Acylimine mediated N-N bond cleavage of pyrazolidinediones and subsequent conversion to dihydropyrimidinediones and malonamides

Article abstract of DOI:10.1016/S0040-4039(00)01865-7

Acylimines 3 were identified as intermediates in the fluorenyl assisted N-N bond cleavage of pyrazolidinediones 1. Subsequent conversion of 3 to dihydropyrimidinediones 4 and malonamides 7-10 is described.

Full text of DOI:10.1016/S0040-4039(00)01865-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1–4
Acylimine mediated NꢀN bond cleavage of pyrazolidinediones
and subsequent conversion to dihydropyrimidinediones and
malonamides
Yong Gong,a,* Mark J. Bauschb and Linhua Wangb
aDepartment of Medicinal Chemistry, Aventis Pharmaceuticals, Bridgewater, NJ 08807, USA
bDepartment of Chemistry and Biochemistry, Southern Illinois University, Carbondale, IL 62901, USA
Received 9 October 2000; accepted 23 October 2000
Abstract—Acylimines 3 were identified as intermediates in the fluorenyl assisted NꢀN bond cleavage of pyrazolidinediones 1.
Subsequent conversion of 3 to dihydropyrimidinediones 4 and malonamides 7–10 is described. © 2000 Published by Elsevier
Science Ltd.
In an initial experiment, reaction of 9-bromofluorene
(9-BrFl) with the potassium salt of 1a (1a–K), gener-
ated in situ from 4,4-diethyl-1-methylpyrazolidine-3,5-
dione and potassium t-butoxide (KOCMe3), provided
three products (Scheme 1). These products were sepa-
rated and characterized as the substitution product,
fluorenyl pyrazolidinedione 2a (5%), the ring opening
product, acylimine 3a (65%) and the insertion product
pyrimidinedione 4a (12%), respectively.11,12
Reductive cleavage of the NꢀN bond under strongly
reducing conditions, e.g. metal (Li, Na) in ammonia,
Raney Nickel, or SmI2, can provide an efficient syn-
thetic route to amino/acylamino and diamino deriva-
tives.1 This type of functionality can also be accessed
by base promoted NꢀN bond cleavage of diazetidi-
nones and acyl hydrazines.2 Acylimines, on the other
hand, are valuable, reactive reagents in the organic
synthesis3 which have served as building blocks for
various amino acid derivatives,4 including the Taxol
A-ring side-chain,5 and b-amido aldehydes.6 Acylimines
have also been invoked as intermediates in the ring
transformation of diazetidinones,7 indazolones,8 and
urazoles.9 However, there is no direct empirical evi-
dence for their formation during these reactions.
The isolation of acylimine 3a is significant, in that, to
our knowledge, this is the first example of a stable
acylimine being generated from NꢀN bond cleavage of
an acyl hydrazine. Our mechanistic proposal for the
formation of acylimine 3a is also illustrated in Scheme
1. Compound 2a, the initial product from the reaction,
undergoes proton exchange with unreacted anion 1a–K
to generate fluorenyl anion 2a–K and pyrazolidine-
dione 1a. Anion 2a–K then promotes the NꢀN bond
cleavage to give acylimine anion 3a–K. Proton ex-
change from 1a to 3a–K forms acylimine 3a, and
regenerates anion 1a–K. The isolation of the insertion
product 4a as a minor component of the reaction
mixture reflects a relatively unfavorable competition
reaction, in which the acylimine anion 3a–K cyclizes to
anion 4a–K, and then is protonated by 1a.
Previously, we reported an efficient insertion of
fluorenylene into urazoles to provide the corresponding
triazinanediones.10 In this letter, we describe the reac-
tion of 9-bromofluorene with pyrazolidinediones lead-
ing to the initial formation of stable acylimine
intermediates which can be converted into cyclic inser-
tion products or to acyclic acylamino/amino deriva-
tives, depending on the reaction conditions.
Schemes 2–6 illustrate some simple manipulations of
this basic reaction system which provide a variety of
products. When pyrazolidinedione 1b (Scheme 2) was
first treated with KOCMe3, and then allowed to react
with 9-BrFl and the crude products further treated with
Keywords: acylimine; cleavage reactions; cyclization; fluorenes; ring
transformations.
* Corresponding
author.
Fax:
1-908-231-3577;
e-mail:
yong.gong@aventis.com
0040-4039/01/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01865-7

2
Y. Gong et al. / Tetrahedron Letters 42 (2001) 1–4
Et
Et
O
Et
Et
O
Et
O
O
O
Et
O
Et
Et
-NMe
NMe
O
O
NMe
-N
N
N
HN NMe
-
1a
4a-K
2a-K
3a-K
1a
KOCMe3
1a
1a
1a-K
O
1a-K
1a-K
Et
Et
O
Et
Et
Et
O
Et
O
O
O
Et
Et
NHMe
NMe
9-BrFl
N
O
NMe
O
N
HN
+
+
KN NMe
1a-K
2a (5%)
3a (65%)
4a (12%)
Scheme 1.
1. KOCMe3; 2. NH4Cl/H2O 91%
O
O
1. KOCMe3
2. 9-BrFl
O
O
NHPh
NPh
O
O
NH
N
+
+
NPh
HN
O
O
OEt
3. EtOH
HN
NPh
1b
2b (24%)
5 (56%)
4b (5%)
Scheme 2.
Ph
ethanol, malonamide 5, the addition product of EtOH
to the corresponding acylimine, was the major product
(56%), along with substitution product 2b (24%) and
insertion product 4b (5%).
Et
O
O
1. KOCMe3
2. 9-BrFl
Ph
Et
O
NPh
HN
O
3. KOCMe3
4. NH4Cl/ H2O
HN
NPh
However, when 2b was subsequently treated with
KOCMe3 and the reaction quenched with aqueous
NH4Cl, 4b was obtained in high yield (91%), pre-
sumably, via the process of deprotonation, cleavage,
cyclization, and protonation, as discussed above.
79%
1c
4c
Scheme 3.
Et
Et
Et
Et
Et
Et
O
O
H
N
O
O
O
MeO
MeO
O
O
O
O
O
RO2C
HN
CO
GGOMe
H2O
NHMe
NHMe
NHMe
NH
N
NH
3a
OMe
DCC
TEA
6
9
7 (R = Me)
8 (R = H)
NaOH/H2O
Scheme 4.

Y. Gong et al. / Tetrahedron Letters 42 (2001) 1–4
3
O
References
Et
Et
O
O
3a
+
1. (a) Song, J.; Hesse, M. Tetrahedron 1993, 49, 6797–6804;
(b) Grabowski, S.; Prinzbach, H. Tetrahedron Lett. 1996,
37, 7951–7954; (c) Itoh, N.; Matsuyama, H.; Yoshida,
M.; Kamigata, N.; Iyoda, M. Heterocycles 1995, 413,
415–418; (d) Barluenga, J.; Fernandez-Mari, F.; Viado,
A. L.; Aguilar, E.; Olano, B.; Garcia-Granda, S.; Moya-
Rubiera, C. Chem. Eur. J. 1999, 5, 883–896; (e) Zupan-
cic, S.; Svete, J.; Stanovnic, B. J. Heterocycl. Chem. 1999,
36, 607–610; (f) Okitsu, O.; Oyamada, H.; Furuta, T.;
Kobayashi, S. Heterocycle 2000, 52, 1143–1162; (g) Over-
man, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C.
J. Am. Chem. Soc. 1997, 119, 7159–7160.
2. (a) Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett.
1997, 38, 2113–2116; (b) Endo, Y.; Uchida, T.;
Yamaguchi, K. Heterocycles 2000, 53, 151–158; (c) Fahr,
E.; Fischer, W. Tetrahedron Lett. 1967, 3291–3293.
3. Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89,
1524–1534.
NHMe
NH2
10a
Scheme 5.
One-pot insertion of fluorenylene into the NꢀN bond is
outlined in Scheme 3. Pyrazolidinedione 1c was first
treated with KOCMe3 and then allowed to react with
9-BrFl. The resulting reaction mixture was further
treated with KOCMe3 before being quenched with
NH4Cl/H2O to give, on isolation, the insertion product
4c (79%).
Cycloaddition of acylimine 3a with 1,1-dimethoxy-
ethylene3 (Scheme 4) produced dihydrooxazine 6, which
was hydrolyzed under mild conditions to ester 7. Fur-
ther hydrolysis of 7 gave acid 8. Coupling of 8 with
glycylglycine methyl ester (GGOMe) yielded the novel
peptide product 9.
4. Beller, M.; Echert, M. Angew. Chem., Int. Ed. 2000, 39,
1011–1027.
5. Swindell, C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889–
5891.
6. Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett.
2000, 2, 585–588.
7. (a) Taylor, E. C.; Clemens, R. J.; Davies, H. M. L.;
Haley, N. F. J. Am. Chem. Soc. 1981, 103, 7659–7660;
(b) Taylor, E. C.; Davies, H. M. L.; Hinkle, J. S. J. Org.
Chem. 1986, 51, 1530–1536.
8. Baiocchi, L.; Picconi, G. Tetrahedron Lett. 1986, 27,
5255–5256.
9. Adam, W.; Grabowski, S.; Hinz, R. F.; Luccini, V.;
Peters, E-M.; Peters, K.; Rebollo, H.; von Schnering, H.
G. Chem. Ber. 1987, 120, 2075–2079.
Acylimine 3a is sensitive to moisture and is hydrolyzed
to malonamide 10a and 9-fluorenone upon standing
(Scheme 5). This observation led us to explore the
practicality of an one-pot approach to 2,2,N-trisubsti-
tuted malonamides (Scheme 6). 1,5,5-Trisubstituted
pyrazolidinediones (1a–d) were treated with KOCMe3,
and allowed to react with 9-BrFl. The resulting reaction
mixtures were then simply exposed to moisture. Grati-
fyingly, 2,2,N-trisubstituted malonamides (10a–d) were
obtained in good yields (59–65%).13 This overall pro-
cess can be considered as reductive cleavage of NꢀN
bond in pyrazolidinedione 1 with the reducing agent
9-BrFl being oxidized to 9-fluorenone.14
10. Robinson, P. D.; Gong, Y.; Bausch, M. J. Acta Crystal-
logr., Sect. C 1996, 52, 2337–2340.
1
11. 2a: mp 138–139°C; IR (KBr) 1706, 1682 cm−1; H NMR
(CDCl3) l 7.29–7.70 (m, 8H), 6.82 (s, 1H), 3.38 (s, 3H),
1.68 (m, 4H), 0.83 (t, J=7.5 Hz, 6H); 13C NMR (CDCl3)
l 174.0, 172.8, 141.8, 141.0, 129.8, 127.9, 55.3, 31.0, 27.4,
8.9. Anal. calcd for C21H22N2O2: C,75.42; H, 6.63; N,
8.38. Found: C, 75.08; H, 6.65; N, 8.42. 3a: IR (KBr)
In conclusion, acylimines have been isolated for the first
time as products from NꢀN bond cleavage of pyrazo-
lidinediones. Further useful transformations of these
intermediates to dihydropyrimidinediones and 2,2,N-
trisubstituted malonamides have been developed.
3366, 1713, 1662 cm−1 1H NMR (CDCl3) l 7.23–7.69
;
(m, 9H), 2.90 (d, J=4.5 Hz, 3H), 2.05 (m, 4H), 0.93 (t,
J=7.5 Hz, 6H); 13C NMR (CDCl3) l 189.3, 171.7, 143.3,
134.7, 133.6, 128.5, 125.6, 120.4, 105.6, 61.4, 28.9, 26.4,
9.7. EI MS m/e 334. 4a: mp 300–301°C; IR (KBr) 3201,
1670, 1626 cm−1; 1H NMR (CDCl3) l 7.33–7.68 (m, 8H),
6.20 (s, 1H), 2.46 (s, 3H), 2.11 (m, 4H), 1.13 (t, J=7.5
Acknowledgements
Y.G. thanks Dr. D. G. McGarry for his suggestions in
the preparation of this manuscript.
a. R1 = Me, R2 = R3 = Et
b. R1 = Ph, R2 = R3 = -(CH2)4-
c. R1 = R2 = Ph, R3 = Et
d. R1 = R2 = R3 = Me
1. KOCMe3
2. 9-BrFl
R2
R2
R3
R3
65%
O
O
O
59%
O
3. H2O
NHR1
HN NR1
NH2
10
58%
61%
1
Scheme 6.
.

4
Y. Gong et al. / Tetrahedron Letters 42 (2001) 1–4
Hz, 6H); 13C NMR (CDCl3) l 170.9, 170.3, 144.1, 139.2,
1996, 52, 2081–2084.
130.9, 129.2, 123.9, 120.7, 79.7, 55.5, 31.9, 29.3, 11.0.
Anal. calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38.
Found: C, 75.34; H, 6.62; N, 8.38.
13. Preparation of tetrasubstituted malonamides from decar-
bonylation of barbituric acids was reported recently:
Jursic, B. S. Tetrahedron Lett. 2000, 41, 5325–5328.
14. With fluorenyl pyrazolidinediones (2) and dihydropyrim-
idinediones (4) as the by-products.
12. For X-ray crystal structure of 4a, see: Gong, Y.;
Robinson, P. D.; Bausch, M. J. Acta Crystallogr., Sect. C
.
.