Titanium(IV) enolates of 2-nitrocarboxylic esters and their oxidative chlorinationa convenient route to α-chloro-α-nitrocarboxylates

Article abstract of DOI:10.1055/s-0031-1290081

A new method for the synthesis of 2-chloro-2-nitrocarboxylic esters from 2-nitrocarboxylates is described. The procedure consists of the oxidative chlorination of titanium(IV) enolates of 2-nitro esters in the presence of ammonium nitrate. Esters of 2-chloro-2-nitrocarboxylic acids are formed in very good to quantitative yields. Application of this method for the chlorination of α,α′-dinitrodicarboxylates leads to α,α′- dichloro-α,α′-dinitrocarboxylic esters with high meso-diastereoselectivity. The absence of ammonium nitrate from the reaction mixture affects the reduction of nitro groups and leads to partial transformation of 2-nitrocarboxylic esters into 2-(hydroxyimino)carboxylates. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290081

LETTER
267
Titanium(IV) Enolates of 2-Nitrocarboxylic Esters and Their Oxidative
Chlorination. A Convenient Route to a-Chloro-a-nitrocarboxylates
A
Convenient
R
ou
a
te to
a
-Chl
r
oro-
a
-ni
i
uxylates sz Cież,* Justyna Kalinowska-Tłuścik
Faculty of Chemistry, Jagiellonian University, ul. Romana Ingardena 3, 30-060 Kraków, Poland
Fax +48(12)6340515; E-mail: ciez@chemia.uj.edu.pl
Received 23 September 2011
ro-2-nitrocarboxylates was described by Yurtanov et al.,5
but alkylation of chloronitroacetic esters was limited only
to the reactions with methyl and ethyl iodide.
Abstract: A new method for the synthesis of 2-chloro-2-nitrocar-
boxylic esters from 2-nitrocarboxylates is described. The procedure
consists of the oxidative chlorination of titanium(IV) enolates of 2-
nitro esters in the presence of ammonium nitrate. Esters of 2-chloro-
2-nitrocarboxylic acids are formed in very good to quantitative
yields. Application of this method for the chlorination of a,a¢-dini-
trodicarboxylates leads to a,a¢-dichloro-a,a¢-dinitrocarboxylic es-
ters with high meso-diastereoselectivity. The absence of ammonium
nitrate from the reaction mixture affects the reduction of nitro
groups and leads to partial transformation of 2-nitrocarboxylic es-
ters into 2-(hydroxyimino)carboxylates.
Our investigations on titanium(IV) enolates provided
strong evidence for a relationship between the stability of
enolates derived from 2-substituted carboxylates and the
substituents at the C-2 position. We noted that, in compar-
ison with earlier investigated titanium(IV) enolates of 2-
isothiocyanocarboxylates15 and 2-azidocarboxylates,16 ti-
tanium(IV) enolates of 2-nitro esters were very stable and
unreactive. They formed easily using a ‘soft enolization
technique’ from ethyl 2-nitrocarboxylates, titanium tetra-
chloride and tertiary amine, and could be stored under ar-
gon at the room temperature for many hours. According to
a known procedure,17 we prepared ethyl 2-nitropropano-
ate (1a) and transformed it into titanium(IV) enolate 2a
(Scheme 1). The enolate was stirred at room temperature
and the process was monitored using TLC and gas chro-
matography. After 24 hours the appearance of two new
products was observed, and their concentration gradually
increased. The process stopped after six days and GC-MS
analysis of the reaction mixture showed the presence of
two main products: ethyl 2-chloro-2-nitropropanoate (3a)
and ethyl 2-(hydroxyimino)propanoate (4a). The postu-
lated structure 3a was confirmed by IR and NMR data,
which were comparable with those presented previously.5
We also detected ethyl 2-nitropropanoate (1a) and esti-
mated its concentration by gas chromatography to be 35%
of the initial amount. Application of a range of 2-nitrocar-
boxylic esters 1b–d gave similar results; we isolated a
mixture of 2-chloro-2-nitrocarboxylate 3b–d, 2-(hydroxy-
imino)carboxylic ester 4b–d and unconsumed starting
material 1b–d.
Key words: oxidative chlorination, titanium enolates, diastereo-
selectivity, esters, transition states
Gem-chloro-nitro compounds have been found to be con-
venient reactants for the synthesis of nitro-substituted
products1 or cyclic systems that incorporate an N-O moi-
ety into heterocyclic ring.2 The presence of two electrone-
gative groups bonded to the same carbon atom exerts
influence not only on its CH-acidity but also on the reac-
tivity of both substituents. Nitro groups in gem-halo-nitro
compounds can be easily silylated giving N,N-bis(silyl-
oxy)enamines3 – products that attract considerable inter-
est owing to their synthetic applications – whereas the
halogen atoms can undergo various substitution reac-
tions.4 The synthetic potential of gem-chloro-nitrocarbo-
xylic acids comes from their polyfunctional nature. Three
electronegative groups bonded to the C-2 atom increases
the CH-acidity of chloronitroacetates and facilitates the
application of these esters in alkylation reactions,5 a-
hydroxyalkylation6 aldol reactions,7 deuteroexchange,8
Michael additions,5 and halogenation.9
Synthesis of 2-chloro-2-nitrocarboxylic esters can be real-
ized in two different ways: from oximino esters and
nitrosyl chloride followed by oxidation of 2-chloro-2-
nitrosocarboxylates,10 and by direct chlorination of 2-ni-
trocarboxylates using chlorine in water,11 chlorine in chlo-
roform,12 N-chlorosuccinimide,13 or sulfuryl dichloride in
diethyl ether.5,14 The described methods were applied not
only for chlorination of nitroacetates but also for the syn-
theses of higher substituted nitrocarboxylates – 2-chloro-
2-nitropropanoates and 2-chloro-2-nitrobutyrates.11a,14 An
alternative attempt to generate higher substituted 2-chlo-
R
OEt
1) TiCl4, CH2Cl2, –15 °C
2) DIEA, –15 °C to r.t.
R
CO2Et
O
N
O
NO2
1a–d
O
Ti
Cl
Cl
Cl
2a–d
R
CO2Et
R
CO2Et
+
N
Cl NO2
HO
3a–d
4a–d
Scheme 1 Transformation of 2-nitrocarboxylates into titanium(IV)
enolates followed by oxidative chlorination at C2 and partial reduc-
tion of the nitro group
SYNLETT 2012, 23, 267–271
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290081; Art ID: B17711ST
x
x.
x
x.
2
0
1
2
© Georg Thieme Verlag Stuttgart · New York

268
D. Cież, J. Kalinowska-Tłuścik
LETTER
Chlorination of some arylacetic acid imides at the C-a po- stoichiometric amount of ammonium nitrate gave ethyl 2-
sition in the presence of titanium(IV) chloride has been chloro-2-nitropropanoate (3a) in quantitatively yield; GC
observed during oxidative homocoupling of some chiral analysis of the crude reaction mixture did not indicate the
3-(arylacetyl)-2-oxazolidinones in the presence of TiCl4 presence of 2-(hydroxyimino)carboxylate (4a). The syn-
and a tertiary amine.19 There is, however, no evidence for thesis was accompanied by emission of nitric oxide (NO),
practical application of TiCl4 in efficient chlorination of which could be formed in a redox process described by the
–
CH-acids. We supposed that the formation of 2-chloro-2- equation: 3TiCl3 + NO3 → 2TiCl4 + TiO2 + NO + Cl–. In-
–
nitrocarboxylates from 2-nitrocarboxylic esters was an deed, the reduction of nitrate (NO3 ) to nitric oxide (NO)
oxidative process supported by titanium(IV), whereas 2- by Ti(III) ions has been previously reported,20 and this
(hydroxyimino)esters were formed from titanium(IV) process has found some applications in the field of analyt-
enolates as a result of reduction by titanium(III) ions. This ical chemistry.
secondary process regenerated titanium(IV), mainly as
unreactive TiO2, and the reaction stopped before all the 2-
nitrocarboxylate was consumed. To examine this hypo-
thesis, we carried out chlorination of ethyl 2-nitropro-
After optimization, we applied the new method for the ox-
idative chlorination of symmetric dimethyl a,a¢-dinitrodi-
carboxylates 1e–g (Scheme 2 and Table 1).21 Starting
dinitro esters 1e–g were prepared according to the general
panoate (1a) in the presence of cerium(IV) ammonium
nitrate (CAN). The solubility of CAN in dichloromethane
was poor, but it was enough to oxidize Ti(III) into Ti(IV)
ions. In the presence of CAN, chlorination of 1a was real-
ized quantitatively and we did not observe any trace of 2-
(hydroxyimino)carboxylate (4a) as a by-product. We not-
ed, however, that a stoichiometric amount of Ce(IV) was
not needed to obtain the chlorination product in quantita-
tive yield. Moreover, we observed release of nitric oxides
in place of formation of cerium(III) salts. This observation
convinced us that Ti(III) ions were oxidized to Ti(IV) by
the nitro groups and not by cerium ions. Indeed, chlorina-
tion of ethyl 2-nitropropanonate (1a) in the presence of a
procedure17 and purified using column chromatography.
Chlorination reactions were carried out in dichlo-
romethane using a stoichiometric amount of ammonium
nitrate as a co-oxidant. The products 3e–g were isolated in
high yields, and analysis of the spectral data confirmed
their structures (Table 1).
Investigation of the obtained symmetrical a,a¢-dichloro-
dinitrodicarboxylates 3e–g led us to interesting conclu-
sions on the stereochemistry of the discovered process.
Although chlorination of the symmetric a,a¢-dinitrodicar-
boxylates should lead to two different diastereoisomeric
forms, NMR data of 3e–g showed the presence only one
Table 1 Oxidative Chlorination of a-Nitrocarboxylic Esters in the Presence of TiCl4/R3N with NH4NO3 (1 equiv) in Dichloromethane at
Room Temperature
Entry
1
Substrate
Time (d) Product
Physical data
Yield (%)
96
CO2Et
NO2
CO2Et
NO2
6
6
6
6
colorless liquid
Cl
3a
1a
1b
1c
CO2Et
NO2
CO2Et
NO2
2
3
4
colorless liquid
colorless liquid
yellowish oil
94
94
95
Cl
3b
CO2Et
NO2
CO2Et
Cl
NO2
3c
H13C6
CO2Et
NO2
H13C6
CO2Et
NO2
Cl
3d
1d
NO2
(CH2)6
NO2
CO2Me
Cl
NO2
Cl
Cl
NO2
colorless solid
mp 77–78 °C
5
6
7
7
85
78
(CH2)4
CO2Me
MeO2C
MeO2C
3e
1e
NO2
(CH2)6
NO2
CO2Me
Cl
NO2
(CH2)6
NO2
colorless solid
mp 45–46 °C
CO2Me
MeO2C
MeO2C
3f
1f
NO2
(CH2)8
NO2
CO2Me
Cl
NO2
(CH2)8
Cl
NO2
colorless solid
mp 42–43 °C
7
7
82
CO2Me
MeO2C
MeO2C
3g
1g
Synlett 2012, 23, 267–271
© Thieme Stuttgart · New York

LETTER
A Convenient Route to a-Chloro-a-nitrocarboxylates
269
NO2
NO2
CO2Me
OMe
OMe
O
O
Ti(IV)Cl2
(CH2)n
MeO2C
N
N
N
N
O
O
O
O
TiCl4
R3N
O
OMe
O
1e–g
OMe
Cl
Cl
– R3NH
O
O
Cl
1) TiCl4, CH2Cl2, –15 °C
2) DIEA, NH4NO3
–15 °C to r.t.
Ti(IV)Cl2
TiCl4
O
O
5
6
OMe
O
Cl
NO
2 Cl
NO2
TiCl3 + Cl
OMe
O
Ti(III)Cl2
CO2Me
N
N
MeO2C
(CH2)n
3e–g
O
•
•
O
N
N
Ti(III)Cl2
O
O
OMe
Cl
Cl
•
TiCl4
TiCl4
OMe
O
Cl Cl
Scheme
with high diastereoselectivity
2
Preparation of meso-dichlorodinitrodicarboxylates
O
Ti(III)Cl2
O
O
Ti(III)Cl2
O
O
•
7
TiCl3 + Cl
of the possible diastereoisomers. X-ray crystal structure
determination carried out on 3g showed that the prepared
product appeared only in the meso form.18 The observed
diastereoselectivity cannot be explained on the basis of a
simple model of chlorination of the titanium(IV) eno-
lates.19 It seems apparent that titanium(IV) enolates of 2-
nitrocarboxylates form more complex, three-dimensional
structures in the solution, which undergo chlorination via
a highly ordered transition state. The precise reaction
mechanism remains unclear. Taking into consideration
the tentative mechanism suggested by Matsumura et al.
for the highly dl-diastereoselective oxidative couplings of
arylacetic acid derivatives,22 we assumed that a similar in-
termediate complex is involved in the chlorination pro-
cess (Scheme 3). In contrast to arylacetic acid derivatives,
2-nitrocarboxylates such as 5 coordinate titanium(IV)
chloride with the nitro group. Proton abstraction gives an
enolate 6, which is subsequently oxidized by titanium(IV)
ions to a radical 7. The low reactivity of this radical comes
from its resonance stabilization and is manifested in sig-
nificantly longer reaction times (up to one week) needed
for the transformation of 7 into the chlorinated product 3.
In contrast to the previously investigated 2-isothiocyana-
tocarboxylates,15 the formed nitro-radical 7 does not un-
dergo oxidative coupling, probably due to electrostatic
repulsion between the electron-rich oxygen atoms of the
two nitro groups. The intermediate 7 can be reduced by
Ti(III) species to 2-(hydroxyimino)carboxylates 423 or oxi-
dized by Ti(IV) and chlorinated at C-2, furnishing 2-chlo-
ro-2-nitrocarboxylic ester 8 (as a titanium(III) complex).
Formation of the 2-(hydroxyimino)carboxylates 4 takes
place only in the absence of co-oxidant (CAN or
NH4NO3) and involves an intramolecular reaction be-
tween Ti(III) ion and coordinated by a Ti(III) nitro group.
We suppose that this mechanism could be responsible for
the highly stereoselective formation of (E)-2-(hydroxy-
imino)carboxylic esters 4. The stereochemical effects of
the chlorination process were not evident for simple 2-ni-
trocarboxylates but became apparent during chlorination
of symmetric a,a¢-dinitrodicarboxylates. Attack of chlo-
rine anions on the coordinated ligands from the opposite
sides of the dimeric intermediate led to meso-substituted
a,a¢-dichlorodinitrodicarboxylates 3e–g.
Cl
OMe
O
N
Ti(III)Cl2
O
O
Cl
MeO2C
NO
2 Cl
NO2
OMe
Cl Cl
– TiCl3
CO2Me
(CH2)n
O
Cl
O
N
meso-3
Ti(III)Cl2
O
8
Scheme 3 A tentative reaction mechanism for the highly diastereo-
selective C-2 chlorination, giving the meso-derivatives 3e–g exclusi-
vely
We assumed that the dimeric transition state 6 is a key
structure before oxidation of the enolate to the radical in-
termediate 7 and reasoned that inhibiting the formation of
complex 6 should have a significant effect on the oxida-
tive chlorination process. To this end, we prepared (4R)-
4-ethyl-3-(2-nitropropanoyl)-1,3-oxazolidin-2-one (9b)
and
3-O-(2-nitropropionyl)-1,2;4,5-di-O-cyclohexy-
lidene-D-fructopyranose (10b; Figure 1). The synthesized
imide 9b and ester 10b easily formed titanium(IV) eno-
lates but no chlorination products were detected. More-
over, reduction of 9b and 10b to derivatives of 2-
(hydroxyimino)propanonic acid, which is usually ob-
served for methyl and ethyl nitrocarboxylates in the ab-
sence of ammonium nitrate, was completely inhibited.
Under these conditions, after six days, we recovered un-
changed starting material. The oxidative chlorination was
restrained, probably due either to steric repulsion between
the large groups or to the formation of different titani-
um(IV) complexes than those depicted in Scheme 3. This
experiment has shown that the described redox processes
observed for titanium(IV) enolates strongly depend on the
structure of the starting 2-nitrocarboxylates.
O
O
O
O
O
O
N
O
O
NO2
Me
O
NO2
O
9b
10b
Figure 1 Structures of 2-nitropropionylimide 9b and ester 10b,
which form titanium(IV) enolates but do not undergo oxidative chlo-
rination
© Thieme Stuttgart · New York
Synlett 2012, 23, 267–271

270
D. Cież, J. Kalinowska-Tłuścik
LETTER
(10) Kissinger, L. W.; Ungnade, H. E. J. Org. Chem. 1958, 23,
1517.
(11) (a) Macbeth, A. K.; Traill, D. J. Chem. Soc. 1925, 896.
(b) Adolph, H. G.; Oersterling, R. E.; Sitzmann, M. J. Org.
Chem. 1968, 33, 4296.
(12) Brintzinger, H.; Janecke, J. Chem. Ber. 1950, 83, 103.
(13) Amrollah-Madjdabadi, A.; Beugelmans, R.; Lechevallier,
A. Synthesis 1986, 828.
(14) Yurtanov, A. I.; Adkhamova, Z. M.; Baidildaeva, S. K. Russ.
Chem. Bull. 1992, 41(5), 891.
(15) Cież, D. Tetrahedron 2007, 63, 4510.
(16) Cież, D. Org. Lett. 2009, 11, 4282.
(17) Kornblum, N.; Blackwood, R. K.; Powers, J. W. J. Am.
The developed, novel method for the oxidative chlorina-
tion of 2-nitrocarboxylates under very mild conditions is
an alternative tool for the efficient preparation of 2-chlo-
ro-2-nitrocarboxylic esters. Application of ammonium ni-
trate as a co-oxidant leads to the formation of chlorination
products in nearly quantitatively yields. The procedure
can be applied to various methyl and ethyl esters of 2-ni-
trocarboxylic acids, provided that the starting ester bears
a substituent at the C-2 position.25 The method can be also
employed for chlorination of a,a¢-dinitrodicarboxylates,
giving the appropriate a,a¢-dichloro-a,a¢-dinitrodicarbox-
ylates in high yields with very high meso-diastereoselec-
tivity.
Chem. Soc. 1957, 79, 2507.
(18) Crystallographic data (excluding structure factors) for the
structure of 3g have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 843131. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(19) Kise, N.; Kumada, K.; Terao, Y.; Ueda, N. Tetrahedron
1998, 54, 2697.
This work was supported by the Polish Ministry of Science and
Higher Education (Grant No. N N204 310037) and the research was
carried out with equipment purchased with financial support of the
European Regional Development Fund in the framework of the
Polish Innovation Economy Operational Program (contract no.
POIG.02.01.00-12-023/08).
(20) (a) Burns, E. A. Anal. Chim. Acta 1962, 26, 143. (b) Al-
Wahid, A.; Townshend, A. Anal. Chim. Acta 1986, 186,
289. (c) Yang, F.; Troncy, E.; Francur, M.; Vinet, B.; Vinay,
P.; Czaika, G.; Blaise, G. Clin. Chem. 1997, 43, 657.
(d) Baezzat, M. R.; Parsaeian, G.; Zare, M. A. Quim. Nova
2011, 34, 607.
(21) Oxidative chlorination of a-nitrocarboxylic esters;
representative synthesis of 3e: A solution of dimethyl 2,7-
dinitrooctanedioate24 (1e; 1.08 g, 3.69 mmol) in CH2Cl2 (40
mL) was cooled under argon to –15 °C and TiCl4 (0.90 mL,
1.55 g, 8.16 mmol, 2.2 equiv) was added in one portion. The
reaction mixture was stirred for 20 min, then DIEA (1.41
mL, 1.05 g, 8.16 mmol, 2.2 equiv) in CH2Cl2 (4 mL) was
added dropwise to form the orange titanium(IV) enolate. The
ice bath was removed and the solution was gradually
warmed to r.t. Fine pulverized ammonium nitrate NH4NO3
(0.59 g, 7.38 mmol, 2 equiv) was added and the flask was
protected against moisture. The reactants were stirred for 7
days, then the solution was poured into concentrated
aqueous NH4Cl (60 mL), stirred, and the lower organic layer
was separated and dried with anhydrous MgSO4. The crude
product isolated after evaporation of CH2Cl2 and purified by
column chromatography (silica gel, 230–400 mesh; CHCl3–
MeOH, 30:1) to give 3e (1.13 g) as a colorless solid.
Mp = 77–78 °C. TLC: Rf = 0.70 (Merck silica gel 60;
CHCl3–MeOH, 30:1). Anal. Calcd for C10H14Cl2N2O8: C,
33.26; H, 3.91; N, 7.76. Found: C, 33.41; H, 3.99; N, 7.59.
1H NMR (CDCl3, 300 MHz): d = 3.90 (s, 6 H, OCH3), 2.63
(m, 2 H, CHaHb), 2.48 (m, 2 H, CHaHb), 1,67 (m, 2 H,
CHcHd), 1.35 (m, 2 H, CHcHd). 13C NMR (CDCl3, 75 MHz):
d = 163.1 (COOMe), 101.5 (C-NO2), 54.7 (OCH3), 38.3
(CH2), 22.6 (CH2). IR (ATR): 2959, 1756, 1566, 1436, 1343,
1264, 1242, 1179, 1103, 1010 cm–1. GC/MS (EI): m/z
(%) = 268 (6) [M+ – NO2 – NO2 – H], 238 (32) [M+ – NO2 –
NO2 – CH3OH], 236 (41) [M+ – Cl – COOCH3 – OCH3], 209
(9) [M+ – H – C(Cl)(NO2)COOCH3], 168 (100) [M+ – NO2
– NO2 – Cl – Cl – OCH3]
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gives only one isomer of two possible 2-(hydroxyimino)
esters. Based on the analysis of the NMR spectra measured
for by-product 4a, we have determined its structure as ethyl
(E)-2-(hydroxyimino)propanoate. Indeed, our assignment
Synlett 2012, 23, 267–271
© Thieme Stuttgart · New York

LETTER
has been confirmed by the literature data. Stereoselective
A Convenient Route to a-Chloro-a-nitrocarboxylates
271
Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2001, 955. (c)
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that the nitro group loses an oxygen atom adjacent to the
ester group during reduction. This observation is very
helpful for investigation of the transition state. For NMR
data of ethyl (E)-2-(hydroxyimino)propanoate, see: (a)
Lampeka, R. D.; Silva, T. Yu.; Skopenko, V. V. Zh. Obshch.
Khim. 1989, 59, 1252. (b) Pitts, M. R.; Harrison, J. R.;
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Synlett 2012, 23, 267–271

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