetic acid, the crude reaction products were diluted
with water and filtered. For compound 23, the product
was purified by silica gel chromatography.
Acknowledgements
We are indebted to Drs. David Rotella, and Rick
Ewing for their helpful discussions during this work.

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H. J. Mason et al. / Tetrahedron Letters 42 (2001) 8931–8934
Table 2.
We are grateful to Dr. Jack Gougoutas and Ms. Mary
Malley for X-ray analysis.
5. Chenard, B. L.; Ronau, R. T.; Schulte, G. K. J. Org.
Chem. 1988, 53, 5175–5177.
6
. Use of CDCl , DMSO-d , pyridine-d , and CD OD as
3 6 5 3
reaction solvents afforded essentially no desired product.
Use of CD CO D afforded products only at elevated
temperatures (50–100°C).
References
3
2
1
. (a) Boger, D. L. Tetrahedron 1983, 39, 2869–2939; (b)
Boger, D. L.; Hong, J.; Hikota, M.; Ishida, M. J. Am.
Chem. Soc. 1999, 121, 2471 (compound 11 in this refer-
ence); (c) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic: San Diego,
7. X-Ray structure of 11.
1987; Vol. 47.
2. (a) Diaz-Ortiz, A.; Carrillo, J. R.; Gomex-Escalonilla, M.
J.; de la Hoz, A.; Moreno, A.; Prieto, P. Synlett 1998,
1
096; (b) Behforouz, M.; Gu, Z.; Stelzer, L. S.; Ahmadian,
M.; Haddad, J.; Scherschel, J. A. Tetrahedron Lett. 1997,
8, 2211; (c) Diaz-Ortiz, A.; Carrillo, J. R.; Cossio, F. P.;
3
Gomex-Escalonilla, M. J.; de la Hoz, A.; Moreno, A.;
Prieto, P. Tetrahedron 2000, 56, 1569–1577; (d) Yu, G.;
Macor, J. E.; Chung, H.-J.; Humora, M.; Katipally, K.;
Wang, Y.; Kim, S. WO 0056719.
3
4
. Yu, G.; Macor, J. E.; Chung, H.-J.; Humora, M.; Kati-
pally, K.; Wang, Y.; Kim, S. WO 0056719.
. Garcia, C.; Melguizo, M.; Cobo, J.; Sanchez, A.;
Nogueras, M.; Lopez, M. D.; Low, J. N. Synlett 2001, 1,
8. (a) Elbannany, A. A.; Ibrahiem, L. I.; Chozlan, S. A. S.
Pharmazie 1988, 43, 128–129; (b) Klemm, LeRoy H.
Trends Heterocyclic Chem. 1997, 5, 37–55.
1
13
9. All final products have been characterized by H,
C
57–60.
NMR, and elemental analysis.