Stereoselective intramolecular coupling of barbituric acids with aliphatic ketones and O-methyl oximes by electroreduction: Radical cyclization mechanism supported by DFT study

Article abstract of DOI:10.1016/j.tetlet.2016.03.035

The electroreductive intramolecular coupling of barbituric acids with aliphatic ketones gave five- and six-membered cyclized products stereospecifically. When the same reactions were carried out with SmI₂, only a five-membered cyclized product was formed as the single stereoisomer different from that obtained by the electroreduction. The cyclized products were stereospecifically transformed to the corresponding deoxygenated compounds by reduction with Et₃SiH-BF₃·Et₂O. Similarly, the electroreductive intramolecular coupling of barbituric acids with O-methyl oximes gave five- and six-membered cyclized products. The DFT calculations suggested that the electroreductive intramolecular coupling proceeds through the protonated radical generated by one-electron transfer and subsequent protonation to the barbituric acid moiety.

Full text of DOI:10.1016/j.tetlet.2016.03.035

Accepted Manuscript
Stereoselective intramolecular coupling of barbituric acids with aliphatic ke-
tones and O-methyl oximes by electroreduction: radical cyclization mechanism
supported by DFT study
Naoki Kise, Takashi Tuji, Toshihiko Sakurai
PII:
S0040-4039(16)30257-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.035
TETL 47423
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
7 January 2016
8 March 2016
11 March 2016
Please cite this article as: Kise, N., Tuji, T., Sakurai, T., Stereoselective intramolecular coupling of barbituric acids
with aliphatic ketones and O-methyl oximes by electroreduction: radical cyclization mechanism supported by DFT
study, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.035
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Stereoselective intramolecular coupling of
barbituric acids with aliphatic ketones and
O-methyl oximes by electroreduction:
radical cyclization mechanism supported by
DFT study
Leave this area blank for abstract info.
Naoki Kise,* Takashi Tuji, Toshihiko Sakurai

1
Tetrahedron Letters
Stereoselective intramolecular coupling of barbituric acids with aliphatic ketones
and O-methyl oximes by electroreduction: radical cyclization mechanism
supported by DFT study
Naoki Kise,* Takashi Tuji, and Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori, University, 4-101, Koyama-cho Minami, Tottori 680-8552, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The electroreductive intramolecular coupling of barbituric acids with aliphatic ketones gave
five- and six-membered cyclized products stereospecifically. When the same reactions were
carried out with SmI2, only five-membered cyclized product was formed as the single
stereoisomer different from that obtained by the electroreduction. The cyclized products were
stereospecifically transformed to the corresponding deoxygenated compounds by reduction with
Et3SiH-BF3•Et2O. Similarly, the electroreductive intramolecular coupling of barbituric acids
with O-methyl oximes gave five- and six-membered cyclized products. The DFT calculations
suggested that the electroreductive intramolecular coupling proceeds through the protonated
radical generated by one-electron transfer and subsequent protonation to the barbituric acid
moiety.
Available online
Keywords:
Electroreduction
Reductive cyclization
Samarium iodide
Barbituric acids
Bicyclic uracils.
2009 Elsevier Ltd. All rights reserved.
Reductive intramolecular coupling of imides with unsaturated
functional groups is a useful method for the construction of
azabicyclo[n.m.0] skeletons.1,2 For this purpose, we have already
disclosed that the intramolecular coupling of aliphatic imides
with ketones, O-methyl oximes,3 and -unsaturated carbonyl
compounds,4 and that of aromatic imides with ketones,
aldehydes,5 and -unsaturated esters6 are realized by
electroreduction (Scheme 1). In this context, we report herein
the electroreductive intramolecular coupling of barbituric acids
with aliphatic ketones (Scheme 2). It is noted that the five- and
six-membered cyclized products were obtained as single
cis,trans-stereoisomers of the possible four stereoisomers by the
electroreduction of 5-(oxoalkyl)barbituric acids. We also tried
the same reactions with SmI2 as a reducing agent, since the
reductive intramolecular coupling of barbituric acids with
alkenes and alkynes with SmI2 has been recently reported.7 Only
five-membered cyclized product was formed as a single cis,cis-
stereoisomer (Scheme 2). The bridge-head hydroxy groups of
these cyclized N,O-acetals were readily deoxygenated by
treatment with Et3SiH-BF3•Et2O8 stereospecifically. In addition,
we found that the reductive intramolecular coupling of barbituric
acids with O-methyl oximes were effected by the
electroreduction of 5-(methoxyimino)barbituric acids (Scheme
3). These reactions are promising for the synthesis of a new class
of bicyclic uracil derivatives.9-11 Moreover, we investigated the
reaction mechanism of the reductive coupling by the
computational method. The DFT calculations suggested that the
reductive cyclization proceeds through the protonated radical
generated by one-electron transfer and subsequent inter- or
intramolecular protonation to the barbituric acid moiety in the
substrate.
Scheme 1. Our already reported works: Electroreductive
intramolecular coupling of aliphatic and aromatic imides with
ketones, O-methyloximes, and aldehydes.
Scheme 2. Reductive intramolecular coupling of barbituric
acids with ketones by electroreduction or SmI2 and following
deoxygenation of the cyclized products.

2
Tetrahedron
determined by X-ray crystallographic analysis and those of 6b
(4a,7a-cis and 7,7a-trans) and 7 (4a,8a-trans and 8,8a-trans)
were assumed by 2D-NMR (COSY and NOESY) analysis. The
stereospecificity in the deoxygenation of 2a,b and 4 can be
explained as shown in Scheme 7. Hydride migration from
Et3SiH to iminium ion intermediate occurs exclusively from the
same side as the neighboring hydroxy group owing to the
chelation of Et3SiH to the hydroxy oxygen atom.
Scheme 3. Electroreductive intramolecular coupling of
barbituric acids with O-methyl oximes.
The
electroreduction
of
1,3,5-trimethyl-5-(3-
oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (1a) was carried
out using a Pb cathode in i-PrOH according to our reported
method3 (Table 1, run 1).12 Although a five-membered cyclized
product 2a was obtained as a single stereoisomer (4a,7a-cis and
7,7a-trans)
in
12%
yield,
1,3,5-trimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (3) was formed as a major product (47%)
by retro-Michael reaction of 1a.13 Fortunately, the use of
acetonitrile as a solvent gave 2a in 60% yield with a small
amount (9%) of 3 (run 2). Other cathode materials brought about
decreasing of the yield of 2a (runs 3-5). Particularly in the case
of Pt cathode, the reduction did not proceed effectively and a
significant amount (>50%) of 1a was recovered (run 5).
Similarly, the electroreduction of 1,3,5-trimethyl-5-(4-
Scheme 5. Reduction of 1a,b with SmI2.
oxopentyl)pyrimidine-2,4,6(1H,3H,5H)-trione
(1b)
stereospecifically gave six-membered cyclized product 4 (4a,8a-
cis and 8,8a-trans) in 64% yield under the same conditions as run
2 in Table 1 (Scheme 4). Incidentally, the results of the reduction
of 1a and 1b with SmI2 in THF were shown in Scheme 5. From
1a, a five-membered cyclized product 2b (4a,7a-cis and 7,7a-cis)
was obtained predominantly in 82% yield. Unfortunately, the
stereoisomer of 4 could not be obtained by the reduction of 1b;
pinacol 5 was the only product. The stereostructures of 2a,b and
4
were confirmed by X-ray crystallographic analysis
(Supplementary data).
Table 1
Electroreduction of 1a
Scheme 6. Reduction of 2a,b and 4 with Et3SiH/BF3•Et2O.
run
Solvent
Cathode
% yielda of 2a
3
1
2
3
4
5
i-PrOH
CH3CN
CH3CN
CH3CN
CH3CN
Pb
Pb
Sn
Zn
Pt
12
60
53
49
15
47
9
Scheme 7. Presumed reaction mechanism of stereospecific
reduction of 2a,b to 6a,b.
13
8
Next, the electroreduction of 3-(1,3,5-trimethyl-2,4,6-
trioxohexahydropyrimidin-5-yl)propanal and butanal O-methyl
oximes (8a,b) was also carried out under the same conditions as
run 2 in Table 1 (Scheme 8). Five-membered cyclized product 9
(76%) was obtained from 8a as a single stereoisomer and its
stereoconfiguration was confirmed to be 4a,7a-cis and 7,7a-trans
by X-ray crystallography. On the other hand, six-membered
cyclized product 10 (62%) was produced from 8b as a mixture of
two diastereomers (60:40 dr). Although the reduction of 9 with
Et3SiH/BF3•Et2O as described above resulted in a complex
mixture, that of 10 afforded a mixture of three stereoisomers of
8a-deoxygenated product 11 (Scheme 9).
9
aIsolated yields.
Scheme 4. Electroreduction of 1b.
The cyclized products 2a,b and 4 could stereospecifically be
reduced to 7a- and 8a-deoxygenated analogs 6a,b and 7,
respectively, by treatment with Et3SiH-BF3•Et2O (Scheme 6).
The stereostructure of 6a (4a,7a-trans and 7,7a-trans) was

3
the intramolecular acetyl group to give radical enolate anion
RE-1a (path b). Radical cyclization of RE-1a is supposed to be
more rapid than that of PR-1a, since radical attack to enolate
anion is, in general, more favorable than that to keto carbonyl
group. The trans-stereospecificity is also explained by this rapid
cyclization of RE-1a. Following one-electron transfer and
protonation furnish 2a. So far, path b seems more likely than
path a. On the other hand, the reductive coupling of 1a with
SmI2 affords 7,7a-cis-cyclized product 2b predominantly
probably due to the formation of Sm-chelated transition state as
shown in Scheme 11.
Scheme 8. Electroreduction of 8a,b.
In conclusion, the electroreduction of 5-(oxoalkyl)barbituric
acids 1a,b gave five- and six-membered cyclized products as
single cis,trans-stereoisomers 2a and 4.
The reductive
cyclization of 1a with SmI2 produced cis,cis-stereoisomer 2b
predominantly. The bicyclic N,O-acetals 2a,b and 4 were
stereospecifically deoxygenated to 6a,b and 7, respectively, by
treatment of Et3SiH-BF3•Et2O. The electroreduction of 5-
(methoxyiminoalkyl)barbituric acids 8a,b afforded five- and six-
membered cyclized products 9 and 10. The DFT calculations for
the transition states of the reductive cyclization of 1a suggested
that the cyclization proceeds through the protonated radical PR-
1a or its enolate anion RE-1a generated by one-electron transfer
to 1a and subsequent inter- or intramolecular protonation.
Scheme 9. Reduction of 10 with Et3SiH/BF3•Et2O.
The cyclic voltammograms of 1a and 1,3,5,5-
tetramethylpyrimidine-2,4,6(1H,3H,5H)- trione (12) in 0.03 M
Bu4NClO4/DMF on a Pb cathode showed a first reduction peak at
-2.30 and -2.20 V vs SCE, respectively. In contrast, aliphatic
ketones gave no reduction peak from 0 to -2.50 V vs SCE. These
results suggest that the electroreductive coupling of 1a was
initiated by the electron transfer to the N,N-dimethylbarbituric
acid moiety in 1a. The DFT calculations of radical anion RA-1a
generated by the one-electron transfer to 1a at the B3LYP/6-
311+G(2d,p) level using the IEFPCM model in acetonitrile also
support this assumption. As shown in Table 2, the C4 and C6
carbons in RA-1a possess high spin density. In our previous
reports, the electroreductive couplings in the absence of TMSCl
are supposed to proceed through the addition of radical anions,3
whereas those in the presence of TMSCl are assumed to be the
nucleophilic addition of O-trimethylsilylated carbanions.4-6
Therefore, we tried to search for the transition states of the
cyclization of RA-1a by the DFT calculations. However this
attempt resulted in failure and, moreover, it was found that even
the optimization of cyclized radical anion trans-CRA converged
with the ring-opened radical RA-1a. These results show that
RA-1a is not the intermediate for the electroreductive cyclization
of 1a. Thus, we calculated the transition states for the cyclization
of protonated radical PR-1a formed by the protonation from
electrolyte to RA-1a. Two transition states trans- and cis-TS
were provided by the DFT method at the same level as above.
As exhibited in Figure 1, cis-cyclization seems to be unfavorable
due to the electronic repulsion between two negative oxygen
atoms. In fact, the calculation results show that trans-TS is
lower in energy than cis-TS (1.71 kcal/mol corresponding to
94.4:5.6 dr). Hence, the presumed reaction mechanism of the
electroreductive coupling of 1a to 2a is illustrated in Scheme 10.
Protonated radical PR-1a produced by one-electron transfer to 1a
and subsequent protonation cyclizes through transition state
trans-TS to give cyclized radical trans-CR. Following one-
electron transfer and protonation to the resulted anion produce
the 7,7a-trans-cyclized product 2a (path a). Alternatively, the
protonation to RA-1a is caused by the proton abstraction from
Table 2.
Spin densities and charges in RA-1a calculated at the
B3LYP/6-311+G(2d,p) level using the IEFPCM model in
acetonitrile.a
atom
C1
spin densityb
0.005227
0.197295
0.005596
0.252735
-0.051001
0.258803
0.018228
0.042636
0.001543
0.033708
0.004231
0.110745
0.139876
0.137561
0.018091
-0.081472
-0.084582
chargec
0.171278
0.514036
0.186384
0.233634
0.431209
0.133272
-0.162261
-0.007662
0.059147
0.367047
-0.056763
-0.698114
-0.676423
-0.653235
-0.533248
-0.158197
-0.150105
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
O1
O2
O3
O4
N1
N2
a Calculated by the Mulliken Population analysis.
b The high values are in bold face.
c Atomic charges with hydrogens summed into heavy atoms.

4
Tetrahedron
Supplementary data
Supplementary data (Experimental procedures, 1H and
13CNMR data, DFT calculation data, X-ray crystallographic data,
and CV data) associated with this article can be found, in the
online version, at http://dx.doi.org/
References and notes
1.
For recent reviews on the reductive cross-coupling of carbonyl
compounds with SmI2, see: (a) Beemelmanns, C.; Ressig, H.-U.
Pure Appl. Chem. 2011, 83, 507. (b) Harb, H. Y.; Proctor, D. J.
Synlett, 2012, 23, 6. (c) Tori, M.; Sono, M. Heterocycles 2014, 89,
1369. (d) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D.-J.
Chem. Rev. 2014, 114, 5959. (e) Just-Baringo, X.; Procter, D. J.
Acc. Chem. Res. 2015, 48, 1263. (f) With low-valent titanium, see:
Streuff, J. Chem. Rec. 2014, 14, 1100.
Figure 1. Optimized structures and relative energies of cis-TS and trans-
TS calculated at the B3LYP/6-311+G(2d,p) level using the IEFPCM model
2.
For recent reviews on the synthesis of azabicyclo[n.m.0]
compounds, see: (a) Lazzaroni, R.; Settambolo, R. Chirality 2011,
23, 730. (b) Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P.
Pure Appl. Chem. 2012, 84, 1633. (c) Pyne, S. G.; Davis, A. S.;
Ritthiwigrom, T.; Au, C. W. G.; Savaspun, K.; Wotherspoon, M.
Pure Appl. Chem. 2013, 85, 1215. (d) Brambilla, M.; Davies, S.
G.; Fletcher, A. M.; Thomson, J. E. Tetrahedron: Asym. 2014, 25,
387. (e) Burtoloso, A. C. B.; Dias, R. M. P.; Bernardim, B. Acc.
Chem. Res. 2015, 48, 921.
in acetonitrile.
3.
Kise, N.; Fukazawa, K.; Sakurai. T. Tetrahedron Lett. 2010, 51,
5767.
4.
5.
Kise, N.; Inoue, Y.; Sakurai, T. Tetrahedron Lett. 2013, 54, 3281.
(a) Kise, N.; Sakurai. T. Tetrahedron Lett. 2010, 51, 70. (b) Kise,
N.; Isemoto, S.; Sakurai, T. J. Org. Chem. 2011, 76, 9856.
Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett. 2009, 11, 4902.
Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D. J.
Angew. Chem. Int. Ed. 2013, 52, 12559.
6.
7.
8.
9.
Szostak, M.; Sautier, B.; Procter, D. J.; Org. Lett. 2014, 16, 452.
For recent reviews on the synthesis of substituted uracils, see: (a)
Novikov, M. S.; Geisman, A. N. Chem. Heterocyclic Comp. 2014,
49, 1426. (b) Pałasz, A.; Cież, D. Eur. J. Med. Chem. 2015, 97,
582.
10. For recent reports on the synthesis of substituted uracils, see: (a)
Pięta, M.; Kędzia, J.; Janecki, T. Tetrahedron Lett. 2015, 56,
1891. (b) Kianmehr, E.; Torabi, M.; Khalkhali, M. R.; Faghih, N.;
Khan, K. M. Eur. J. Org. Chem. 2015, 2796. (c) Saftić, D.;
Vianello, R.; Žinić , B. Eur. J. Org. Chem. 2015, 7695. (d)
Perrone, S.; Capua, M.; Salomone, A.; Troisi, L. J. Org. Chem.
2015, 80, 8189. (e) Pałasz, A.; Cież, D.; Musielak, B.;
Kalinowska-Tłuścik, J. Tetrahedron 2015, 71, 8911. (f) Úr, G.;
Kálai, T.; Hideg, K. Tetrahedron Lett. 2016, 57, 778.
11. We recently reported the electroreductive intermolecular coupling
of uracils with aromatic ketones. see: Kise, N.; Miyamoto, H.;
Hamada, Y.; Sakurai. T. Tetrahedron Lett. 2015, 56, 4599.
12. All the products were determined by spectroscopic analysis. See,
Supplementary data.
13. Starting material 1a was prepared by Michael addition of 3 to
methyl vinyl ketone.
Scheme 10. Presumed reaction mechanism of
electroreductive cyclization of 1a.
Scheme 11. Presumed reaction mechanism of reductive
cyclization of 1a with SmI2.

5
Highlights
► Electroreductive cyclization of barbituric acids with aliphatic ketones and O-methyl oximes.
► Stereoselective synthesis of five- and six-membered cyclized products.
► Stereoselective reduction of the cyclized products with Et3SiH-BF3•Et2O.
► Radical cyclization mechanism suggested by DFT study.