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3608
M. Kamal Raj et al. / Tetrahedron Letters 52 (2011) 3605–3609
O
CH3
O
CH3
O
CH3
CH3
CH3
OH
O
O
CH3
NH C+
O
-
H2O
+H
-
CH3CH2OCOCH2CH3
NH
O
NH
O
OH+2
N
N
N
O
Molecular Formula = C14H18N2O4
Exact Mass 278.1266
Molecular Formula
Exact Mass
=
=
C14H19N2O4
279.1339
Molecular Formula
Exact Mass
=
=
C
14H17N2O3
=
261.1239
NH+3
-
NH3
NH+2
N
-
CO
N
C+
O
O
Molecular Formula
Exact Mass
=
C7H8N
Molecular Formula
Exact Mass
=
C8H6NO
Molecular Formula
Exact Mass
=
C8H9N2O
=
106.0656
=
132.0449
=
149.0714
Figure 4. Tandem time-of-flight mass fragmentation pathway.
of bis-ureide under our experimental conditions. The treatment of
benzaldehyde and urea with aqueous potassium carbonate solution
at 50–60 °C in the absence of ethyl acetoacetate was studied for the
formation of bis-ureide. Analysis of reaction samples by mass spec-
trometry found no evidence of bis-ureide formation thus ruling out
the possibility of bis-ureide pathway.
subsequently cyclises and eliminates water to yield the desired
dihydropyrimidine.
Acknowledgements
The authors thank Dr. Ian Ashworth, Dr. Tony Bristow, Dr.
Hefang Pan, and members of AstraZeneca for their review and com-
ments.. This refers to ATP No. 11/0382 from AstraZeneca.
In order to enhance the yield of the Biginelli product by sup-
pressing the formation of (13), we performed a reaction by adding
ethyl acetoacetate drop wise at 55–60 °C. A reaction sample was
withdrawn for mass spectral analysis after 1 h. Two peaks corre-
sponding to mass m/z 191 and m/z 279 (see Supplementary data)
were observed along with the decarboxylated intermediate (13)
and the Biginelli product (4). The reaction mixture was again ana-
lysed after 5 h and the peak corresponding to mass m/z 191 had
disappeared. This suggests the formation of a plausible intermedi-
ate that has m/z 191 (Fig. 1) which could further react with benz-
aldehyde to give an intermediate corresponding to mass m/z 279
that might undergo a combination of cyclization and elimination
to give Biginelli product (4). From the plausible molecular formulae
we are proposing hemiaminal structure (14) for the intermediate
having m/z 191 (Fig. 1).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.011.
References and notes
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In order to assign the structure for the intermediate corre-
sponding to the mass m/z 279, the reaction mass was further ana-
lysed by Positive ESI Accurate mass TOF LC–MS. In this analysis
structure of the molecular ion peak of m/z 279.1337 with a mass
measurement error of less than 5 ppm (Fig. 2) could be assigned
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C14H19N2O4 as shown in Table 1. Logically 15b could form by the
addition of urea to benzylidene acetoacetate (7), the latter being
formed by the Knoevenagel condensation of benzaldehyde and
ethyl acetoacetate. This possibility, from our earlier experimental
data, is ruled out as 7 did not give rise to Biginelli product.
The protonated molecule at m/z 279.13 was selected as the pre-
cursor ion for ESI Accurate mass LC–MS/MS analysis and MS/MS
spectrum attached as Figure 3. Molecular formulae generated for
the molecular ions of fragments are within a mass error of 5 ppm
(Table 2). Based on the molecular formulae generated for the frag-
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and 4 we propose the hemiaminal structure (15a).
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Based on these results we suggest the reaction mechanism for
Biginelli reaction under our experimental conditions to proceed
via two hemiaminal intermediates (14) and (15a) as shown in
Scheme 6.
Reaction monitoring using ESI/MS and ESI/MS-MS for two and
three component mixtures indicates that the Biginelli reaction
proceeds via a hemiaminal (14 and 15a) pathway under basic
conditions. According to ESI/MS measurements, there is no
evidence for the formation of bis-ureide under base catalysis.
Interception of the initial hemiaminal intermediate (14) by
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