Facile Synthesis of 3-N-Alkyl Pyrimidin-2,4-diones from N-Sulfonyloxy Maleimides and Amines

Article abstract of DOI:10.1021/acs.orglett.5b02079

Reaction of variously substituted N-trifluoromethanesulfonyloxy maleimides with primary amines in the presence of potassium carbonate in DMF at room temperature results in the formation of 3-N-alkyl pyrimidin-2,4-diones in good yield.

Full text of DOI:10.1021/acs.orglett.5b02079

Letter
pubs.acs.org/OrgLett
Facile Synthesis of 3‑N‑Alkyl Pyrimidin-2,4-diones from
N‑Sulfonyloxy Maleimides and Amines
Girish C. Sati and David Crich*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: Reaction of variously substituted N-trifluoromethanesulfonyloxy
maleimides with primary amines in the presence of potassium carbonate in DMF at
room temperature results in the formation of 3-N-alkyl pyrimidin-2,4-diones in good
yield.
itrogen-based heterocycles are important constituents of
N
a large fraction of approved pharmaceuticals.1−3 The
pyrimidines are second only to the pyridines in occurrence
frequency of nitrogen heterocycles in approved drugs.1−3 The
development of new routes to novel classes of substituted
pyrimidines is therefore of inherent importance to medicinal
chemistry and the drug discovery process. By adapting the
limited precedent on the nucleophilic ring opening by
hydroxide and borohydride of N-toluenesulfonyloxy maleimide
and phthalimide derivatives, followed by Lossen rearrangement
and either hydrolysis or ring closure,4,5 we have discovered, and
report here, a new method for the synthesis of 3-N-alkyl
pyrimidin-2,4-diones from maleic anhydrides via reaction of the
derived N-sulfonyloxy maleimides with amines (Scheme 1).
The N-hydroxy maleimides 1−4 were converted to the
corresponding N-trifloxy imides 5−8 by reaction with triflic
anhydride in dichloromethane in the presence of pyridine
(Table 1). In the key reaction, stirring of the N-trifloxy imides
5−8 in DMF at room temperature in the presence of potassium
carbonate and a primary amine 9−13 smoothly afforded a
series of 3-N-alkyl pyrimidin-2,4-diones 14−27 (Table 1).
The examples presented in Table 1 reveal that the overall
process functions with a range of 2,3-disubstituted maleimides
including dialkyl (entries 1−3), diaryl (entries 4−6), mixed
alkyl, aryl (entries 7−9), and fused bicyclic (entries 10 and 11)
systems. The table also illustrates the successful employment of
a range of primary amines with varying degrees of steric
hindrance and functionality.
Scheme 1. Pyrimidindione Synthesis
Concerning the use of the unsymmetrically substituted N-
trifloxy 2-methyl-3-phenylmaleimide 7 as an electrophile (Table
1, entries 7−9) two regioisomeric products are formed with a
modest preference for the isomer arising from initial
nucleophilic attack by the amine on the carbonyl group vicinal
to the larger substituent. Presumably this modest preference for
nucleophilic attack vicinal to the larger substituent, which is
reminiscent of the regioselectivities observed in the nucleophilic
ring openings of 2,2-dimethylsuccinic anhydride and 2,2-
dimethyl succinimide,9,10 reflects the greater hindrance to the
approach of the nucleophile along the Burgi−Dunitz trajectory
in the formation of the minor isomer.
Brief heating of commercial 2,3-dimethyl and 2,3-diphenyl
maleic anhydride with hydroxylamine hydrochloride and
sodium acetate in aqueous ethanol6 gave the corresponding
N-hydroxy maleimides 1 and 2 in 74% and 80% yield,
respectively. Condensation of phenylacetic acid and sodium
pyruvate in acetic anhydride afforded 2-methyl-3-phenyl maleic
anhydride in 53% yield,7 which on stirring at room temperature
with hydroxylamine hydrochloride and sodium acetate gave N-
hydroxy-2-methyl-3-phenyl maleimide 3 in 90% yield. The
conversion of commercial cyclohexene-1,2-dicarboxylic anhy-
dride to the corresponding N-hydroxy maleimide 48 was best
achieved by heating with hydroxylamine hydrochloride and
sodium acetate to give an intermediate hydroxamic acid. This
was followed by cyclization with acetic anhydride to give the N-
acetoxy imide5,6 in 25% yield and, finally, deacetylation with
benzylamine at room temperature5 yielding 4 in 62% yield
(Supporting Information).
Although not isolated and characterized in each case owing
to the formation of regioisomeric and/or diastereomeric
mixtures, typical byproducts from these reactions were amido
Received: July 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02079
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Synthesis of N-Trifloxy Imides and 3-N-Alkylpyrimidin-2,4-diones
ureas. Thus, by way of example, the amido urea 28 was isolated
in 7% yield from the preparation of 17 (Table 1, entry 4).
isocyanate. Finally, nucleophilic attack of the amide on the
isocyanate yields the products. External attack by a further
equivalent of amine on the amido isocyanate affords the
byproduct amido ureas (Scheme 2).
Precedent for this mechanism derives from the work of Hurd
and co-workers who studied the decomposition of the
disodium salt of O,O′-dibenzoyl phthalohydroxamic acid in
water at reflux. The observed formation of 3-N-benzoyloxy
quinazolinedione in 37% yield was considered to involve
Lossen rearrangement of a single of the two activated
hydroxamate derivatives to give an isocyanate that was
subsequently trapped intramoleculary by nucleophilic attack
of the second hydroxamate salt.14 Lossen rearrangement of
sodium succinohydroxamate on reaction with benzenesulfonyl
Mechanistically, we envisage the formation of the pyrimdin-
diones to involve nucleophilic ring opening by the amine to
give an O-triflated amido hydroxamic acid derivative that
undergoes rapid Lossen rearrangement11−13 to afford an amido
B
DOI: 10.1021/acs.orglett.5b02079
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 2. Reaction Mechanism
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02079.
Full experimental details and copies of 1H and 13C NMR
spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dcrich@chem.wayne.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professors Andrea Vasella (ETH) and Erik C Bottger
(University of Zurich) for helpful discussions.
̈
C
DOI: 10.1021/acs.orglett.5b02079
Org. Lett. XXXX, XXX, XXX−XXX