An electrochemical interpretation of the mechanism of the chemical decarboxylation of 6-carboxyperhydropyrimidin-4-ones

Article abstract of DOI:10.1016/j.tet.2004.02.052

The present work analyzes the anodic oxidation of the tetrabutylammonium salt of 1-benzoyl-2(S)-tert-butyl-6(S)-carboxyperhydropyrimidin-4-one, which is a useful starting material in the synthesis of enantiopure α-substituted β-amino acids. It was demonstrated that in CH₂Cl₂ solvent, the anodic oxidation reaction results in fast and complete decarboxylation, followed by proton elimination thereby leading to the same product of chemical (diacetoxyiodobenzene) oxidative decarboxylation. The electrochemical mechanism involves two electron transfer steps, but appears as a monoelectronic process owing to the release of one proton from the key acyliminium carbocation intermediate. The relative stability of this intermediate and the suppression of any solvolysis reaction in CH ₂Cl₂ allow for the detection of the acyliminium intermediate by means of cyclic voltammetry experiments. By contrast, in the presence of a nucleophilic solvent such as acetonitrile, the acyliminium intermediate is trapped in a typical Ritter reaction.

Full text of DOI:10.1016/j.tet.2004.02.052

Tetrahedron 60 (2004) 3605–3610
An electrochemical interpretation of the mechanism
of the chemical decarboxylation
of 6-carboxyperhydropyrimidin-4-ones
†
Mart ´ı n A. Iglesias-Arteaga, Eusebio Juaristi and Felipe J. Gonz a´ lez
*
Departamento de Qu ´ı mica, Centro de Investigaci o´ n y de Estudios Avanzados del Instituto Polit e´ cnico Nacional,
Apartado Postal 14-740, 07000-M e´ xico, D.F., Mexico
Received 26 January 2004; revised 25 February 2004; accepted 25 February 2004
Abstract—The present work analyzes the anodic oxidation of the tetrabutylammonium salt of 1-benzoyl-2(S)-tert-butyl-6(S)-
carboxyperhydropyrimidin-4-one, which is a useful starting material in the synthesis of enantiopure a-substituted b-amino acids. It was
demonstrated that in CH Cl solvent, the anodic oxidation reaction results in fast and complete decarboxylation, followed by proton
2 2
elimination thereby leading to the same product of chemical (diacetoxyiodobenzene) oxidative decarboxylation. The electrochemical
mechanism involves two electron transfer steps, but appears as a monoelectronic process owing to the release of one proton from the key
2 2
acyliminium carbocation intermediate. The relative stability of this intermediate and the suppression of any solvolysis reaction in CH Cl
allow for the detection of the acyliminium intermediate by means of cyclic voltammetry experiments. By contrast, in the presence of a
nucleophilic solvent such as acetonitrile, the acyliminium intermediate is trapped in a typical Ritter reaction.
q 2004 Published by Elsevier Ltd.
4
,5
1
. Introduction
enantioselective synthesis of a-substituted b-amino acids,
was treated with the DIB/I /TMSCl/NaI reagent mixture,
heterocyclic enone 2 was formed in good yield (Eq. 3).
2
6
,7
Diacetoxyiodobenzene (DIB) is now a well recognized
reagent with numerous applications in synthetic organic
chemistry. Particularly useful is the employment of
diacetoxyiodobenzene/iodine as an effective mixture of
reagents in the oxidative decarboxylation of carboxylic
1
2
acids (Eq. 1).
ð3Þ
DIB=I
–CO2
R-CO H ꢀꢀꢀ ! R-CO I ꢀꢀꢀ ! R-I
ð1Þ
2
2
In this context, Su a´ rez and co-workers have recently
demonstrated that DIB-mediated radical decarboxylation–
oxidation of a-amino acids can be successfully comple-
mented by nucleophilic trapping of the generated iminium
The formation of enone 2 was accounted for in terms of a
three-step radical decarboxylation–oxidation–b-elimin-
ation sequence, as outlined in Scheme 1.
3
6
ion (Eq. 2).
The proposal advanced in Scheme 1 is based on reasonable
2
,3
ð2Þ
mechanistic considerations, and it is supported by recent
reports concerning the anodic oxidation of benzylic and
8
–11
aliphatic carboxylic acid salts,
indicating the inter-
By contrast, when 1-benzoyl-2(S)-tert-butyl-6(S)-carboxy-
perhydropyrimidin-4-one, 1, a useful intermediate for the
vention of both radical and carbocation intermediates
(Scheme 2).
Keywords: Oxidative decarboxylation; Non-Kolbe electrochemical
reaction; Ritter reaction; Pyrimidinone carboxylic acid.
The present report describes the results of a voltammetric
study of the decarboxylation process for the tetrabutyl-
ammonium salt of the carboxylic acid 1. The main goal in
this study was to establish the participation of radical 3
and/or iminium ion 4 as intermediates in the formation of
enone 2.
*
Corresponding author. Tel.: þ52-55-57473722; fax: þ52-55-57477132;
e-mail address: fgonzale@mail.cinvestav.mx
†
Present address: Departamento de Qu ´ı mica Org a´ nica, Facultad de
Qu ´ı mica, Universidad Nacional Aut o´ noma de M e´ xico, Ciudad
Universitaria, 04510 M e´ xico, D.F., M e´ xico.
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.02.052

3606
M. A. Iglesias-Arteaga et al. / Tetrahedron 60 (2004) 3605–3610
Scheme 1. Proposed mechanism for the DIB-induced decarboxylation of
1
6
.
Figure 1. Cyclic voltammetry of (a) 0.82 mM of tetrabutylammonium
carboxylate 7 and (b) 1.63 mM of compound 2 in CH Cl
þ0.2 M
2
2
2
1
4 6
n-Bu NPF on glassy carbon electrode (3 mm f) at 0.1 V s .
electrodes. Two chemically irreversible waves are observed,
corresponding to the oxidation of the starting salt at
þ
E ¼1.07 V/Ag/Ag and to the oxidation of the electrolysis
p
þ
initial anodic oxidation corresponds to enone 2 was
product at E ¼1.88 V/Ag/Ag . That the product of the
p
demonstrated by separate electrochemical oxidation of this
4
b,h,6
previously reported
heterocyclic enone (Fig. 1(b)).
8
,9a
Based on literature precedent, it can be proposed that
one-electron anodic oxidation of carboxylate 7 affords the
8
–11
Scheme 2. Electrochemical decarboxylation of carboxylate salts.
1
4,15
O-radical 8 that immediately loses CO
9
C-radical 3 (Scheme 3).
to give the
2
b
2
. Results and discussion
2.1. Electrochemical oxidation of the
tetrabutylammonium salt of carboxylic acid 1 in CH Cl2
2
1
2
Several years ago, Konopelski and co-workers reported
the electrolysis of pyrimidinone carboxylic acid 5 in
methanol, at very high potential conditions. The non-
Kolbe type product 6 obtained, was the result of
nucleophilic solvent (methanol) addition to the inter-
Scheme 3. Mechanistic pathway for the one-electron oxidative decarbox-
ylation of carboxylate 7 to give C-radical 3.
1
3
mediate (Eq. 4).
Owing to the anticipated lability of the resulting aminoketal
9
, no attempts to trap this intermediate were made.
2.2. Electrochemical oxidation of tetrabutylammonium
carboxylate 7 in CH Cl and CH CN
ð4Þ
2
2
3
By comparison with data reported for the oxidation
1
6,17
potentials of common radicals,
the one assigned to the
Nevertheless, recent developments in the electrochemical
oxidative decarboxylation protocol have demonstrated that
carboxylic acid salts decarboxylate under milder
electrolytic conditions, relative to those required with the
corresponding carboxylic acids. The use of tetrabutyl-
ammonium carboxylate salts has proven particularly
oxidation peak potential of carboxylate 7 is substantially
higher (.500 mV), and this observation can be interpreted
in terms of a rapid oxidation of radical 3 to delocalized
carbocation 4. Indeed, the reversible wave observed at
0.227 V/Ag/Ag in Figure 2(a), which shows the
voltammetric behavior of 7 at the more rapid scan rate of
þ
8
–11
21
z
þ
convenient.
10 V s , may correspond to the redox couple R /R .
Generally, the reactivity of such intermediates is so high
that their voltammetric detection is difficult even at higher
scan rates. However, the participation of the electron pair of
the vicinal nitrogen contributes to the greater stability of
Figure 1(a) shows the voltammetric behavior of the
oxidative electrochemical process of the tetrabutyl-
ammonium carboxylate 7 in CH Cl , using glassy carbon
2
2

M. A. Iglesias-Arteaga et al. / Tetrahedron 60 (2004) 3605–3610
3607
Figure 2. Cyclic voltammetry of carboxylate 7 on glassy carbon electrode
2
1
(
(
3 mm f) at 10 V s . (a) 1.13 mM in CH
b) 1.69 mM in CH NPF
CNþ0.2 M n-Bu
2
Cl
2
þ0.2 M n-Bu
4 6
NPF .
Figure 3. Cyclic voltammetry of 1.13 mM of carboxylate salt 7 in
3
4
6
.
CH
.1 V s at different concentrations of CH
c) 3.8 mM.
2
Cl
2
þ0.2 M n-Bu
4
NPF
6
on glassy carbon electrode (3 mm f) at
2
1
0
(
3
CN (a) 0 mM, (b) 1.9 mM,
acyliminium cation 4, allowing for its detection. The fact
that the addition of acetonitrile causes the disappearance of
this reversible signal (Fig. 2(b)), suggests that this
acyliminium carbocation is trapped in a Ritter type
particular the formation of carboxylic acid 1 during the
proton-elimination step (4!2) are supported by the results
of a constant potential electrolysis experiment. The imposed
1
8
solvolytic reaction to give intermediate 9 (Scheme 4).
potential of electrolysis was selected to be 150 mV more
anodic than the peak potential value measured at 0.1 V s2
1
.
Figure 4(a) shows the voltammogram of 7 before the
constant potential electrolysis. Following complete
electrolysis (Fig. 4(b)), the signal corresponding to the
oxidation of enone 2 is the only one observed. Addition of
tetrabutylammonium hydroxide produces the recovery of
the oxidation signal of the carboxylate 7 now with half of
the initial current intensity (Fig. 4(c)). The value of the total
charge consumed in the electrolysis corresponds to an
2
apparent electron number close to one (napp¼0.96 e ),
which indicates that the mechanism is globally mono-
electronic. This is consistent with the global stoichiometry
derived from the sequence of reactions proposed here;
although the mechanism comprises the transference of two
electrons, it appears monoelectronic due to the proton
elimination step, which results in the neutralization of half
the initial concentration of carboxylate 7.
Scheme 4. Radical oxidation and carbocation nucleophilic trapping.
Furthermore, cyclic voltammograms in CH Cl conducted
2
2
in the presence of increasing amounts of acetonitrile
Fig. 3(a)–(c)) show that the concentration of the reaction
2.4. Electrochemical evidence for intermolecular
hydrogen bonding
(
product decreases with the increase of the concentration of
acetonitrile, suggesting that the product of the electrolysis of
the carboxylate salt 7 in CH Cl is indeed a substrate
As it can be noticed in Figure 4(b), following complete
electrolysis, the signal corresponding to the enone 2 is
slightly shifted toward more anodic potential, taking as
reference the corresponding signal obtained before the
electrolysis (Fig. 4(a)). Furthermore, the peak potential of
the regenerated carboxylate 7 shows the same tendency.
2
2
amenable to nucleophilic trapping.
.3. Constant potential electrolysis experiment
The previous experiments indicate that in pure CH Cl the
2
2
2
solvolysis of the cation 4 is precluded. Therefore, the
efficient formation of enone 2 in these conditions (Section
In order to explain both peak displacements, additional
experiments were carried out. Considering that after the
total electrolysis of carboxylate 7 both the carboxylic acid 1
and enone 2 coexist, the oxidation process of 2 in the
presence of the carboxylic acid 1 was conducted. Consistent
with the electrolysis experiment, it is observed that the
oxidation wave of 2 is displaced toward more anodic
2
.1) may be interpreted in terms of intermolecular transfer
of a proton at C(5) in iminium ion 4 to carboxylate 7
Scheme 5).
(
The mechanistic proposal advanced in Scheme 5, and in

3608
M. A. Iglesias-Arteaga et al. / Tetrahedron 60 (2004) 3605–3610
Scheme 5. Mechanistic hypothesis for the in situ formation of enone 2 during anodic oxidation of carboxylate salt 7.
potentials. This result can be explained in terms of
intermolecular association between both products of
reaction, through hydrogen bond formation. Consideration
of the structures of 1 and 2, suggests that an interaction
could be established between the carbonyl oxygen of ring
amide 2 and the hydroxyl group of 1 (see Scheme 6(a)). In
this interaction, it is expected that a decrease of the partial
negative charge on the carbonyl of 2 results in its more
difficult oxidation.
NH group of 2 (see Scheme 6(b)), resulting in its more
difficult oxidation.
3. Conclusions
The efficient decarboxylation of pyrimidinone carboxylic
acid 1 was achieved under mild oxidative electrolytic
conditions via the tetrabutylammonium carboxylate 7, in the
non-nucleophilic solvent CH Cl .
By the same token, the neutralization of the carboxylic acid
1
2
2
obtained in the electrolysis experiment (Fig. 4(c)) results
in the coexistence of the carboxylate 7 and the enone 2.
Thus, the oxidation process of 7 in the presence of the enone
The accumulated evidence supports an initial one-electron
loss, followed by rapid decarboxylation, so that carboxylate
7 is converted to radical 3. A second electron transfer
produces the nitrogen-stabilized cationic species 4 that
eliminates a b-proton by intermolecular proton transfer to
the available carboxylate 7. Thus, enone 2 is produced in a
process that involves two electron-transfer steps that
appears, nevertheless, monoelectronic owing to such release
of a proton from acyliminium cation 4.
2
was carried out. The shift of the oxidation signal of the
carboxylate 7 toward more anodic potentials (35 mV), can
be attributed to hydrogen bond interaction between the NH
group of 2 and the negative oxygen of 7. Accordingly, the
negative charge of the carboxylate 7 is stabilized with the
The suppression of any solvolysis reaction in CH Cl
2
2
solvent allows for the detection of cationic intermediate 4 in
the cyclic voltammetry experiments, at 10 V s2 . By
contrast, in the presence of a nucleophilic solvent such as
1
Figure 4. Cyclic voltammetry of 1.0 mM of tetrabutylammonium
carboxylate 7 in CH
(
2
Cl
2
þ0.2 M n-Bu
4
NPF
3 mm f) at 0.1 V s . (a) Before the electrolysis. (b) After complete
electrolysis. (c) After complete electrolysis and following addition of
.5 mM n-Bu NOH.
6
on glassy carbon electrode
2
1
Scheme 6. Intermolecular hydrogen bond associations (a) between 1 and
enone 2 and (b) between carboxylate 7 and enone 2.
0
4

M. A. Iglesias-Arteaga et al. / Tetrahedron 60 (2004) 3605–3610
3609
acetonitrile, intermediate 4 is trapped in a typical Ritter
reaction.
244. (b) Prakash, O.; Singh, P. S. Aldrichimica Acta 1994, 27,
15 and references cited therein.
2
. (a) Concepci o´ n, J. I.; Francisco, C. G.; Freire, R.; Hern a´ ndez,
R.; Salazar, J. A.; Su a´ rez, E. J. Org. Chem. 1986, 51, 402.
(b) Francisco, C. G.; Freire, R.; Rodr ´ı guez, M. S.; Su a´ rez, E.
Tetrahedron Lett. 1995, 36, 2141. (c) Boto, A.; Hern a´ ndez, R.;
Su a´ rez, E. Tetrahedron Lett. 1999, 40, 5945. (d) Lee, S.;
Fuchs, P. L. Org. Lett. 2002, 4, 317.
The present report shows the great potential that electro-
chemical techniques have in the study or verification of
organic reaction mechanisms.
3
4
. Boto, A.; Hern a´ ndez, R.; Su a´ rez, E. J. Org. Chem. 2000, 65,
4
. Experimental
4
930.
. (a) Chu, K. S.; Negrete, G. R.; Konopelski, J. P. J. Org. Chem.
991, 56, 5196. (b) Juaristi, E.; Quintana, D. Tetrahedron:
CH Cl and CH CN (spectrophotometric grade) were used
2
as solvents. Tetrabutylammonium hexafluorophosphate
99%) was the supporting electrolyte. The tetrabutyl-
2
3
1
Asymmetry 1992, 3, 723. (c) Juaristi, E.; Quintana, D.;
Balderas, M.; Garc ´ı a-P e´ rez, E. Tetrahedron: Asymmetry
(
ammonium pyrimidine-carboxylate 7 was prepared by
mixing stoichiometric amounts of the corresponding
carboxylic acid and tetrabutylammonium hydroxide in
anhydrous methanol, which was then removed under
reduced pressure. The obtained glassy solid was dried in a
vacuum pump for several hours to provide the solid salt. An
authentic sample of the expected decarboxylation product,
enone 2, was obtained following our recently reported
1
996, 7, 2233. (d) Juaristi, E.; L o´ pez-Ruiz, H.; Madrigal, D.;
Ram ´ı rez-Quir o´ s, Y.; Escalante, J. J. Org. Chem. 1998, 63,
706. (e) Juaristi, E.; Balderas, M.; Ram ´ı rez-Quir o´ s, Y.
4
Tetrahedron: Asymmetry 1998, 9, 3881. (f) Juaristi, E.;
Balderas, M.; L o´ pez-Ruiz, H.; Jim e´ nez-P e´ rez, V. M.; Kaiser-
Carril, M. L.; Ram ´ı rez-Quir o´ s, Y. Tetrahedron: Asymmetry
1
999, 10, 3493. (g) Seebach, D.; Boog, A.; Schweizer, W. B.
Eur. J. Org. Chem. 1999, 335. (h) Juaristi, E. In 1-Benzoyl-
(S)-tert-butyl-3-methylperhydropyrimidin-4-one; Paquette,
6
,7
tandem chemical decarboxylation protocol.
2
L. A., Rigby, J. H., Roush, W. R., Wipf, P., Eds.; 2002;
e-EROS; http://www3.interscience.wiley.com/reference.html.
The electrochemical apparatus consisted of a potentiostat
DEA-332 (Radiometer, Copenhagen) with positive feed-
back compensation. A conventional three-electrode cell was
used to carry out the voltammetric experiments. The work
electrode was a 3 mm diameter glassy carbon disk. This
electrode was carefully polished with 1 mm alumina powder
and ultrasonically rinsed with ethanol before each run. The
counter electrode was a platinum screen and the reference
(
i) Juaristi, E. 1-Benzoyl-2(S)-tert-butyl-3-methyl-perhydro-
pyrimidin-4-one. In Handbook of Reagents for Organic
Synthesis. Chiral Reagents for Asymmetric Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 2003; pp 53–56.
. For general reviews on the enantioselective synthesis of
b-amino acids, see: (a) Juaristi, E.; Quintana, D.; Escalante, J.
Aldrichimica Acta 1994, 27, 3. (b) Cole, D. C. Tetrahedron
5
þ
electrode was an aqueous saturated Ag/Ag electrode. A
1
994, 50, 9517. (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev.
996, 25, 117. (d) In Enantioselective synthesis of b-amino
salt bridge, containing 0.2 M n-Bu NPF þCH Cl , con-
4
6
2
2
1
nected the cell with the reference electrode.
acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
e) Juaristi, E.; L o´ pez-Ru ´ı z, H. Curr. Med. Chem. 1999, 6,
83. (f) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(
4
.1. Voltammetric and electrolysis experiments
9
6
7
8
9
. Iglesias-Arteaga, M. A.; Avila-Ort ´ı z, C. G.; Juaristi, E.
Tetrahedron Lett. 2002, 43, 5297.
Cyclic voltammetry experiments were carried out by using
a carboxylate solution which was deoxygenated by dry
argon bubbling. After this, an argon atmosphere was
maintained over the solutions during each experimental
run. All electrochemical experiments were performed at
room temperature. The electrolysis of the carboxylate 7
. See also: Iglesias-Arteaga, M. A.; Castellanos, E.; Juaristi, E.
Tetrahedron: Asymmetry 2003, 14, 577.
. Isse, A. A.; Gennaro, A.; Maran, F. Acta Chem. Scand. 1999,
5
3, 1013.
. (a) Andrieux, C. P.; Gonz a´ lez, F.; Saveant, J.-M.
J. Electroanal. Chem. 2001, 498, 171. (b) An alternative
mechanism for electron transfer and bond breaking involves
the formation of a zwitterionic radical 10, which after an
intramolecular dissociative electron transfer (Ref. 9a) would
afford the C-radical 3.
(
20 mM), was carried out in a 10 mL divided cell.
The working electrode was a 5 mm diameter glassy
carbon rod. The electrolysis potential was selected to be
150 mV more positive than the peak potential of the
carboxylate 7.
Acknowledgements
We are indebted to Conacyt, M e´ xico, for financial support
via grants 33023-E and G23710-E, and for the C a´ tedra
Patrimonial de Excelencia granted to MAIA. We are also
grateful to Mar ´ı a Luisa Kaiser for technical assistance, and
to the referees for useful comments and suggestions.
This alternative mechanism may be discarded owing to the
fact that the parent amide moiety in enone 2 is more difficult to
oxidize than the carboxylate group in substrate 7, that is
approximately 800 mV more anodic. Furthermore, the transfer
coefficient (a¼0.501) obtained from the variation of the peak
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M. A. Iglesias-Arteaga et al. / Tetrahedron 60 (2004) 3605–3610
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