L. N. Burgula et al. / Tetrahedron Letters 53 (2012) 2639–2642
2641
following reaction with urea gives an intermediate, characterized
by HRMS and NMR (Supplementary data). Finally, the intermediate
undergoes ring closure to yield the cyclized product (4, 9).
The crystal structure of 5-isopropyl-6-methyluracil (5) and that
of 6-phenyluracil (6) is demonstrated in Figure 2. The crystal struc-
ture of 5 shows a highly organized pattern with alternative hydro-
phobic and hydrophilic layers. The branched alkane chain forms
the hydrophobic layer whereas, the polar C(4)@O(2) accounts for
the hydrophilic interactions (Supplementary data). The crystal
structure of 6 also shows a self-assembled pattern through H-
BF3.Et2O
O
O
O
O
BF3.Et2O
R1
OEt
R2
R1
OEt
R2
4a. R1 = nPr, R2= H
9a. R1 = H, R2= Bn
- H2O NH2CONH2
O
R2
R1
HN
O
O
R2
- EtOH
NH
OEt
bonding (2.03 and 2.17 Å) as well as strong p–p interactions
(3.65 Å) between the phenyl and the heterocyclic ring.29
R1
N
H
O
NH2
4. R1 = nPr, R2= H
9. R1 = H, R2= Bn
Intermediate
Acknowledgments
We sincerely thank Professor R. C. Boruah, RRL Jorhat, India, for
providing the microwave reactor facility. We acknowledge the help
and cooperation of Dr. G. Das, IIT Guwahati, India, in analyzing the
crystal data. We also thank CSIR (New Delhi, India, Grant No.
02(0017)/11/EMR-II) for financial support.
Figure 1. Proposed mechanism of formation of nucleobases using Lewis acid.
at C-5 and C-6 positions. In order to test the robustness of the meth-
od, we have used b-aldehydo ester as substrate instead of a b-keto-
ester, which also shows rapid conversion (compound 9). The
versatility of the method was further demonstrated by the synthe-
sis of cytosine derivatives, 11 and 12. The optimized irradiation
times in Table 1 reflect completion of reactions, monitored by
checking TLC (thin layer chromatography) (see Fig. 1).
The yields of the cyclization reactions, in most cases, were sig-
nificantly increased by addition of BF3ÁEt2O as Lewis acid. This was
particularly evident for substrate (10a) which yielded a very low
amount of compound 10 in the absence of the Lewis acid. Addition
of BF3ÁEt2O also led to the reduction of the reaction time from
8–15 min to 4–7 min. The mechanism of the reaction is proposed
in Figure 2 where, in the first step, the carbonyl carbon of the
substrate b-ketoester (4a, 9a) is activated by the Lewis acid. The
Supplementary data
Supplementary data associated with this article can be found, in
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Figure 2. (a) Packing diagram of 5 showing organized layered structure. (b) Packing
diagram of 6 showing H-bonding (N–H. . .O@C, green dash) and p-stacking (purple
colored dummy atoms) interactions. Blue and red represents ‘N’ and ‘O’ atoms
respectively.