Oxidative nucleophilic substitution of hydrogen in nitroarenes with carbanions of protected serine and threonine esters

Article abstract of DOI:10.1002/ejoc.201000498

The reactions of carbanions of protected serine and threonine esters with nitroarenes were studied. The main process involves the addition of the carbanions to the para position of the nitroarenes, which is occupied by a hydrogen atom, to form σ^H

Full text of DOI:10.1002/ejoc.201000498

FULL PAPER
DOI: 10.1002/ejoc.201000498
Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes with
Carbanions of Protected Serine and Threonine Esters
Daniel Sulikowski[a] and Mieczysław Ma˛kosza*[a]
Dedicated to Professor Wojciech Stec on the occasion of his 70th birthday
Keywords: Carbanions / Nitroarenes / Amino acids / Oxidation / Nucleophilic substitution
The reactions of carbanions of protected serine and threonine
esters with nitroarenes were studied. The main process in-
volves the addition of the carbanions to the para position of
the nitroarenes, which is occupied by a hydrogen atom, to
form σH adducts that are subsequently oxidized by 2,3-
atives of the protected serine and threonine. Oxidation of the
σH adducts with dimethyldioxirane resulted in the formation
of the corresponding p-hydroxyaryl derivatives of these
amino acids. Addition of the carbanions of the protected thre-
onine ester is a highly stereoselective process controlled by
dichloro-5,6-dicyanobenzoquinone to give p-nitroaryl deriv- the second chiral center of threonine.
nine,[11] serine,[11] and proline[12] molecules by oxidative nu-
Introduction
cleophilic substitution of hydrogen (ONSH) in nitroarenes
with carbanions of properly protected amino acids. The
carbanion of -proline, protected in the form of the N,O-
acetal of pivalaldehyde, added to the nitroarenes in the para
position to the nitro group in a stereoselective manner to
produce, after oxidation, one diastereoisomer of the nitro-
arylated product.[12] Thus, the ONSH reaction proceeded in
this case with self-reproduction of chirality.[13] Interestingly,
the zinc enolate of N-TFA-protected tert-butyl glycinate
does not react with nitroarenes by addition to the ring but
by direct reaction with the nitro group.[14]
In this paper we present a full account of our studies
of the ONSH reaction in nitroarenes with carbanions of
protected serine and threonine that leads to α-(p-nitroaryl-
ated) and p-hydroxyarylated serine and threonine. The
ONSH reaction consists of addition of nucleophilic agents
to electron-deficient arenes in positions occupied by a hy-
drogen atom to form σH adducts that are subsequently oxi-
dized by external oxidants to form products of nucleophilic
substitution of hydrogen.[15] The addition is, as a rule, a
reversible process, and nucleophiles are sensitive to oxi-
dation; thus, the reaction can proceed successfully when the
addition equilibrium is shifted towards the σH adducts. Be-
cause nucleophiles add to electron-deficient aromatic rings
in positions occupied by hydrogen faster than in equally
activated positions occupied by halogen atoms or other
substituents, the ONSH reaction is a process of general
character and with a wide scope of applications.[15] The re-
action is of general character also with respect to the nu-
cleophiles. This way, it is possible to introduce a variety of
substituents, such as OH,[16] NH2,[17] and P(O)Ph2,[18] and
Unnatural α-amino acids are important starting materi-
als for the synthesis of pharmaceutically interesting mole-
cules such as peptidomimetics, enzyme inhibitors, confor-
mationally constrained peptides, and so on.[1,2] Of particu-
lar interest are α,α-disubstituted α-amino acids because of
their special properties as fragments of peptide chains and
their use as building blocks for biologically active com-
pounds.[3–5] Due to the great importance of α,α-disubsti-
tuted α-amino acids, their synthesis was subject of intensive
studies and a number of methods have been developed.[3,6]
Amongst α,α-disubstituted amino acids, α-substituted ser-
ine and threonine derivatives are of special interest because
their hydroxy groups can stabilize the α-helical secondary
structures of enzymes.[7] They have been inter alia employed
as components of biologically active peptidomimetics.[8]
There are numerous methods elaborated for the introduc-
tion of substituents into the α-positions of serine and threo-
nine, including reactions of electrophilic partners with carb-
anions of properly protected amino acids.[9] However, to
our best knowledge, there are no examples reported of the
direct introduction of aryl groups by this way. α-Aryl serine
derivatives are usually obtained through a multistep process
based on the Strecker reaction,[10a] or by addition of
organolithium reagents to an imine bond.[10b]
Recently, we published preliminary reports that p-ni-
troaryl substituents can be readily introduced into ala-
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44, 01-224 Warsaw, Poland
Fax: +48-22-6326681
E-mail: icho-s@icho.edu.pl
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Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes
a wide range of carbon substituents[11,12,19,20] into electron- its amide in 7% yield. Perhaps due to the bulkiness of the
deficient arenes. Of particular value is the oxidative nucleo- carbanion of 1a, its σH adduct is not fully oxidized by per-
philic alkylation of nitroarenes with Grignard rea- manganate; furthermore, partial ammonolysis of 1a takes
gents[21a–21e] and alkyllithium compounds[21f] and the syn- place during the reaction, which may also cause a partial
thesis of nitroarylated acetic acid derivatives.[22] Oxidation reduction in the yield. We observed earlier that permanga-
of σH adducts of nucleophiles to nitroarenes can be effected nate oxidation of σH adducts is very sensitive to steric hin-
by a variety of oxidants such as dichlorodicyanobenzo- drance.[19]
quinone (DDQ),[11,12,19e,20c,23] bromine,[23] KMnO4,[19a,19b,20c]
oxygen,[20] and cerium ammonium nitrate.[24] There are
many examples of anodic oxidation of σH adducts.[25] The
oxidation of σH adducts with these oxidants provides prod-
ucts in which the hydrogen atom in the nitro aromatic ring
has been replaced by a nucleophilic moiety. The oxidation
of σH adducts with dimethyldioxirane (DMD) proceeds dif-
ferently. This oxidizing agent attacks the negatively charged
nitro group of the σH adducts, giving substituted phenols
as the products.[26]
Results and Discussion
Scheme 2. ONSH in nitroarenes with the carbanion of 1a: synthesis
of nitroarylated serine derivatives.
In our preliminary communication, it was reported that
the carbanion of ethyl 2-phenyl-1,3-oxazoline-4-carboxylate
(1a) adds to nitroarenes in the para position to the nitro
Table 1. Results of the ONSH reaction of nitroarenes with the carb-
group. Subsequent oxidation of the produced σH adducts
anion of 1a as in Scheme 2.
with DDQ gave α-(p-nitroarylated) derivatives of serine. Al-
Nitroarene, Z
DDQ
G = NO2
DMD
G = OH
though oxazoline 1a was used in an enantiomerically pure
form prepared from readily available -serine, generation of
the planar carbanion and further addition results in com-
plete racemization. Protected serine derivative 1a can be ob-
tained in very good yield by direct condensation of -serine
ethyl ester hydrochloride with ethyl benzimidate hydrochlo-
ride in the presence of triethylamine (Scheme 1).[27]
Product % Yield Product % Yield
H
2-F
3-F
2-Cl
3-Cl
2-MeO
3-MeO
2
2aa
3aa
4aa
5aa
6aa
73
54[b]
50
73
70
2ab
53
3[a]
4
4aa
5ab
6ab
7ab
8ab
8aa
46
55
51
33
35
30
5a
6
7
8
8aa
60
3-Me
2-CN
3-CN
3-CF3
2-Cl-3-CN
9
9aa
10aa
37
55
10
11
12
13
10aa
11ab
41
59
12aa
25
13ab
50
Scheme 1. Synthesis of protected serine in the form of oxazoline
1a.
4-EtO-2-NO2Py 14
14aa
71
[a] Reaction carried out at –78 °C. [b] Additionally product of sub-
stitution of fluorine was obtained.
Oxazoline 1a, being a reasonably strong CH acid, can
be readily deprotonated by tBuOK in THF/DMF at low
temperature. The produced carbanion is a sufficiently
According to the same protocol, 1a was treated with a
strong nucleophile, so its addition to nitrobenzene at –40 °C series of ortho- and meta-substituted nitrobenzenes to give
proceeds to completion. Due to its bulkiness, the carbanion the expected p-nitroarylated protected serines 2aa–10aa,
of 1a (Scheme 2, Table 1) adds to nitrobenzenes selectively usually in good yields. It should be stressed that the carban-
in the para position to the nitro group. Treatment of the ion of 1a is sufficiently nucleophilic to ensure its complete
produced solution of the σH adduct with DDQ dissolved in addition to nitroarenes even in the case of nitroarenes of
THF and warming of the mixture results in the formation lower activity such as nitrobenzene or 3-nitroanisole.
of the expected p-nitrophenyl derivative of protected serine
Interestingly, the reaction of the carbanion of 1a with
2aa in a good yield of 73%. Attempts to carry out the reac- 2-chloronitrobenzene, when carried out at –40 °C, gave a
tion in liquid ammonia with potassium permanganate as mixture of two products: the expected product of ONSH,
the oxidant and 2-cyanonitrobenzene (10) as the substrate 5aa, and the product of substitution of chlorine. At –78 °C,
at –78 °C gave a mixture of product 10aa (9%) and its the reaction proceeded selectively as ONSH to give pure
amide (39%). An analogous reaction carried out in THF/ 5aa in high yield. On the other hand, the reaction of the
DMF followed by treatment with solid potassium perman- carbanion of 1a with 2-fluoronitrobenzene, even if carried
ganate and liquid ammonia gave 10aa in 42% yield and out at –78 °C, proceeded partially as SNAr of fluorine,
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D. Sulikowski, M. Makosza
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whereas at –40 °C SNAr was the main process. Nitroaryl- tically pure -threonine as one anti (trans) diastereoisomer,
ated products 2aa–14aa are stable compounds and can be two chiral centers are presented. We expected that the ste-
isolated and purified by standard chromatographic tech- reochemistry of the addition of the carbanion of 1b to ni-
niques.
troarenes should be controlled by the vicinal stereogenic
When a solution of the σH adduct of the carbanion of center to produce single diastereomeric σH adducts, which
1a to nitrobenzene produced according to the standard pro- upon oxidation with DDQ or DMD should give single dia-
cedure was treated with an acetone solution of DMD pre- stereoisomers of the nitroarylated and hydroxyarylated
pared in accordance with the procedure of Adam,[28] the α- products.
(p-hydroxyphenyl) derivative of 1a, phenol 2ab, was ob-
Thus, in this way, self-reproduction of chirality shall be
tained. Similarly, the σH adducts produced by addition of observed.[9a,30] Indeed, when a mixture of 1b and nitroben-
the carbanion of 1a to other nitroarenes upon oxidation by zene dissolved in THF/DMF was treated with tBuOK at
DMD in acetone gave expected p-hydroxyarylated oxazol- low temperature (–78 °C) and the produced σH adduct oxi-
ines 3ab–10ab. The oxidation step was not fully chemoselec- dized with DDQ, expected nitroarylated oxazoline 2ba was
tive, as mostly one product obtained from oxidation of the obtained as one diastereoisomer in an excellent yield of
negatively charged nitro group in the σH adducts was pro- 79%. The configuration of representative diastereomer 2ba
1
duced. However, in the case of the σH adducts of 1a to 2- was established on the basis of H NMR spectroscopic ex-
cyanonitrobenzene (10) and 3-fluoronitrobenzene (4), oxi- periments through NOE analysis (Figure 1).
dation with DMD gave exclusively nitroaryl derivative 10aa
and 4aa, respectively. Related dichotomy in the DMD oxi-
dation was observed in the case of the oxidation of nitro-
benzylic carbanions. Depending on the nature of the carb-
anions and the conditions, the oxidation resulted in hydrox-
ylation of the carbanionic moiety and/or conversion of the
Figure 1. NOE experiment for 2ba.
nitronate group into a carbonyl group, so methylene quin-
one derivatives are produced.[29]
The product structure suggests that addition of the carb-
anions to the nitroarene proceeds from the opposite side in
relation to the methyl group. The resulting configuration
can be designated as -allo-threonine.
In the ONSH reaction of the carbanion of 1b with a
series of nitroarenes, nitroarylated products 2ba–14ba were
obtained, usually in good and very good yields. Noteworthy
is that the yields are significantly higher than those ob-
tained for 1a, although one might expect that the oxidation
of the σH adduct derived from 1b (Table 2, Scheme 5)
should be more difficult than that obtained from 1a due to
the bulkiness of the former.
Nitroarylated oxazolines, for example, 2aa, 2ab, and 5ab,
can be readily hydrolyzed to nitroarylated serine derivatives
by simple heating with aqueous HCl/THF followed by pre-
cipitation with propylene oxide. Representative yields are
presented in Scheme 3.
Table 2. Results of the ONSH reaction of nitroarenes with the carb-
anion of 1b as in Scheme 5.
Scheme 3. Hydrolysis of nitroarylated oxazolines.
Nitroarene, Z
DDQ
G = NO2
DMD
G = OH
Next, we studied the possibility of oxidative nitroaryl-
ation of the carbanion of -threonine protected in the form
of oxazoline 1b. This precursor was obtained by an analo-
gous reaction of the ethyl ester of -threonine hydrochloride
with ethyl benzimidate hydrochloride, as presented in
Scheme 4.
Product % Yield Product % Yield
H
3-F
2
4
2ba
4ba
79
91
2bb
4bb
4ba
60
58
20
2-Cl
3-Cl
3-MeO
2-CN
3-CN
5
5ba
6ba
79
80
29
70
79
78
6
6bb
70
8
8ba
10
11
10ba
11ba
14ba
10ba
11bb
54
59
4-EtO-2-NO2Py 14
The results of nitroarylation of 1b are presented in
Table 3. Oxidation of the σH adducts by DMD also resulted
in the formation of the appropriate phenols in good yields.
Scheme 4. Synthesis of -threonine protected in the form of oxazol-
ine 1b.
Oxazoline 1a obtained from -serine as one enantiomer, The oxidation chemoselectivity of these σH adducts by this
in the deprotonation–nitroarylation process gave racemic oxidant is superior to the σH adduct of 1a and the nitro-
products 2aa–14aa. In oxazoline 1b, obtained from op- arenes. Although oxidation of the σH adduct to 2-
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Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes
by oxidation of the intermediate σH adducts with DDQ or
DMD gave the appropriate nitroarylated and hydroxyaryl-
ated products as in Scheme 7. The results are presented in
Table 3.
Scheme 7. ONSH reaction of nitroarenes with the carbanion of 1c.
Synthesis of nitroarylated -allo-threonine derivatives.
Scheme 5. ONSH in nitroarenes with carbanion of 1b.
The products of nitroarylation and hydroxyarylation of
1c have the same analytical data as those obtained from 1b,
except for the optical rotation, thus proving that they are
in fact enantiomers of the ONSH products obtained from
1b.
cyanonitrobenzene solely gave product 10ba, in the reaction
of 3-fluoronitrobenzene, desired phenol 4bb was obtained
as the main product.
Table 3. Results of the ONSH reaction of nitroarenes with the carb-
anion of 1c as in Scheme 7.
Conclusions
We have elaborated a convenient method for the intro-
duction of nitroaryl rings into serine and threonine deriva-
tives by oxidative nucleophilic substitution of hydrogen
(ONSH) of nitroarenes. Carbanions of appropriate esters of
-serine and -threonine protected in the form of oxazolines
(1a and 1b, respectively) add to nitroarenes in the para posi-
tion to the nitro group. Subsequent oxidation of the formed
σH products with DDQ provides access to nitroarylated,
quaternary, protected racemic serine and optically pure -
allo-threonine derivatives. Simple changing of the oxidant
to an acetonic solution of DMD gave the respective p-hy-
droxyarylated derivatives. Furthermore, oxazoline 1c, being
a diastereoisomer of 1b, obtained from threonine ethyl ester
hydrochloride in a two-step procedure, enters the ONSH
under the conditions optimized for 1b, giving products with
the -allo-threonine configuration. Thus, starting from -
threonine we were able to obtain both enantiomers of α-(p-
nitroaryl)-allo-threonine derivatives in addition to those of
α-(p-hydroxyaryl)-allo-threonine derivatives. All oxazoline
derivatives of serine and threonine can be simply hydrolyzed
according to known procedures to give p-nitroaryl and p-
hydroxyaryl derivatives as the pure free amino acids or their
esters.
Nitroarene, Z
DDQ
G = NO2
DMD
G = OH
Product % Yield Product % Yield
H
3-Cl
3-MeO
3-CN
2
2ca
6ca
10ca
76
77
70
2cb
6cb
58
70
6
8
11
11cb
59
The chiral center in the β-position of the carbanion of
1b controlled the stereochemistry of the addition of the
carbanion to the nitroaromatic rings, so the obtained
ONSH products have the -allo-threonine configuration.
One could therefore expect that the synthesis of the dia-
stereoisomer of oxazoline 1b being an epimer at the β car-
bon shall give access to its enantiomer with the -allo-threo-
nine configuration. The synthesis of such a carbanion pre-
cursor can be done by at least two ways. The simplest
method, which is analogous to the synthesis of 1b, starts
with the ethyl ester of -allo-threonine hydrochloride and
ethyl benzimidate hydrochloride. Due to the high cost of
pure -allo-threonine, we decided to use another approach.
Using the same threonine ester as in the synthesis of 1b
and conducting Nbenzoylation followed by cyclization by
treatment of the benzoyl derivative with thionyl chloride,
we obtained desired epimeric carbanion precursor 1c
(Scheme 6).
Experimental Section
General Methods: All reactions were carried out under an atmo-
sphere of dry argon. THF was distilled from potassium benzophe-
none ketyl, and DMF was distilled from calcium hydride. All other
solvents used in the purification step were distilled. Silica gel Merck
60 (230–400 mesh) was used for column chromatography. The ethyl
ester of serine and threonine protected in the form of oxazolines
were obtained by known procedures.[31]
Scheme 6. Synthesis of protected diastereomeric oxazoline in the
form of oxazoline 1c.
As we expected, 1c being the epimer of 1b behaved in
ONSH reaction analogously to 1b. Treatment of a mixture
Procedure for the Nitroarylation of the Oxazoline Derivative of Ser-
ine (1a) and Threonine (1b and 1c): To a solution of 1a, 1b, or 1c
of 1c and nitroarene tBuOK at low temperature followed (1.0 mmol) and nitroarene (2.0 mmol) in a mixture of THF (10 mL)
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D. Sulikowski, M. Makosza
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FULL PAPER
and DMF (2 mL) cooled to –40 °C (1a) or –78 °C (1b and 1c, or for (358.33): calcd. C 60.34, H 4.22, N 7.82; found C 60.19, H 4.21, N
reaction 1a with 3 or 5) was added tBuOK (1.0  in THF, 1.1 mL,
1.1 mmol) over 15 min. After 30 min at this temperature, a solution
of DDQ (272 mg, 1.2 mmol) in THF (1 mL) was added. After
5 min, the cooling bath was removed, and the reaction mixture was
allowed to reach room temperature. Then, the reaction mixture was
poured into dichloromethane (75 mL) and washed with water
(3ϫ100 mL) and brine (100 mL). The organic phase was dried
with anhydrous sodium sulfate, the solvents were evaporated, and
the crude products were purified by column chromatography (hex-
ane/ethyl acetate).
7.65.
Ethyl 4-(3-Chloro-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxyl-
ate (5aa): Yield: 273 mg, 73%; white crystals; m.p. 82–84 °C. IR
(KBr): ν = 3104, 2978, 1738, 1634, 1528, 1355, 1248, 1101 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 2.3 Hz, 1 H), 8.16
(dd, J = 2.3, 8.8 Hz, 1 H), 8.12–8.05 (m, 2 H), 8.03 (d, J = 8.8 Hz,
1 H), 7.60–6.50 (m, 1 H), 7.51–7.43 (m, 2 H), 5.66 (d, J = 9.2 Hz,
1 H, -CH2-), 4.35 (d, J = 9.2 Hz, 1 H, -CH2-), 4.35–4.26 (m, 1 H,
OCH2CH3), 4.22–4.13 (m, 1 H, OCH2CH3), 1.21 (t, J = 7.2 Hz, 3
H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7,
167.0, 147.9, 147.7, 132.4, 132.4, 129.8, 128.9, 128.5, 126.5, 124.7,
122.0, 80.1, 76.1, 62.9, 13.9 ppm. LRMS (ESI+): m/z = 375 [M +
H]+. C18H15ClN2O5 (374.78): calcd. C 57.69, H 4.03, N 7.47; found
C 58.06, H 4.01, N 7.25.
Procedure for the Hydroxyarylation of the Oxazoline Derivative of
Serine (1a) and Threonine (1b and 1c): To a solution of 1a, 1b, or
1c (1.0 mmol) and nitroarene (2.0 mmol) in a mixture of THF
(10 mL) and DMF (2 mL) cooled to –40 °C (1a) or –78 °C (1b and
1c, or for reaction 1a with 3 or 5) was added tBuOK (1.0  in THF,
1.1 mL, 1.1 mmol) over 15 min. After 30 min at this temperature,
a solution of DMD (1.2 mmol) in acetone was added. After 5 min,
the cooling bath was removed, and the reaction mixture was al-
lowed to reach room temperature. The solvents were evaporated
under reduced pressure, and the residue was partitioned between
water (50 mL) and dichloromethane (100 mL). The organic phase
was dried with anhydrous sodium sulfate, the solvents were evapo-
rated, and the crude products were purified by column chromatog-
raphy (hexane/ethyl acetate).
Ethyl 4-(2-Chloro-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxyl-
ate (6aa): Yield: 262 mg, 70%; oil. IR (film, CH Cl ): ν = 2982,
˜
2
2
1734, 1641, 1529, 1357, 1257, 1098 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.12–8.07 (m, 2 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.74 (d,
J = 1.9 Hz, 1 H), 7.59–7.44 (m, 4 H), 5.38 (d, J = 8.9 Hz, 1 H,
-CH2-), 4.40 (d, J = 8.9 Hz, 1 H, -CH2-), 4.26 (dq, J = 5.2, 7.2 Hz,
2 H, OCH2CH3), 1.25 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.7, 166.3, 147.4, 147.2, 132.4,
129.5, 128.9, 128.5, 127.7, 126.4, 126.0, 125.0, 80.1, 76.20, 62.8,
13.9 ppm. LRMS (ESI+): m/z = 375 [M + H]+. C18H15ClN2O5
(374.78): calcd. C 57.69, H 4.03, N 7.47; found C 57.48, H 4.04, N
7.33.
Ethyl 4-(4-Nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxylate (2aa):
Yield: 248 mg, 73%; oil. IR (film): ν = 2982, 1732, 1641, 1523,
˜
1350, 1259, 1098, 856 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.26–
8.22 (m, 2 H), 8.12–8.08 (m, 2 H), 7.70–7.65 (m, 2 H), 7.59–7.53
(m, 1 H), 7.50–7.45 (m, 2 H), 5.41 (d, J = 8.8 Hz, 1 H, -CH2-),
4.41 (d, J = 8.8 Hz, 1 H, -CH2-), 4.27–4.14 (m, 2 H, OCH2CH3),
1.22 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.1, 166.1, 148.7, 147.6, 132.3, 128.8, 128.5, 126.8,
126.6, 123.9, 80.6, 76.3, 62.7, 13.9 ppm. LRMS (ESI+): m/z = 341
[M + H]+. C18H16N2O5 (340.34): calcd. C 63.53, H 4.74, N 8.23;
found C 63.35, H 4.69, N 8.10.
Ethyl 4-(2-Methoxy-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carb-
oxylate (8aa): Yield: 222 mg, 60%; white crystals; m.p. 80–83 °C.
IR (KBr): ν = 3109, 2981, 1736, 1643, 1521, 1345, 1246, 1022 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.10–8.06 (m, 2 H), 7.89 (dd, J
= 2.2, 8.3 Hz, 1 H, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.72 (d, J =
2.2 Hz, 1 H), 7.57–7.52 (m, 1 H), 7.48–7.41 (m, 2 H), 5.56 (d, J =
9.1 Hz, 1 H, -CH2-), 4.34–4.25 (m, 1 H), 4.19 (d, J = 9.1 Hz, 1 H,
-CH2-), 4.15–4.06 (m, 1 H, OCH2CH3), 3.93 (s, 3 H, OCH3), 1.17
(t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.5, 166.6, 155.7, 148.6, 138.7, 132.2, 128.8, 128.4,
127.8, 126.9, 116.2, 105.2, 78.2, 76.5, 62.1, 56.0, 14.0 ppm. LRMS
(ESI+): m/z = 371 [M + H]+. C19H18N2O6 (370.36): C 61.61, H
4.90, N 7.56; found C 61.90, H 5.12, N 7.33.
Ethyl 4-(2-Fluoro-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxyl-
ate (3aa): Yield: 193 mg, 54%; oil. IR (film): ν = 2989, 1741, 1641,
˜
1528, 1348, 1236 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.10–8.08
(m, 3 H), 7.58–7.54 (m, 1 H), 7.52 (d, J = 1.8, 11.8 Hz, 1 H), 7.49–
7.45 (m, 2 H), 7.41–7.37 (m, 2 H), 5.38 (d, J = 9.0 Hz, 1 H,
-CH2-), 4.40 (d, J = 9.0 Hz, 1 H, -CH2-), 4.30–4.21 (m, 2 H,
OCH2CH3), 1.17 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.6, 166.4, 155.6 (d, J = 212 Hz), 150.4
(d, J = 6.2 Hz), 136.7 (d, J = 6.3 Hz), 132.4, 128.9, 128.7, 128.6,
128.5, 126.5, 126.5 (d, J = 7.8 Hz), 121.8 (d, J = 3.5 Hz), 121.8 (d,
J = 116.5 Hz), 80.2 (d, J = 0.8 Hz), 76.2 (d, J = 76.1 Hz), 62.8,
13.9 ppm. LRMS (ESI+): m/z = 359 [M + H]+. C18H15FN2O5
(358.33): calcd. C 60.33, H 4.22, N 7.82; found C 60.52, H 4.21, N
7.92.
Ethyl
oxylate (9aa): Yield: 131 mg, 37%; white crystals; m.p. 147–148 °C.
IR (film, CH Cl ): ν = 2982, 1734, 1641, 1523, 1347, 1235 cm–1.
4-(2-Methyl-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carb-
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 8.16–8.07 (m, 2 H), 8.06–8.02
(m, 1 H), 7.99–7.91 (m, 1 H), 7.57–7.52 (m, 2 H), 7.49–7.43 (m, 2
H), 5.61 (d, J = 8.6 Hz, 1 H, -CH2-), 4.25 (d, J = 8.6 Hz, 1 H,
-CH2-), 4.30–4.16 (m, 2 H, OCH2CH3), 2.28 (s, 3 H, CH3), 1.21 (t,
J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.6, 165.9, 147.9, 147.3, 135.5, 132.3, 128.8, 128.4, 128.3,
126.6, 125.6, 121.2, 80.2, 75.5, 62.3, 19.9, 13.9 ppm. LRMS (ESI+):
m/z = 355 [M + H]+. C19H18N2O5 (354.36): C 64.40, H 5.12, N
7.91; found C 64.33, H 5.13, N 7.70.
Ethyl 4-(2-Fluoro-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxyl-
ate (4aa): Yield: 179 mg, 50%; white crystals; m.p. 113–115 °C. IR
(KBr): ν = 3088, 2979, 1740, 1636, 1524, 1358, 1247, 1098,
Ethyl 4-(3-Cyano-4-nitrophenyl)-2-phenyl-1,3-oxazoline-4-carboxyl-
˜
977 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.11–8.06 (m, 3 H), ate (10aa): Yield: 201 mg, 55%; white crystals; m.p. 134–136 °C.
7.98–7.91 (m, 2 H), 7.60–7.53 (m, 1 H), 7.50–7.43 (m, 2 H), 5.54
IR (KBr): ν = 3038, 2988, 2973, 2238, 1736, 1641, 1533, 1348 cm–1.
˜
(dd, J = 1.6, 9.1 Hz, 1 H, 1 H, -CH2-), 4.34 (dd, J = 1.6, 9.1 Hz, 1 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.8 Hz, 1 H), 8.13–
H, -CH2-), 4.32–4.14 (m, 2 H, OCH2CH3), 1.21 (t, J = 7.2 Hz, 3
H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.6,
167.0, 158.7 (d, J = 250 Hz), 148.4 (d, J = 8.5 Hz), 137.1 (d, J =
8.07 (m, 3 H), 7.29 (dd, J = 1.9, 8.8 Hz, 1 H), 7.61–7.65 (m, 1 H),
7.51–7.46 (m, 2 H), 5.40 (d, J = 8.9 Hz, 1 H, -CH2-), 4.43 (d, J =
8.9 Hz, 1 H, -CH2-), 4.26 (q, J = 7.2 Hz, 2 H, OCH2CH3), 1.25 (t,
16 Hz), 132.4, 129.3 (d, J = 5.1 Hz), 128.9, 128.5, 126.5, 119.6 (d, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3):
J = 3.4 Hz), 111.1 (d, J = 26 Hz), 77.6, 76.1 (d, J = 4.3 Hz), 62.8,
δ = 170.3, 166.8, 149.1, 147.8, 133.5, 132.6, 131.2, 128.9, 128.6,
13.9 ppm. LRMS (ESI+): m/z = 359 [M + H]+. C18H15FN2O5 126.1, 125.8, 114.7, 108.4, 80.0, 76.1, 63.1, 29.7, 13.9 ppm. LRMS
4222
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4218–4226

Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes
(ESI+): m/z = 366 [M + H]+. C19H15N3O5 (356.35): C 62.46, H [M + H]+. C18H16ClNO4 (345.78): C 62.52, H 4.66, N 4.05; found
4.14, N 11.50; found C 62.64, H 4.29, N 11.10.
C 62.88, H 4.54, N 4.22.
Ethyl
4-(3-Methoxy-4-hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-
Ethyl 4-[2-(Trifluoromethyl)-4-nitrophenyl]-2-phenyl-1,3-oxazoline-
carboxylate (7ab): Yield: 112 mg, 33%; yellow crystals; m.p. 75–
79 °C. IR (film, CH Cl ): ν = 3367 (br.), 2976, 2234, 1736, 1637,
4-carboxylate (12aa): Yield: 102 mg, 25%; oil. IR (film, CH2Cl2):
ν = 3091, 2984, 2258, 1745, 1642, 1532, 1312, 1176 cm–1. 1H NMR
˜
˜
2
2
1299 cm–1. H NMR (500 MHz, CDCl3): δ = 8.12–8.08 (m, 2 H),
7.55–7.50 (m, 1 H), 7.45–7.42 (m, 2 H), 7.05 (s, 1 H), 6.89 (d, J =
1.1 Hz, 2 H), 5.32 (d, J = 8.8 Hz, 1 H, -CH2-), 4.40 (d, J = 8.8 Hz,
1 H, -CH2-), 4.31–4.19 (m, 2 H, OCH2CH3), 3.90 (s, 3 H, OCH3),
1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 172.2, 165.2, 146.6, 145.3, 133.8, 131.9, 128.8, 128.4,
127.2, 118.3, 114.5, 108.3, 80.4, 76.9, 62.1, 56.0, 14.0 ppm. LRMS
(ESI+): m/z = 342 [M + H]+. C19H19NO5 (341.36): C 66.85, H 5.61,
N 4.10; found C 66.97, H 5.66, N 4.26.
1
(400 MHz, CDCl3): δ = 8.59–8.54 (m, 1 H), 8.43–8.35 (m, 2 H),
8.11–8.06 (m, 2 H), 7.60–7.54 (m, 1 H), 7.50–7.44 (m, 2 H), 5.51
(d, J = 9.2 Hz, 1 H, -CH2-), 4.39 (d, J = 9.2 Hz, 1 H, -CH2-), 4.26–
4.14 (m,
2 H, OCH2CH3), 1.19 (t, J = 7.2 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8, 166.5,
147.3, 146.5, 132.5, 131.2, 129.9, 128.1 (q, J = 33 Hz), 126.6, 126.4,
123.2 (q, J = 274 Hz), 123.1 (q, J = 5.2 Hz), 80.1, 76.3 (q, J =
6.9 Hz), 62.8, 13.7 ppm. LRMS (ESI+): m/z = 409 [M + H]+.
C19H15F3N2O5 (408.33): C 55.89, H 3.70, N 6.86; found C 55.78,
H 3.62, N 6.78.
Ethyl
carboxylate (8ab): Yield: 119 mg, 35%; yellow crystals; m.p. 124–
126 °C. IR (film, CH Cl ): ν = 3198 (br.), 2979, 1735, 1634, 1497,
4-(2-Methoxy-4-hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-
Ethyl 4-(3-Ethoxy-4-nitro-2-pyridyl)-2-phenyl-1,3-oxazoline-4-carb-
˜
2
2
oxylate (14aa): Yield: 273 mg, 71%; white crystals; m.p. 92–95 °C.
1252, 1200 cm–1. H NMR (500 MHz, CDCl3): δ = 8.12–8.08 (m,
2 H), 7.55–7.50 (m, 1 H), 7.48–7.42 (m, 2 H), 7.38 (d, J = 8.3 Hz,
1 H), 6.41 (d, J = 2.4 Hz, 1 H), 6.38 (dd, J = 2.4, 8.3 Hz, 1 H,
-CH2-), 5.52 (d, J = 8.8 Hz, 1 H, -CH2-), 4.30–4.20 (m, 2 H,
OCH2CH3), 3.72 (s, 3 H, OCH3), 1.16 (t, J = 7.2 Hz, 3 H,
-OCH2CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2, 165.2,
146.6, 145.3, 133.8, 131.9, 128.8, 128.4, 127.2, 118.3, 114.5, 107.0,
96.1, 77.5, 61.9, 55.3, 14.0 ppm. LRMS (ESI+): m/z = 342 [M +
H]+. C19H19NO5 (341.36): C 66.85, H 5.61, N 4.10; found C 66.56,
H 5.43, N 4.41.
1
IR (KBr): ν = 2985, 1739, 1638, 1602, 1519, 1356, 1255, 1027 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.93 (s, 1 H), 8.11–8.04 (m, 2
H), 7.58–7.53 (m, 1 H), 7.51–7.42 (m, 3 H), 5.42 (d, J = 9.4 Hz, 1
H, -CH2-), 4.75 (d, J = 9.4 Hz, 1 H, -CH2-), 4.40–4.17 (m, 4 H,
OCH2CH3), 1.51 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.22 (t, J =
7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.9, 167.0, 166.6, 159.1, 146.6, 135.8, 132.3, 128.8, 128.5, 126.7,
107.2, 82.3, 75.0, 66.0, 62.6, 14.2, 14.0 ppm. LRMS (ESI+): m/z =
386 [M + H]+. C19H19N3O6 (385.38): C 59.22, H 4.97, N 10.90;
found C 59.42, H 5.06, N 10.86.
Ethyl 4-(2-Cyano-4-hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-carb-
oxylate (11ab): Yield: 198 mg, 59%; white crystals; m.p. 152–
Ethyl
4-(4-Hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-carboxylate
(2ab): Yield: 165 mg, 53%; yellow crystals; m.p. 145–147 °C. IR
155 °C. IR (film, CH Cl ): ν = 3367 (br.), 2976, 2234, 1736, 1637,
(film, CH Cl ): ν = 3193 (br.), 2982, 1728, 1637, 1515, 1260 cm–1.
˜
2
2
˜
2
2
1
1299 cm–1. H NMR (400 MHz, CDCl3): δ = 8.08–8.05 (m, 2 H),
7.64 (d, J = 8.4 Hz, 1 H), 7.57–7.52 (m, 2 H), 7.47–7.43 (m, 2 H),
7.10 (d, J = 2.6 Hz, 1 H), 7.00 (dd, J = 2.9, 8.8 Hz, 1 H), 5.61 (d,
J = 8.8 Hz, 1 H, -CH2-), 4.46 (d, J = 8.8 Hz, 1 H, -CH2-), 4.34–
1H NMR (400 MHz, CDCl3): δ = 8.10–8.06 (m, 2 H), 6.81–6.76
(m, 2 H), 7.54–7.49 (m, 2 H), 7.45–7.40 (m, 1 H), 7.27–7.24 (m, 2
H), 5.30 (d, J = 8.8 Hz, 1 H, -CH2-), 4.43 (d, J = 8.8 Hz, 1 H,
-CH2-), 4.30–4.14 (m, 2 H, OCH2CH3), 1.19 (t, J = 7.2 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3, 165.5,
155.9, 133.2, 132.1, 128.8, 128.4, 126.9, 126.7, 115.8, 80.1, 76.9,
62.2, 13.9 ppm. LRMS (ESI+): m/z = 312 [M + H]+. C18H17NO4
(311.33): C 69.44, H 5.50, N 4.50; found C 68.93, H 5.48, N 4.66.
4.20 (m,
2 H, OCH2CH3), 1.25 (t, J = 7.2 Hz, 3 H,
-OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.7, 167.0,
155.8, 137.8, 132.4, 129.1, 128.9, 128.5, 126.4, 120.5 (2 C), 117.5,
110.6, 79.6, 77.0, 63.0, 13.9 ppm. LRMS (ESI+): m/z = 337 [M +
H]+. C19H16N2O4 (336.35): C 67.85, H 4.79, N 8.33; found C 67.01,
H 4.78, N 8.15.
Ethyl 4-(3-Chloro-4-hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-carb-
oxylate (5ab): Yield: 190 mg, 55%; yellow crystals; m.p. 109–
112 °C. IR (film, CH Cl ): ν = 3200 (br.), 2983, 1729, 1637, 1497,
Ethyl 4-(5-Chloro-2-cyano-4-hydroxyphenyl)-2-phenyl-1,3-oxazol-
ine-4-carboxylate (13ab): Yield: 186 mg, 50%; white crystals. IR
˜
2
2
1294, 1259 cm–1. H NMR (400 MHz, CDCl3): δ = 8.11–8.07 (m,
2 H), 7.56–7.41 (m, 3 H), 7.26 (s, 1 H), 7.23 (dd, J = 2.3, 8.5 Hz,
1 H), 7.00 (d, J = 8.5 Hz, 1 H), 5.30 (d, J = 8.8 Hz, 1 H, -CH2-),
4.39 (d, J = 8.8 Hz, 1 H, -CH2-), 4.32–4.18 (m, 2 H, OCH2CH3),
1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.9, 165.6, 151.1, 135.0, 132.1, 128.8, 128.4, 127.0,
126.5, 125.6, 120.2, 116.4, 79.9, 76.7, 62.3, 14.0 ppm. LRMS
(ESI+): m/z = 346 [M + H]+. C18H16ClNO4 (345.78) C 62.52, H
4.66, N 4.05; found C 62.30, H 4.77, N 4.77.
1
(film, CH Cl ): ν = 3346 (br.), 2983, 2227, 1739, 1637, 1292, 1256,
˜
2
2
1
1098, 695 cm–1. H NMR (500 MHz, CDCl3): δ = 8.09–8.06 (m, 2
H), 7.82 (s, 1 H), 7.57–7.52 (m, 1 H), 7.47–7.43 (m, 2 H), 7.27 (s,
1 H), 5.60 (d, J = 8.8 Hz, 1 H, -CH2-), 4.45 (d, J = 8.8 Hz, 1 H,
-CH2-), 4.35–4.21 (m, 2 H, OCH2CH3), 1.25 (t, J = 7.2 Hz, 3 H,
-OCH2CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.1, 167.1,
151.8, 138.8, 132.5, 129.2, 128.9, 128.5, 126.2, 126.0, 121.1, 116.8,
109.0, 79.2, 76.7, 63.1, 13.9 ppm. LRMS (ESI+): m/z = 393 [M +
Na]+. C19H15ClN2O5 (370.78): C 61.55, H 4.08, N 7.56, Cl 9.56;
found C 61.28, H 4.15, N 7.79, Cl 9.40.
Ethyl 4-(3-Chloro-4-hydroxyphenyl)-2-phenyl-1,3-oxazoline-4-carb-
oxylate (6ab): Yield: 176 mg, 51%; yellow crystals; m.p. 137–
α-(4-Nitrophenyl)serine (2aac): Yield: 174 mg, 77%; white solid;
140 °C. IR (film, CH Cl ): ν = 3413 (br.), 2982, 1736, 1632, 1495,
˜
2
2
m.p. Ͼ350 °C (decomp.). IR (KBr): ν = 3215, 3080, 2517, 1649,
˜
1
1272, 1243 cm–1. H NMR (400 MHz, CDCl3): δ = 8.20–7.90 (m,
2 H), 7.56–7.52 (m, 2 H), 7.48–7.42 (m, 2 H), 6.88 (d, J = 2.6 Hz,
1 H), 6.71 (dd, J = 2.6, 8.6 Hz, 1 H), 5.64 (d, J = 8.8 Hz, 1 H,
-CH2-), 4.37 (d, J = 8.8 Hz, 1 H, -CH2-), 4.32–4.25 (m, 1 H,
OCH2CH3), 4.17–4.12 (m, 1 H, OCH2CH3), 1.20 (t, J = 7.2 Hz, 3
H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9,
166.8, 156.4, 132.5, 131.7, 130.1, 129.2, 129.0, 128.5, 126.5, 117.0,
114.1, 96.1, 79.3, 77.2, 62.6, 13.9 ppm. LRMS (ESI+): m/z = 346
1
1607, 1521, 1390, 1340 cm–1. H NMR (400 MHz, D2O/DCl): δ =
8.26 (d, J = 9.1 Hz, 2 H), 7.69 (d, J = 9.1 Hz, 2 H), 4.42 (d, J =
12.1 Hz, 1 H, -CH2-), 4.19 (d, J = 12.1 Hz, 1 H, -CH2-) ppm. 13C
NMR (100 MHz, D2O/DCl): δ = 170.5, 148.5, 139.3, 127.6, 124.7,
66.8, 63.8 ppm. LRMS (ESI+): m/z = 227 [M + H]+.
α-(4-Hydroxyphenyl)serine (2abc): Yield: 115 mg, 69%; white solid;
m.p. Ͼ350 °C (decomp.). IR (KBr): ν = 3440, 3261, 3098, 1653,
˜
Eur. J. Org. Chem. 2010, 4218–4226
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4223

D. Sulikowski, M. Makosza
˛
FULL PAPER
1568, 1518, 1376, 1186, 1057 cm–1. 1H NMR (400 MHz, D2O/ 129.2, 128.9, 128.5, 127.0, 126.5, 116.8, 113.5, 84.9, 82.4, 63.0, 18.3,
DCl): δ = 7.13 (d, J = 9.0 Hz, 2 H), 6.74 (d, J = 9.0 Hz, 2 H), 4.21 14.0 ppm. LRMS (ESI+): m/z = 389 [M + H]+. C19H17ClN2O5
(d, J = 11.9 Hz, 1 H, -CH2-), 4.00 (d, J = 11.4 Hz, 1 H, (388.81): calcd. C 58.69, H 4.41, N 7.20; found C 58.79, H 4.56, N
-CH2-) ppm. 13C NMR (100 MHz, D2O/DCl): δ = 171.3, 156.8, 7.09.
127.5, 123.4, 116.1, 66.2, 63.2 ppm. LRMS (ESI––): m/z = 196 [M –
Ethyl (4R,5R)-5-Methyl-4-(2-methoxy-4-nitrophenyl)-2-phenyl-1,3-
H]–.
oxazoline-2-carboxylate (8ba): Yield: 112 mg, 29%; oil. [α]1D9
=
α-(3-Chloro-4-hydroxyphenyl)serine (5abc): Yield: 184 mg, 80%;
–174.8 (c = 0.500, CHCl ). IR (film): ν = 2981, 2942, 1738, 1647,
˜
3
white solid; m.p. Ͼ350 °C (decomp.). IR (KBr): ν = 3092, 2708,
1525, 1347, 1252, 1236, 1029 cm–1. 1H NMR (400 MHz, CDCl3):
˜
1632, 1513, 1360, 1518, 1296, 1057 cm–1. 1H NMR (400 MHz, δ = 8.07–8.04 (m, 2 H), 7.89–7.85 (m, 2 H), 7.76 (d, J = 1.9 Hz, 1
D2O/DCl): δ = 7.31 (d, J = 2.4 Hz, 1 H), 7.07 (dd, J = 2.4, 8.6 Hz,
1 H), 6.88 (d, J = 8.8 Hz, 1 H), 4.21 (d, J = 12.1 Hz, 1 H, -CH2-),
4.00 (d, J = 12.1 Hz, 1 H, -CH2-) ppm. 13C NMR (100 MHz, D2O/
H), 7.76–7.50 (m, 1 H), 7.47–7.42 (m, 2 H), 4.88 (q, J = 6.6 Hz, 1
H, CH-CH3), 4.26–4.20 (m, 1 H, OCH2CH3), 4.16–4.10 (m, 1 H,
OCH2CH3), 3.96 (s, 3 H), 1.80 (d, J = 6.6 Hz, 3 H, CHCH3), 1.20
DCl): δ = 170.8, 152.8, 127.8, 125.8, 124.6, 121.0, 117.3, 65.9, (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
63.2 ppm. LRMS (ESI–): m/z = 230 [M – H]–.
CDCl3): δ = 169.0, 165.7, 157.1, 148.5, 132.0, 128.7, 128.4, 128.3,
127.4, 127.3, 116.0, 105.9, 85.4, 80.6, 61.5, 55.8, 17.3, 14.1 ppm.
LRMS (ESI+): m/z = 385 [M + H]+. C20H20N2O6 (384.34): calcd.
C 62.49, H 5.24, N 7.29; found C 62.22, H 5.52, N 7.04.
Ethyl (4R,5R)-5-Methyl-4-(4-nitrophenyl)-2-phenyl-1,3-oxazoline-2-
carboxylate (2ba): Yield: 280 mg, 79%; oil. [α]1D9 = –36.0 (c = 1.100,
CHCl ). IR (film): ν = 3387, 2984, 1733, 1649, 1522, 1351,
˜
3
1237 cm–1. H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 9.1 Hz, Ethyl (4R,5R)-5-Methyl-4-(3-cyano-4-nitrophenyl)-2-phenyl-1,3-ox-
1
2 H), 8.10–8.07 (m, 2 H), 7.85 (d, J = 9.1 Hz, 2 H), 7.58–7.52 (m, azoline-2-carboxylate (10ba): Yield: 266 mg, 70%; oil. [α]2D0 = –48.0
1 H), 7.49–7.45 (m, 2 H), 4.98 (q, J = 6.6 Hz, 1 H, CH-CH3), 4.28–
(c = 1.100, CHCl ). IR (film): ν = 3070, 2984, 2235, 1734, 1648,
˜
3
4.20 (m, 2 H, OCH2CH3), 1.67 (d, J = 6.6 Hz, 3 H, -CH-CH3), 1534, 1346, 1232, 1052 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.26 (t, J = 7.2 Hz, 3 H, -CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.6, 165.3, 148.9, 147.4, 132.1, 128.7, 128.4, 127.7,
127.0, 123.3, 85.1, 82.3, 62.3, 17.6, 14.1 ppm. LRMS (ESI+): m/z
= 355 [M + H]+. C19H18N2O5 (354.36): C 64.40, H 5.21, N 7.91;
found C 64.23, H 5.21, N 7.81.
8.32 (d, J = 8.8 Hz, 1 H), 8.24 (d, J = 1.7 Hz, 1 H), 8.14–8.06 (m,
3 H), 7.60–7.55 (m, 1 H), 7.51–7.44 (m, 3 H), 4.92 (q, J = 6.5 Hz,
1 H, CH-CH3), 4.31–4.20 (m, 2 H, OCH2CH3), 1.69 (d, J = 6.5 Hz,
3 H, CHCH3), 1.29 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.8, 166.1, 149.3, 147.6, 134.2, 132.5,
132.2, 128.7, 128.5, 126.5, 125.3, 114.9, 107.8, 85.1, 81.8, 62.7, 17.5,
14.0 ppm. LRMS (ESI+): m/z = 380 [M + H]+. C20H17N3O5
(379.37): calcd. C 63.32, H 4.54, N 11.08; found C 63.35, H 4.76,
N 10.69.
Ethyl (4R,5R)-5-Methyl-4-(3-fluoro-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-2-carboxylate (4ba): Yield: 339 mg, 91%; oil. [α]1D9 = –108.4
(c = 1.000, CHCl ). IR (film): ν = 3111, 2985, 1739, 1652, 1530,
˜
3
1353, 1235, 1081 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.12–8.04
(m, 4 H), 8.02–7.97 (m, 1 H), 7.58–7.31 (m, 1 H), 7.49–7.43 (m, 2
H), 5.00 (dq, J = 1.7, 6.4 Hz, 1 H, CH-CH3), 4.29–4.18 (m, 2 H,
OCH2CH3), 1.75 (dd, J = 1.7, 6.5 Hz, 3 H, CH-CH3), 1.25 (t, J =
7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.4, 166.0, 160.0 (d, J = 250 Hz), 148.3 (d, J = 9.4 Hz), 137.2 (d,
J = 13.7 Hz), 132.2, 129.7 (d, J = 5.2 Hz), 128.7, 128.4, 126.9, 119.1
(d, J = 3.5 Hz), 111.7 (d, J = 27.5 Hz), 84.9 (d, J = 4.3 Hz), 80.9
(d, J = 2.5 Hz), 62.3, 16.7, 14.0 ppm. 19F NMR (376 MHz, CDCl3):
δ = –107.7 to –107.8 (m) ppm. LRMS (ESI+): m/z = 373 [M +
H]+. C19H17FN2O5 (372.35): calcd. C 61.29, H 4.60, N 7.57; found
C 61.06, H 4.77, N 7.44.
Ethyl (4R,5R)-5-Methyl-4-(2-cyano-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-2-carboxylate (11ba): Yield: 299 mg, 79%; white crystals;
m.p. 94–95 °C. [α]1D9 = –120.0 (c = 0.750, CHCl ). IR (film): ν =
˜
3
3083, 2985, 2233, 1735, 1649, 1532, 1354, 1239, 697 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.30 (d, J = 2.0 Hz, 1 H), 8.12 (d, J =
2.4 Hz, 1 H), 8.11–8.05 (m, 2 H), 7.96 (d, J = 8.6 Hz), 7.59–7.53
(m, 1 H), 7.50–7.44 (m, 2 H), 5.07 (q, J = 6.6 Hz, 1 H, CH-CH3),
4.31–4.18 (m, 2 H, OCH2CH3), 1.98 (d, J = 6.6 Hz, 3 H, CHCH3),
1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.1, 166.1, 147.7, 147.6, 134.0, 132.3, 129.7, 128.8,
128.5, 126.8, 125.5, 121.7, 85.2, 81.4, 62.2, 18.1, 13.9 ppm. LRMS
(ESI+): m/z = 380 [M + H]+. C20H17N3O5 (379.37): calcd. C 63.32,
H 4.54, N 11.08; found C 63.43, H 4.46, N 11.11.
Ethyl (4R,5R)-5-Methyl-4-(2-chloro-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-2-carboxylate (5ba): Yield: 307 mg, 79%; oil. [α]2D0 = –31.7
(c = 0.525, CHCl ). IR (film): ν = 2983, 1733, 1650, 1530, 1346,
Ethyl (4R,5R)-5-Methyl-4-(4-ethoxy-5-nitro-2-pyridyl)-2-phenyl-1,3-
oxazoline-2-carboxylate (14ba): Yield: 311 mg, 78%; white crystals;
˜
3
1
1237, 1053 cm–1. H NMR (400 MHz, CDCl3): δ = 8.10–8.06 (m,
2 H), 7.90–7.87 (m, 1 H), 7.70 (dd, J = 2.0, 8.6 Hz, 1 H), 7.56–7.52
m.p. 55–56 °C. [α]1D9 = +52.2 (c = 0.750, CHCl ). IR (KBr): ν =
˜
3
(m, 2 H), 7.50–7.44 (m, 2 H), 4.92 (q, J = 6.6 Hz, 1 H, CH-CH3), 2985, 1738, 1598, 1580, 1354, 1298, 1233 cm–1. 1H NMR
4.29–4.20 (m, 2 H, OCH2CH3), 1.65 (d, J = 6.6 Hz, 3 H, CH-CH3), (400 MHz, CDCl3): δ = 8.96 (s, 1 H), 8.10–8.02 (m, 2 H), 7.53 (s,
1.27 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, 1 H), 7.56–7.48 (m, 2 H), 7.48–7.40 (m, 2 H), 5.59 (q, J = 6.6 Hz,
CDCl3): δ = 169.2, 165.6, 147.9, 147.1, 132.3, 130.4, 128.7, 128.5,
127.0, 128.8, 126.1, 125.4, 85.1, 81.8, 62.5, 17.5, 14.1 ppm. LRMS
(ESI+): m/z = 389 [M + H]+. C19H17ClN2O5 (388.81): calcd. C
58.69, H 4.41, N 7.20; found C 58.93, H 4.60, N 7.08.
1 H, CH-CH3), 4.30 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.22 (q, J =
7.2 Hz, 2 H, OCH2CH3), 1.69 (d, J = 6.5 Hz, 3 H, OCH2CH3),
1.50 (t, J = 7.0 Hz, 3 H, CHCH3), 1.23 (t, J = 7.2 Hz, 3 H,
-OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2, 166.1,
165.3, 158.6, 145.9, 135.8, 132.0, 128.5, 128.4, 128.3, 127.1, 127.0,
107.9, 83.9, 82.4, 65.8, 62.0, 17.0, 14.0 (2 C) ppm. LRMS (ESI+):
m/z = 400 [M + H]+. C20H21N3O6 (399.40): calcd. C 60.14, H 5.30,
N 10.52; found C 59.91, H 5.20, N 10.47.
Ethyl (4R,5R)-5-Methyl-4-(3-chloro-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-2-carboxylate (6ba): Yield: 311 mg, 80%; oil. [α]2D0 = –219.7
(c = 1.150, CHCl ). IR (film): ν = 2984, 2905, 1742, 1645, 1525,
˜
3
1
1349, 1235 cm–1. H NMR (400 MHz, CDCl3): δ = 8.59–8.61 (m,
1 H), 8.36 (dd, J = 2.6, 8.8 Hz, 1 H), 8.19 (dd, J = 0.4, 8.8 Hz, 2
Ethyl (4R,5R)-5-Methyl-4-(4-hydroxyphenyl)-2-phenyl-1,3-oxazol-
H), 7.60–7.55 (m, 2 H), 7.50–7.45 (m, 2 H), 5.82 (q, J = 6.4 Hz, 1 ine-2-carboxylate (2bb): Yield: 195 mg, 60%; white crystals; m.p.
H, CH-CH3), 4.44–4.25 (m, 2 H, OCH2CH3), 1.82 (d, J = 6.4 Hz, 178–180 °C. [α]1D9 = –13.3 (c = 1.000, CHCl ). IR (KBr): ν = 3100
˜
3
CH-CH3), 1.31 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(br.), 2985, 2939, 1736, 1644, 1515, 1244, 1046, 697 cm–1. 1H NMR
(100 MHz, CDCl3): δ = 168.0, 166.0, 152.2, 147.0, 132.5, 129.9, (400 MHz, CDCl3): δ = 8.06–8.02 (m, 2 H), 7.49–7.43 (m, 1 H),
4224
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4218–4226

Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes
7.40–7.33 (m, 4 H), 6.78–6.74 (m, 2 H), 5.04 (q, J = 6.4 Hz, 1 H,
178–180 °C. [α]1D9 = +13.9 (c = 1.000, CHCl3); analytical data iden-
CH-CH3), 4.20–4.11 (m, 2 H, OCH2CH3), 1.56 (d, J = 6.5 Hz, 3 tical to that of 2bb.
H, CHCH3), 1.17 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR
Ethyl (4S,5S)-5-Methyl-4-(2-chloro-4-hydroxyphenyl)-2-phenyl-1,3-
(100 MHz, CDCl3): δ = 170.9, 164.7, 156.1, 132.8, 131.9, 128.6,
128.3, 127.4, 127.0, 115.5, 85.3, 81.9, 61.8, 17.5, 14.0 ppm. LRMS
(ESI+): m/z = 326 [M + H]+. C19H19NO4 (325.36): calcd. C 70.14,
H 5.89, N 4.30; found C 70.06, H 6.04, N 4.27.
oxazoline-4-carboxylate (6cb): Yield: 252 mg, 70%; white crystals;
m.p. 146–147 °C. [α]1D9 = +189.0 (c = 0.900, CHCl3); analytical data
identical to that of 6bb.
Ethyl (4S,5S)-5-Methyl-4-(2-cyano-4-hydroxyphenyl)-2-phenyl-1,3-
oxazoline-2-carboxylate (11cb): Yield: 207 mg, 58%; white crystals;
m.p. 118–119 °C. [α]1D9 = +119.1 (c = 1.000, CHCl3); analytical data
identical to that of 11bb.
Ethyl (4R,5R)-5-Methyl-4-(2-fluoro-4-hydroxyphenyl)-2-phenyl-1,3-
oxazoline-2-carboxylate (4bb): Yield: 199 mg, 58%; oil. [α]1D9
=
–28.2 (c = 0.700, CHCl ). IR (film, CH Cl ): ν = 3384 (br.), 2982,
˜
3
2
2
1
1737, 1627, 1451, 1240, 694 cm–1. H NMR (400 MHz, CDCl3): δ
= 8.06–8.02 (m, 2 H), 7.54–7.48 (m, 2 H), 7.46–7.38 (m, 2 H), 6.58–
6.50 (m, 2 H), 5.06 (q, J = 6.4 Hz, 1 H, CH-CH3), 4.25–4.15 (m, 2
H, OCH2CH3), 1.67 (d, J = 6.4 Hz, 3 H, CHCH3), 1.22 (t, J =
7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.0, 165.3, 160.9 (d, J = 245 Hz), 157.2 (d, J = 12 Hz), 132.0 (d,
J = 38 Hz), 128.7 (d, J = 6.1 Hz), 128.6 (d, J = 4.7 Hz), 128.5 (d,
J = 12.5 Hz), 121.2 (d, J = 13 Hz), 111.0, 103.9 (d, J = 4.7 Hz),
156.1, 132.8, 131.9, 128.6, 128.3, 127.4, 127.2, 127.0, 115.5, 85.3,
81.9, 61.8, 17.5, 14.0 ppm. LRMS (ESI+): m/z = 344 [M + H]+.
C19H18FNO4 (343.36): calcd. C 66.46, H 5.28, N 4.08; found C
67.00, H 5.31, N 4.21.
Ethyl Ester of N-Benzoyl-α-(4-nitrophenyl)-
Yield: 279 mg, 75%; solidifying oil. [α]1D9 = –31.5 (c = 0.275,
CHCl ). IR (film, CH Cl ): ν = 3386, 2983, 1825, 1653, 1522, 1349,
D-allo-threonine (2bac):
˜
3
2
2
1271, 1109 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J =
8.9 Hz, 2 H), 7.93 (d, J = 8.9 Hz), 7.81–7.92 (m, 2 H), 7.56–7.49
(m, 1 H), 7.42 (t, J = 7.8 Hz, 2 H), 6.03 (q, J = 6.3 Hz, 1 H, CH-
CH3), 4.31–4.16 (m, 2 H, -OCH2CH3), 1.42 (d, J = 6.3 Hz, 3 H,
CHCH3), 1.26 (t, J = 7.1 Hz, 3 H, -OCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.5, 168.2, 147.7, 143.5, 133.3, 129.1,
128.4, 127.7, 127.3, 123.3, 74.1, 67.0, 62.4, 19.2, 15.3 ppm. LRMS
(ESI+): m/z = 373 [M + H]+. C19H20N2O6 (372.38): calcd. C 61.28,
H 5.41, N 7.52; found C 61.56, H 5.46, N 7.42.
Ethyl (4R,5R)-5-Methyl-4-(2-chloro-4-hydroxyphenyl)-2-phenyl-1,3-
oxazoline-2-carboxylate (6bb): Yield: 252 mg, 70%; white crystals;
m.p. 146–147 °C. [α]1D9 = –184.5 (c = 0.900, CHCl ). IR (KBr): ν =
Acknowledgments
˜
3
3330 (br.), 2983, 1738, 1639, 1495, 1450, 1235, 696 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.36–8.08 (m, 2 H), 7.54–7.49 (m, 2 H),
7.46–7.38 (m, 2 H), 6.86 (d, J = 2.5 Hz, 1 H), 6.63 (dd, J = 2.5,
8.6 Hz, 1 H), 5.10 (q, J = 6.5 Hz, 1 H, CH-CH3), 4.25–4.15 (m, 2
H, OCH2CH3), 1.79 (d, J = 6.5 Hz, 3 H, CHCH3), 1.20 (t, J =
7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.9, 165.8, 156.4, 133.3, 132.1, 131.6, 128.9, 128.7, 128.4, 127.0,
118.0, 114.1, 85.5, 80.8, 61.9, 17.6, 13.9 ppm. LRMS (ESI+): m/z
= 360 [M + H]+. C19H18ClNO4 (359.81): calcd. C 63.43, H 5.05,
N 3.89; found C 63.17, H 5.15, N 4.07.
This work was partially supported by the Ministerium of Science
and Higher Education (Grant N204 0304 33). Special thanks to
Wiesław Kamin´ski for his linguistic support.
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Ethyl (4R,5R)-5-Methyl-4-(2-cyano-4-hydroxyphenyl)-2-phenyl-1,3-
oxazoline-2-carboxylate (11bb): Yield: 207 mg, 59%; white crystals;
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˜
3
3334 (br.), 2985, 2228, 1738, 1645, 1495, 1451, 1239, 696 cm–1. H
1
NMR (400 MHz, CDCl3): δ = 8.03–8.01 (m, 2 H), 7.60 (d, J =
8.8 Hz, 1 H), 7.51–7.45 (m, 1 H), 7.43–7.35 (m, 2 H), 7.17 (d, J =
2.7 Hz, 1 H), 6.97 (dd, J = 2.7, 8.5 Hz, 1 H), 5.30 (q, J = 6.4 Hz,
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3 H, CHCH3), 1.25 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 169.7, 165.7, 156.3, 135.8, 132.3,
129.0, 128.7, 128.4, 126.5, 121.7, 120.2, 118.5, 111.8, 85.1, 81.6,
62.6, 17.8, 13.9 ppm. LRMS (ESI+): m/z = 351 [M + H]+.
C20H18N2O4 (350.37): calcd. C 68.56, H 5.18, N 8.00; found C
68.55, H 5.33, N 7.95.
Ethyl (4S,5S)-5-Methyl-4-(4-nitrophenyl)-2-phenyl-1,3-oxazoline-2-
carboxylate (2ca): Yield: 269 mg, 76%; oil. [α]1D9 = +36.2 (c = 1.100,
CHCl3); analytical data identical to that of 2ba.
Ethyl (4S,5S)-5-Methyl-4-(2-chloro-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-4-carboxylate (6ca): Yield: 300 mg, 77%; oil. [α]2D0 = –229.1
(c = 1.150, CHCl3); analytical data identical to that of 6ba.
Ethyl (4S,5S)-5-Methyl-4-(3-cyano-4-nitrophenyl)-2-phenyl-1,3-ox-
azoline-4-carboxylate (10ca): Yield: 265 mg, 70%; oil. [α]1D9 = –51.0
(c = 1.100, CHCl3); analytical data identical to that of 10ba.
Ethyl (4S,5S)-5-Methyl-4-(4-hydroxyphenyl)-2-phenyl-1,3-oxazol-
ine-4-carboxylate (2cb): Yield: 188 mg, 58%; white crystals; m.p.
Eur. J. Org. Chem. 2010, 4218–4226
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4225

D. Sulikowski, M. Makosza
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Received: April 12, 2010
Published Online: June 17, 2010
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