Electrochemical carboxylation of N-(2-bromopropionyl)-4R-phenyloxazolidin-2-one: An efficient route to unsymmetrical methylmalonic ester derivatives

Article abstract of DOI:10.1021/ol025939z

(Matrix presented) Electrochemical carboxylation of N-(2-bromopropionyl)-4R-phenyloxazolidin-2-one aimed at the synthesis and chiral resolution of unsymmetrical methylmalonic ester derivatives is described. The presence of the Evans' chiral auxiliary perm

Full text of DOI:10.1021/ol025939z

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2617-2620
Electrochemical Carboxylation of
N-(2-Bromopropionyl)-4R-
phenyloxazolidin-2-one: An Efficient
Route to Unsymmetrical Methylmalonic
Ester Derivatives
,†
,‡
Marta Feroci,* Achille Inesi,* Monica Orsini,‡ and Laura Palombi‡
Dipartimento di Ingegneria Chimica, Materiali, Materie Prime e Metallurgia,
UniVersita` “La Sapienza”, Via Castro Laurenziano, 7, I-00161 Roma, Italy,
and Dipartimento di Chimica, Ingegneria Chimica e Materiali,
UniVersita` degli Studi, I-67040, Monteluco di Roio, L'Aquila, Italy
marta.feroci@uniroma1.it
Received March 28, 2002
ABSTRACT
Electrochemical carboxylation of N-(2-bromopropionyl)-4R-phenyloxazolidin-2-one aimed at the synthesis and chiral resolution of unsymmetrical
methylmalonic ester derivatives is described. The presence of the Evans’ chiral auxiliary permits an easy resolution of the mixture of the two
diastereoisomers.
Optically active R-monoalkylmalonic derivatives are valuable
building blocks in asymmetric synthesis, providing access
to unsymmetrical 2-substituted 1,3-propandiols in an enan-
tiomerically enriched form.1,2 The common chemical ap-
proach to these chiral malonates in enantiopure form consists
of the resolution of the diastereoisomeric mixtures by means
of a chiral resolving agent (typically an optically active
alcohol1 such as menthol or 8-phenylmenthol). Menthyl and
8-phenylmenthyl half-esters of methylmalonic acid have been
obtained in 62 and 60% yields, respectively, and were
composed of the two isomers in a ∼3:2 ratio. They could
be converted into the corresponding chiral diol derivative
by reduction (after activation).1
The electrochemical methodology permits the carboxyla-
tion3 in the R-position to carbonyl groups by direct reduction
of R-haloketones in the presence of carbon dioxide4,5 (50-
57% yields in R-ketocarboxylic acids) or by direct reduction
of vinyl triflates also in the presence of carbon dioxide6,7
(28-77% yields in cyclic R-ketocarboxylic acids and 33-
67% yields in linear ones). To our knowledge, no electro-
(3) Silvestri, G. In Carbon Dioxide as a Source of Carbon; Aresta, M.,
Forti, G., Eds.; D. Reidel Publishing Company: Dordrecht, Holland, 1987;
pp 339-369.
* Corresponding authors. Phone: +39-06-49766780. Fax: +39-06-
49766749. E-mail (A.I.): inesi@ing.univaq.it.
† University of Rome.
(4) Carelli, I.; Curulli, A.; Inesi, A.; Zeuli, E. J. Chem. Res., Synop. 1988,
154-155; J. Chem. Res., Miniprint 1988, 1276-1296.
(5) Carelli, I.; Curulli, A.; Inesi, A.; Zeuli, E. J. Chem. Res., Synop. 1990,
74-75; J. Chem. Res., Miniprint 1990, 620-644.
(6) Kamekawa, H.; Senboku, H.; Tokuda, M. Tetrahedron Lett. 1998,
39, 1591-1594.
‡ University of L’Aquila.
(1) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Fukumoto, K.;
Kametani, T. J. Chem. Soc., Perkin Trans. 1 1989, 897-903.
(2) Harada, T.; Hayashiya, T.; Wada, I.; Iwa-ake, N.; Oku, A. J. Am.
Chem. Soc. 1987, 109, 527-532.
(7) Senboku, H.; Fujimura, Y.; Kamekawa, H.; Tokuda, M. Electrochim.
Acta 2000, 45, 2995-3003.
10.1021/ol025939z CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002

Table 1. Electrolysesa of Solutions of 1 under Different Experimental Conditions
products (yield, %)b
entry
anode/cathode
solvent/electrolyte
T
3
4
2a + 2b
drc
1
2
3
4
5
6
7
8
9
Mg/Pbd
Mg/Pbd
Mg/Pbd
Mg/Pb
Mg/Pbf
Mg/Pb
Mg/Pt
Mg/Ptf
Al/Pt
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
rt
33
65
72
37
32
22
30
20
22
36
15
5
62
40
55
70
36
78
27
57:43
65:35
83:17
63:37e
69:31e
59:41e
60:40e
68:32
59:41e
52:48e
-10 °C
-20 °C
-20 °C
-20 °C
-40 °C
-20 °C
-20 °C
-20 °C
-20 °C
5
53
7
22
10
10
Al/Ptf
a Compound 1 (2 F/mol), undivided cells, galvanostatic conditions (I ) 4 mA/cm2). b Yields of isolated products, calculated with respect to the starting
oxazolidinone 1. c Diastereoisomeric ratio was determined by 1H NMR. d Et3N was added to the solution prior to electrolysis. These electrolyses were
carried out under potentiostatic conditions (E ) -1.7 V vs SCE). e Starting material was recovered at the end of the electrolysis. f Et3N was added to the
solution prior to electrolysis.
chemical carboxylation of R-haloesters or amides has been
reported.
was continuously bubbling. Various experimental conditions
have been considered, and the results are reported in Table
1. All the electrolysis products are described in Figure 1.
Here we report our preliminary results for the electro-
chemical carboxylation of N-(2-bromopropionyl)-4R-phe-
nyloxazolidin-2-one aimed at the synthesis and chiral
resolution of unsymmetrical methylmalonic ester derivatives.
The subsequent selective reduction of the amidic function
in the presence of the methyl ester group, to yield the
corresponding chiral alcohol, is well described in the
literature.8
The advantage of this kind of approach is that the resolving
agent is present in the molecule prior to the introduction of
the second carbonyl group by carboxylation, so it allows the
transformation of this second function in an acid or ester in
an easy way without the side reaction of diester formation.
The starting material was N-(2-bromopropionyl)-4R-phe-
nyloxazolidin-2-one 1 (Scheme 1), both as an epimeric
Figure 1
Scheme 1
The two diastereoisomers 2a and 2b could be easily separated
by column chromatography.
The yields in carboxylated products are influenced by
various factors: electrolysis temperature (Table 1, entries
1-4 and 6), solvent system (Table 1, entries 3 and 5), and
electrode material (cathode, Table 1, entries 4 and 7; anode,
Table 1, entries 7 and 9). The higher yields in 2a + 2b (78%,
Table 1, entry 9) were obtained using aluminum as a
sacrificial anode and platinum as a cathode, in THF/Bu4-
NBF4 as a solvent-electrolyte system, at -20 °C under
galvanostatic conditions. In this case, the diastereoisomeric
ratio between the two carboxylated products was ∼3:2. If
the reaction was carried out in MeCN-Et4NClO4,10 the yields
were lower (Table 1, entries 1-3), while the dr increased
slightly with decreasing the temperature. MeCN probably
mixture and as pure diastereoisomers, and the outcome of
the reaction was the same in all cases (no memory of chirality
was evidenced).
The electrolyses9 were carried out on solutions (solvent-
supporting electrolyte) containing 1 in which carbon dioxide
(8) Tietze, F.; Schu¨nke, C. Angew. Chem., Int. Ed. Engl. 1995, 34 (16),
1731-1733.
2618
Org. Lett., Vol. 4, No. 16, 2002

Figure 3
presence of 4 among the electrolysis products is probably
due to the decomposition of the enolate ion via a ketene
pathway.12
Figure 2
When the ammonium salt was replaced by LiClO4, no
carboxylated product could be isolated from the electrolyzed
solution. Only 6% in 2a + 2b was obtained working with
divided cells in the same experimental conditions as those
of entry 9 (Table 1).
acts as a proton donor; in fact, when this solvent was used,
the yields in reduced product 3 were very high to the
detriment of those of the carboxylated products.
The role of Et3N in this reaction is not so clear: Evans11
reported that Et3N forms a kind of aggregated complex with
the enolate that derives from the reduction of the C-Br bond,
so it should enhance the diastereoselectivity of the carboxy-
lation reaction; on the other hand, the yields in 2a + 2b are
considerably lowered by the presence of the amine. The
In all cases, the more abundant diastereoisomer13 is 2a,
as demonstrated by the X-ray analysis (Figure 2). This is
probably due to the preferential “non-Evans” conformation14
(that is, the nonchelated one) of the enolate ion during the
carboxylation (Figure 3). In fact, in our experimental
conditions, the concentration of the metallic ion, which
derives from the consumption of the sacrificial anode and
could chelate both oxygen atoms, is probably too low with
respect to the concentration of the supporting electrolyte
cation R4N+, which can coordinate but not chelate both
carbonyl oxygen atoms. It is also possible that in a solvent
such as THF, the metallic cation is not free but ion-paired
with the bromide released during the electrolysis.
When the two diastereoisomeric esters (2a and 2b) were
allowed to epimerize separately (by reaction with Et3N in
CD3CN), the equilibrium ratio of 2a:2b was 2:3 in both cases,
so we can deduce that in our experimental conditions the
reaction is partially controlled by kinetic factors.
(9) General Procedure. A solution of 3-(2-bromopropionyl)-4R-phenyl-
2-oxazolidinone16 1 in 30 mL of THF-0.2 mol/L Bu4NBF4 was electrolyzed
(undivided cells, Pt or Pb cathode, Al or Mg anode, at -20 °C) under
galvanostatic conditions (I ) 4 mA/cm2) in the presence of carbon dioxide
(p ) 1 atm). After the consumption of 2 Faradays per mol of 1, the current
flow was stopped, the solvent evaporated under reduced pressure, and the
residue poured into water. This aqueous phase was extracted with diethyl
ether (3 × 30 mL), and this organic solution was worked up as usual, giving
the starting material 1, (R)-(-)-4-phenyl-3-propionyl-2-oxazolidinone 3,17
and (R)-(-)-4-phenyl-2-oxazolidinone 4, if any. The aqueous solution was
then acidified (pH ≈ 3) with dilute HCl and extracted again with ether.
This second ethereal phase was cooled at 0 °C and treated with ethereal
CH2N2.18 (CAUTION! Diazomethane is toxic and prone to cause develop-
ment of specific sensitivity; in addition, it is potentially explosive). The
usual workup gave the mixture of 2a and 2b, whose ratio was calculated
by 1H NMR. The two pure isomers were obtained after column chroma-
tography (8:2 n-hexanes-ethyl acetate as the eluent). 3-(2-Methoxycar-
bonylpropionyl)-4S-phenyl-2-oxazolidinone (Less Polar Isomer) 2a. 1H
NMR δ (CDCl3): 7.40-7.25 (m, 5H, ar), 5.46 (dd, 1H, J ) 8.9 Hz, J )
3.7 Hz, OCHH), 4.70 (t, 1H, J ) 8.9 Hz, N.-CH), 4.53 (q, 1H, J ) 7.2
Hz, CHCO2CH3), 4.29 (dd, 1H, J ) 8.9 Hz, J ) 3.7 Hz, OCHH), 3.71 (s,
3H, CO2CH3), 1.40 (d, 3H, J ) 7.2 Hz, CH3CHCO2CH3). 13C NMR δ
(CDCl3): 170.81, 169.08, 153.69, 138.80, 129.25, 128.85, 125.94, 70.19,
57.79, 52.53, 45.66, 13.19. GC-MS m/z: 277 (M+., 3%), 218 (M+ - CO2-
Any attempt to carboxylate by electrochemical means
(using electrogenerated bases) the starting material not
containing the bromine atom (i.e., N-propionyl-4R-phenyl-
oxazolidin-2-one) failed, so the use of a halogenated deriva-
tive seems necessary.15
(12) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(13) This kind of molecule exhibits a quite low kinetic acidity; they are,
in fact, quite stable to silica gel chromatography and can be isolated in
pure enantiomeric form. See: Evans, D. A.; Ennis, M. D.; Le, T. J. Am.
Chem. Soc. 1984, 106, 1154-1156.
(14) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J.
Am. Chem. Soc. 1993, 115, 2613-2621.
(15) Any attempt to obtain 2a + 2b by metalation and carboxylation
(using Mg or Zn under classical reaction conditions, followed by the addition
of CO2) failed.
(16) Ito, Y.; Sasaki, A.; Tamoto, K.; Sunagawa, M.; Terashima, S.
Tetrahedron 1991, 47, 2801-2820.
(17) Ager, D. J.; Allen, D. R.; Schaad, D. R. Synthesis 1996, 1283-
1285.
CH3, 3%), 162 (73%), 104 (85%), 77 (79%), 59 (100%). [R]20 -96.9 (c
0.96, AcOEt). 3-(2-Methoxycarbonylpropionyl)-4R-phenyl-2-oxazolidi-
none (More Polar Isomer) 2b. H NMR δ (CDCl3): 7.40-7.31 (m, 5H,
D
1
ar), 5.44 (dd, 1H, J ) 9.0 Hz, J ) 3.9 Hz, OCHH), 4.71 (t, 1H, J ) 9.0
Hz, N.-CH), 4.49 (q, 1H, J ) 7.2 Hz, CHCO2CH3), 4.25 (dd, 1H, J ) 9.0
Hz, J ) 3.9 Hz, OCHH), 3.67 (s, 3H, CO2CH3), 1.39 (d, 3H, J ) 7.2 Hz,
CH3CHCO2CH3). 13C NMR δ (CDCl3): 170.67, 168.81, 153.68, 138.39,
129.08, 128.70, 125.82, 70.30, 57.88, 52.36, 45.55, 12.95. GC-MS m/z:
277 (M+., 3%), 218 (M+ - CO2CH3, 3%), 162 (73%), 104 (85%), 77 (79%),
59 (100%). [R]2D0 -44.6 (c 0.87, AcOEt).
(10) CAUTION! Although in more than 100 experiments no particular
safety problem has been encountered, the use of perchlorates in organic
solvent must be considered as potentially dangerous (explosive). Take
adequate precautions.
(11) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urp`ı, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(18) de Boer, T. J.; Backer, H. J. Organic Syntheses; Wiley: New York,
1963; Collect. Vol. IV, pp 250-253.
Org. Lett., Vol. 4, No. 16, 2002
2619

Table 2. Electrochemical Carboxylation of N-(R-Bromoacyl)-4R-phenyloxazolidin-2-onesa
a Starting bromide (2 F/mol). Electrolysis conditions: entry 9, Table 1. b Yields of isolated products, calculated with respect to the starting bromide.
c Diastereoisomeric ratio was determined by 1H NMR. d Chemical shifts of the hydrogen atoms of the methoxycarbonyl group (1H NMR, ppm with respect
to tetramethylsilane) of the major and minor diastereoisomers, respectively. e This electrolysis is reported in Table 1 (entry 9), and cited here for comparison.
f Starting material was a chloride (instead of a bromide), and the electrolysis was stopped after 3 F/mol.
To test the applicability of this electrochemical carboxy-
lation, the investigation was extended to N-(R-bromoacyl)-
4R-phenyloxazolidin-2-ones other than the title one (see
Table 2). As expected, when the alkyl group is replaced by
a phenyl one, the electrochemical carboxylation does not take
place and only the reduction product can be detected. Further
investigations are necessary to improve these results.
Acknowledgment. This work was supported by research
grants from M.U.R.S.T. (Cofin 2000) and C.N.R., Rome,
Italy. The authors thank Mr. M. Di Pilato for his contribution
to the experimental part of this work and Prof. Fabio
Marchetti for the X-ray analysis.
Supporting Information Available: Characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, the electrochemical methodology permits
the synthesis in good yields and the easy resolution of
methylmalonic ester derivatives by reduction and carboxy-
lation of (4R)-3-(2-bromopropionyl)-4-phenyl-2-oxazolidi-
none.
OL025939Z
2620
Org. Lett., Vol. 4, No. 16, 2002