Studies towards the synthesis of alkyl N-(4-nitrophenyl)-3/2-oxomorpholine- 2/3-carboxylates

Article abstract of DOI:10.1002/hlca.201300085

The syntheses of methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a) and ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate (5b), important building blocks for the synthesis of factor Xa inhibitor rivaroxaban analogs with potential dual antithrombotic activity, via Rh₂(OAc) ₄-catalyzed O-H and N-H carbene insertion reactions are described.

Full text of DOI:10.1002/hlca.201300085

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Studies towards the Synthesis of Alkyl N-(4-Nitrophenyl)-3/2-oxomorpholine-
2/3-carboxylates
by Urosˇ Trstenjak, Janez Ilasˇ, and Danijel Kikelj*
ˇ
ˇ
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana
(fax: þ 386-1-4258-031; e-mail: danijel.kikelj@ffa.uni-lj.si)
The syntheses of methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a) and ethyl 4-(4-
nitrophenyl)-2-oxomorpholine-3-carboxylate (5b), important building blocks for the synthesis of factor
Xa inhibitor rivaroxaban analogs with potential dual antithrombotic activity, via Rh2(OAc)4-catalyzed
OꢀH and NꢀH carbene insertion reactions are described.
1. Introduction. – Development of efficient synthetic methodologies is frequently
driven by the need of novel key intermediates for the synthesis of bioactive compounds
of pharmaceutical interest. The morpholin-3-one (1) and morpholin-2-one (2)
skeletons, and their derivatives are important synthons for the design of bioactive
compounds and reagents [1]. In the course of our medicinal-chemistry program aimed
at discovering dual antithrombotic compounds with highly overlapping factor Xa
inhibitor and fibrinogen receptor antagonist pharmacophores [2], protected 4-(4-
nitrophenyl)-3-oxomorpholine-2-carboxylates and 4-(4-nitrophenyl)-2-oxomorpho-
line-3-carboxylates, 3 and 5, respectively, were required in order to functionalize the
parent oxomorpholin moiety of the lead compound with a negatively charged
carboxylate group.
2,4-Disubstituted morpholin-3-ones had previously been prepared by either one- or
two-bond cyclization reactions (formation of O(1)ꢀC(2) bond, formation of O(1)ꢀC(6)
bond, or concurrent formation of O(1)ꢀC(2) and C(3)ꢀN(4) bonds) [1][3 – 7] or by
direct functionalization of 4-substituted morpholin-3-ones at C(2), using strong bases
and various electrophilic reagents [8 – 13] (Scheme 1). Ethyl 3-oxo-4-phenylmorpho-
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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line-2-carboxylate (4) [14] is the only known 4-phenylmorpholin-3-one derivative
bearing a protected carboxylate group that closely resembles our target compounds 3.
Although 3b and 4 differ solely in the p-NO2 substituent on a Ph ring, a direct transfer
of the methodology for synthesizing 4, comprising O(1)ꢀC(2) bond-formation by
intramolecular insertion of a carbene generated from a-diazo ester 6 into the OꢀH
bond of the 4-(2-hydroxyethyl) moiety [14] (Scheme 2), proved to be useless for
preparing 3b. We, therefore, explored alternative methods for the synthesis of this key
intermediate and isomeric 2-oxomorpholine-3-carboxylates 5. This finally resulted in a
four-step Rh2(OAc)4-catalyzed synthesis of the hitherto unknown methyl 4-(4-nitro-
phenyl)-3-oxomorpholine-2-carboxylate (3a) and in a simple Rh2(OAc)4-promoted
preparation of ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate (5b), the latter
being the first 4-arylmorpholin-2-one bearing a protected 3-carboxylate group. A
synthesis of closely related ethyl 4-[(benzyloxy)carbonyl]-2-oxomorpholine-3-carbox-
ylate by Rh2(OAc)4-catalyzed NꢀH insertion has previously been unsuccessful [15].
Scheme 1
Scheme 2. Rh2(OAc)4-Catalyzed Cyclization [14]
2. Results and Discussion. – We initially planned to synthesize 3a by exploiting the
strategy of O(1)ꢀC(2) bond-formation by intramolecular nucleophilic substitution of
Br in 7 (cf. Scheme 3). To this end, to prepare methyl 2-bromo-3-[(2-hydroxyethyl)(4-
nitrophenyl)amino]-3-oxopropanoate (7), 2-[(4-nitrophenyl)amino]ethanol (8) [16]
was reacted, in the presence of Et3N in CH2Cl2, with either methyl 2-bromo-3-chloro-3-

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Scheme 3. Planned Synthesis of 3a by Intramolecular Nucleophilic Substitution
oxopropanoate (9)1) or methyl 3-chloro-3-oxopropanoate (10; Scheme 4). Compound
9 was prepared by treating 10 with Br2 in a mixture of CH2Cl2 and CCl4 and these
reaction conditions were also intended to be used in the synthesis of 7 from
intermediate 11. However, after reacting 8 with 9 or 10, analysis of the reaction
products revealed that the negative inductive and mesomeric effects of the p-NO2
group in 8 decreased the nucleophilicity of the secondary amine N-atom to such an
extent that O-acylation predominated over N-acylation, resulting in O-acylated
compounds 12 and 13, and N,O-diacylated products 12a and 13a. N-Acylated products
7 and 11 were not detected in the mixtures (Scheme 4). In the attempt to obtain 12
from 13, bromination took place preferentially on the Ph ring to give products 14 and
14a (Scheme 5) in which the Br-atom entered into the position meta2) to the NO2
group.
The unexpected access to 1-methyl 3-{2-[(4-nitrophenyl)amino]ethyl} 2-bromo-
malonate (12) offered us the opportunity to prepare, by its cyclization, methyl 4-(4-
nitrophenyl)-2-oxo-morpholine-3-carboxylate (5a). To obtain 5a, compound 12 was
refluxed with a base in THF, but intramolecular substitution of the Br-atom with the
secondary amine did not take place.
In our next attempt to obtain ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carbox-
ylate (5b), we combined our earlier observation that O-acylation of 2-[(4-nitro-
phenyl)amino]ethanol (8) is preferred over N-acylation in the RhII-catalyzed approach
for preparation of ethyl 3-oxo-4-phenylmorpholine-2-carboxylate (4) [14]. To our
satisfaction, O-acylation of 8 with ethyl 3-chloro-2-diazo-3-oxopropanoate (15) [14] in
the presence of Et3N afforded 1-ethyl 3-{2-[(4-nitrophenyl)amino]ethyl}-2-diazomal-
onate (16) which, via subsequent Rh2(OAc)4-catalyzed intramolecular NꢀH carbene
insertion, afforded 5b [17] (Scheme 6).
Our attempts to prepare the isomeric alkyl 3-oxomorpholin-2-carboxylates 3 first
relied on synthetic strategies of direct functionalization of N-substituted morpholin-3-
one derivatives. This appeared feasible because of the acidic character of the H-atoms
at C(2) in the morpholin-3-one ring [4][8][9]. Preparation of 4-(4-nitrophenyl)mor-
1
1
)
)
According to H-NMR analysis, crude 9 could be a mixture of 2-bromo-3-chloro-3-oxopropanoate
and 2-bromo-3-bromo-3-oxopropanoate, and was used without purification.
2
The position of the Br-atom meta to the NO2 group on Ph of compounds 14 and 14a was confirmed
by H,13C-HMBC analysis.
1

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Scheme 4
Scheme 5
pholin-3-one (20) from 17 via 19 [18] was thus targeted by several attempts, in which
reagents, bases, solvents, and reaction temperatures were varied, to introduce the
ethoxycarbonyl moiety at C(2) of the morpholin-3-one moiety (Scheme 7 and Table).
Although the N-Me analog of 3b has been synthesized in this way, using ClHCOOEt
and lithium diisopropylamide (LDA) as a base [8], our attempts to synthesize 3b under
these conditions were not successful.

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Scheme 6
Scheme 7
Table. Reaction Conditions Applied in Attempted Synthesis of 3b from 20
Reagent
Base
Solvent
Temp. [8]
ClCOOEt
ClCOOEt
(EtO)2CO
(EtO)2CO
LDA
NaH
NaH
THF
THF/DMF
THF
ꢀ 80 – 20
Reflux
Reflux
Reflux
NaOEt
EtOH
The failure in synthesizing 7 (Scheme 4) and in attempts to introduce the 2-
ethoxycarbonyl group to morpholin-3-one 20 (Scheme 7), coupled with the successful
preparation of 5b, stimulated us to consider the Rh2(OAc)4-catalyzed carbene insertion
reaction also for preparing alkyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylates 3.
In our first attempt to exploit the Rh2(OAc)4-catalyzed intramolecular OꢀH insertion
reaction, we planned to prepare 3b by nitration of the known ethyl 3-oxo-4-
phenylmorpholine-2-carboxylate (4) [14] obtained from ethyl 2-diazo-3-[(2-hydroxy-
ethyl)(phenyl)amino]-3-oxopropanoate (6; Scheme 8). Although the synthesis of 4 has
been described and could be repeated in low yields, we developed another synthetic
pathway for its preparation. 2-(Phenylamino)ethanol (17) was N-acylated with ethyl 3-
chloro-3-oxopropanoate (21) to afford ethyl 3-[(2-hydroxyethyl)(phenyl)amino]-3-
oxopropanoate (22). In this case, stimulated by the NO2 group, N-acylation took place
rather than the O-acylation in case of the substrate 8. In the next step, TsN3 (23) was

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2165
Scheme 8
used as a reagent to introduce the diazo group3) at C(2) of 22 to give 6, which was
cyclized to compound 4 using Rh2(OAc)4 catalysis. Compound 4 was then nitrated in
HNO3/H2SO4, but 1H-NMR analysis of the crude product indicated nitration of the Ph
ring in the ortho- and para-positions4), and absence of the COOEt group, rendering
this last step unpromising for the synthesis of 3b. Methyl 2-diazo-3-[(2-hydroxyeth-
yl)(4-nitrophenyl)amino]-3-oxopropanoate (28), a p-NO2 derivative of 6, was, there-
fore, prepared (Scheme 9), and synthesis of the desired methyl 4-(4-nitrophenyl)-3-
oxomorpholine-2-carboxylate (3a) attempted by analogy to the synthesis of 4 [14] (cf.
Scheme 2).
To this end, 4-nitroaniline (24) was first N-acylated with 10, and the resulting methyl
3-[(4-nitrophenyl)amino]-3-oxopropanoate (25) was subjected to diazotization with
TsN3 (23). The product was isolated from Et2O as the Et3NHþ salt 26, which, due to the
increased nucleophilicity of its amide N-atom, reacted smoothly in the nucleophilic
substitution of 2-bromoethanol (27) to afford 28. However, when 28 was treated with
Rh2(OAc)4 in CH2Cl2 at room temperature, followed by refluxing in CH2Cl2, benzene,
THF, or H2O, intramolecular carbene insertion into the OꢀH bond did not take place,
and 3a could not be obtained by this strategy. To explore whether failure of cyclization
was due to an unfavorable distance of the OH to the N2 group of 28, methyl 2-diazo-3-
[(3-hydroxypropyl)(4-nitrophenyl)amino]-3-oxopropanoate (31) and methyl 2-diazo-
3
)
Acylation of CH2N2 by the reaction of CH2N2 with acyl halides or anhydrides, and diazo transfer of
an azide reagent to the C-atom adjacent to a C¼O group are two basic methods for preparation of
a-diazocarbonyl compounds.
Chemical shifts and coupling constants of three aromatic H-atoms in the 1H-NMR spectrum of the
product: 8.86 (d, Jm ¼ 2.5), 8.57 (dd, Jo ¼ 8.7, Jm ¼ 2.5), 7.70 (d, Jo ¼ 8.7).
4
)

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Scheme 9
3-{[2-(hydroxymethyl)benzyl](4-nitrophenyl)amino}-3-oxopropanoate (32) were pre-
pared from 26 (Scheme 9). They also could not be cyclized in the presence of
Rh2(OAc)4, indicating that the synthetic pathway used to prepare 4 [14] is not generally
applicable. Since synthesis of ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate
(5b; Scheme 6) was accomplished despite the presence of the NO2 group, we concluded
that the latter does not affect the activity of Rh2(OAc)4 as catalyst. Instead of an in-
depth analysis to explain these unsuccessful attempts at cyclization, we explored an
alternative synthetic pathway for the construction of the 3-oxomorpholine skeleton.
Methyl 3-[(4-nitrophenyl)amino]-3-oxopropanoate (25) was subjected to diazotization
with TsN3 (23) in the presence of 1,8-diazabicycloundec-7-ene (DBU) to give methyl 2-
diazo-3-[(4-nitrophenyl)amino]-3-oxopropanoate (33), which could also be obtained
by treating a CH2Cl2 solution of 26 with 10% citric acid. Compound 33 and 2-

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bromoethanol (27), in the presence of Rh2(OAc)4, afforded methyl 2-(2-bromo-
ethoxy)-3-[(4-nitrophenyl)amino]-3-oxopropanoate (34), which finally gave 3a5) [17]
by intramolecular nucleophilic substitution (Scheme 9).
3. Conclusions. – As a result of in-depth studies of several feasible approaches
towards the synthesis of alkyl N-(4-nitrophenyl)-3/2-oxomorpholine-2/3-carboxylates,
we have developed successful strategies for Rh2(OAc)4-catalyzed preparation of
methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a) starting from 4-nitro-
aniline, and of ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate (5b) starting
from 2-[(4-nitrophenyl)amino]ethanol. Both compounds are important intermediates
in the synthesis of compounds with potential cardiovascular activities and, in general,
versatile building blocks for the synthesis of bioactive compounds of pharmaceutical
interest.
Experimental Part
General. Chemicals obtained from Aldrich Chemical Co., Acros, and Alfa Aesar were used without
purification. Anal. TLC: Merck silica gel (60 F254) plates (0.25 mm); visualization with UV light and
ninhydrin. Column chromatography (CC): silica gel 60 (SiO2; particle size 240 – 400 mesh; Merck). M.p.:
Reichert hot-stage microscope; uncorrected. IR Spectra: PerkinꢀElmer FT-IR System Spectrum BX or
Nicolet Nexus 470 FT-IR spectrometer. 1H- and 13C-NMR spectra: at 300 (400) and 75 (100) MHz, resp.,
on a Bruker AVANCE DPX300 or a Bruker AVANCE III spectrometer in (D6)DMSO or CDCl3 at 295K;
spectra assigned by using gradient COSY, HSQC, and HMBC experiments. MS: VG Analytical Autospec
Q mass spectrometer. Microanalyses: Perkin-Elmer C,H,N analyzer 240 C. All reported yields refer to
purified products.
2-[(4-Nitrophenyl)amino]ethanol (8) [16]. 2-Aminoethanol (3.02 ml, 50 mmol) and 1-fluoro-4-
nitrobenzene (7.76 g, 55 mmol) were dissolved in DMSO (75 ml). After addition of anh. K2CO3 (10.37 g,
75 mmol), the mixture was stirred for 15 h at 558. The mixture was then poured into cold H2O (500 ml)
and extracted with AcOEt (3 ꢁ 100 ml), which was further dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude product was recrystallized from MeOH to yield 8 (7.32 g, 80%).
M.p.108 – 1118 ([16]: 1088). 1H-NMR (300 MHz, CDCl3): 8.12 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 6.60 (d, J ¼
9.2, HꢀC(2), HꢀC(6)); 4.87 (s, NH); 3.93 (q, J ¼ 5.3, CH2OH); 3.42 (q, J ¼ 5.3, NHCH2); 1.61 (t, J ¼ 5.1,
OH).
Methyl 2-[(4-Nitrophenyl)amino]ethyl 2-Bromopropanedioate (12) and 2-[(2-Bromo-3-methoxy-3-
oxopropanoyl)(4-nitrophenyl)amino]ethyl Methyl 2-Bromopropanedioate (12a). A soln. of Br2 (0.80 g,
5 mmol) in anh. CCl4 (2.5 ml) was added dropwise to a stirred boiling soln. of methyl 3-chloro-3-
oxopropanoate (0.68 g, 5 mmol) in the same solvent (10 ml). The mixture was then stirred for 15 h at r.t.,
and the solvent was removed under reduced pressure. Half of the crude product, which was according to
the 1H-NMR spectrum identified as a mixture [18] of methyl 2-bromo-3-chloro-3-oxopropanoate (9) and
methyl 2,3-dibromo-3-oxopropanoate, was dissolved in THF (3 ml) and added to the soln. of 8 (0.45 g,
2.5 mmol) and K2CO3 (0.52 g, 3.75 mmol) in THF (10 ml) at 08. The mixture was, after 2 h at 08, poured
into H2O (15 ml) and extracted with AcOEt (3 ꢁ 15 ml). The org. phase was dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was purified by flash CC (FCC; CH2Cl2/MeOH;
99 :1) to afford 12 and 12a.
Data of 12. Yield: 11%. Yellow oil. IR (neat): 3398, 2975, 1741, 1605, 1480, 1311, 1205, 1145, 1113,
1035, 911, 839, 753, 662, 628, 569, 492. 1H-NMR (300 MHz, CDCl3): 8.12 (d, J ¼ 9.2, HꢀC(3), HꢀC(5));
5
)
Methyl 2-[(4-nitrophenyl)carbamoyl]oxetane-2-carboxylate was isolated as a by-product resulting
from undesired intramolecular nucleophilic substitution of the Br-atom with the carbanion resulting
from H-atom abstraction from malonic intermediate 34.

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6.61 (d, J ¼ 9.2, HꢀC(2), HꢀC(6)); 4.90 (s, CHBr); 4.85 (t, J ¼ 9.1, NH); 4.47 – 4.53 (m, CH2O); 3.85 (s,
Me); 3.59 (dd, J ¼ 5.9, CH2N). 13C-NMR (75 MHz, CDCl3): 41.3 (BrCH); 41.9 (NHCH2); 54.2 (Me);
64.9 (CH2O); 111.4 (C(2), C(6)); 126.5 (C(3), C(5)); 138.5 (C(4)); 152.8 (C(1)); 164.6 (CH2OCO); 165.4
(COOMe). ESI-MS: 362 (6, [M þ H]þ for 81Br), 360 (6, [M þ H]þ for 79Br), 151 (100). HR-ESI-MS:
359.9963 ([M þ H]þ, C12H13BrN2O6þ ; calc. 359.9956). Anal. calc. for C12H13N2O6Br (361.15): C 39.91, H
3.63, N 7.76; found: C 39.94, H 3.81, N 7.59.
Data of 12a. Yield: 6%. Yellow oil. IR (neat): 2958, 1744, 1676, 1594, 1525, 1436, 1348, 1310, 1151,
1
1014, 856, 756, 700. H-NMR (300 MHz, CDCl3): 8.38 (d, J ¼ 8.9, HꢀC(3), HꢀC(5)); 7.62 (d, J ¼ 8.9,
HꢀC(2), HꢀC(6)); 4.81 (s, BrCH); 4.73 (s, BrCH); 4.45 (t, J ¼ 4.8, CH2O); 4.10 (t, J ¼ 4.8, CH2N); 3.84 (s,
Me); 3.82 (d, J ¼ 2.3, Me). ESI-MS: 542 (0.15, [M þ H]þ for 81Br), 540 (0.3, [M þ H]þ for 81Br/79Br), 538
(0.15, [M þ H]þ for 79Br), 151 (100). HR-ESI-MS: 537.9238 ([M þ H]þ, C16H16Br2N2Oþ9 ; calc. 537.9222).
Methyl 2-[(4-Nitrophenyl)amino]ethyl Propanedioate (13) and 2-[(3-Methoxy-3-oxopropanoyl)(4-
nitrophenyl)amino]ethyl Methyl Propanedioate (13a). Compound 10 (1.37 g, 10 mmol) was diluted with
THF (5 ml) and added to the soln. of 8 (1.81 g, 10 mmol) and K2CO3 (1.86 g, 13.5 mmol) in THF (15 ml)
at 08. The mixture was, after 2 h at 08, poured into H2O (25 ml) and extracted with AcOEt (3 ꢁ 25 ml).
The org. phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue was
purified by FCC (CH2Cl2/MeOH, 49 :1) to furnish 13 and 13a.
Data of 13. Yield: 29%. Yellow oil. IR (neat): 3349, 1758, 1604, 1551, 1472, 1436, 1286, 1036, 905, 833,
753, 697, 680, 573. 1H-NMR (300 MHz, CDCl3): 8.08 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 6.59 (d, J ¼ 9.2,
HꢀC(2), HꢀC(6)); 4.73 (s, NH); 4.41 (t, J ¼ 5.4, CH2O); 3.75 (s, Me); 3.54 (t, J ¼ 5.4, CH2N); 3.43 (s,
COCH2CO). 13C-NMR (75 MHz, CDCl3): 41.2 (COCH2CO); 42.1 (NHCH2); 52.8 (Me); 63.3 (CH2O);
111.3 (C(2), C(6)); 126.4 (C(3), C(5)); 138.4 (C(4)); 152.9 (C(1)); 166.5 (CH2OCOCH2); 167.3
(COOMe). ESI-MS: 283 (18, [M þ H]þ), 165 (100). HR-ESI-MS: 283.0930 ([M þ H]þ, C12H15N2Oþ6 ;
calc. 283.0930). Anal. calc. for C12H14N2O6 (282.09): C 51.06, H 5.00, N 9.93; found: C 51.28, H 4.92, N
9.89.
Data of 13a. Yield: 18%. Yellow oil. IR (neat): 2956, 1740, 1670, 1594, 1347, 1155, 1015, 856, 757, 702.
1H-NMR (300 MHz, CDCl3): 8.32 (d, J ¼ 9.0, HꢀC(3), HꢀC(5)); 7.52 (d, J ¼ 9.0, HꢀC(2), HꢀC(6)); 4.34
(t, J ¼ 5.3, CH2O); 4.07 (t, J ¼ 5.3, CH2N); 3.74 (s, Me); 3.69 (s, Me); 3.33 (s, COCH2CO); 3.26 (s,
COCH2CO). ESI-MS: 383 (5, [M þ H]þ), 265 (100). HR-ESI-MS: 383.1086 ([M þ H]þ, C16H19N2Oþ9 ;
calc. 383.1091). Anal. calc. for C16H18N2O9 (382.10): C 50.26, H 4.75, N 7.33; found: C 50.44, H 4.90, N
7.41.
2-[(2-Bromo-4-nitrophenyl)amino]ethyl Methyl Propanedioate (14) and 2-[(2-Bromo-4-nitropheny-
l)amino]ethyl Methyl 2-Bromopropanedioate (14a). A soln. of Br2 (1.36 g, 8.5 mmol) in anh. CCl4 (5 ml)
was added dropwise to a stirred boiling soln. of 13 (1.74 g, 6.17 mmol) in CH2Cl2/CCl4 (15 ml). The
mixture was then stirred for 15 h at r.t., and the solvent was removed under reduced pressure. The residue
was purified by FCC (CH2Cl2/MeOH (99 :1) to give 14 and 14a.
Data of 14. Yield: 55%. Yellow oil. IR (neat): 3383, 2956, 1736, 1593, 1502, 1327, 1154, 1119, 1031,
897, 747, 689. 1H-NMR (300 MHz, CDCl3): 8.39 (d, J ¼ 2.6, HꢀC(3)); 8.13 (dd, J ¼ 9.1, 2.5, HꢀC(5)); 6.66
(d, J ¼ 9.1, HꢀC(6)); 5.41 (t, NH); 4.45 (t, J ¼ 5.5, CH2O); 3.76 (s, Me); 3.62 (dd, J ¼ 11.0, 5.6, CH2N); 3.45
(s, COCH2CO). ESI-MS: 363 (10, [M þ H]þ for 81Br), 361 (10, [M þ H]þ for 79Br), 243 (100), 245 (100).
HR-ESI-MS: 361.0036 ([M þ H]þ, C12H14BrN2O6þ ; calc. 361.0035). Anal. calc. for C12H13BrN2O6
(360.00): C 39.91, H 3.63, N 7.76; found: C 40.18, H 3.48, N 7.76.
Data of 14a. Yield: 17%. Yellow oil. IR (neat): 3390, 3087, 2957, 2641, 2443, 2229, 1744, 1593, 1501,
1450, 1394, 1324, 1155, 1120, 1029, 897, 814, 746, 647. 1H-NMR (300 MHz, CDCl3): 8.34 (d, J ¼ 2.5,
HꢀC(3)); 8.09 (dd, J ¼ 9.1, 2.5, HꢀC(5)); 6.66 (d, J ¼ 9.1, HꢀC(6)); 5.39 (t, J ¼ 5.3, NH); 4.91 (s, BrCH);
3.82 (s, Me); 4.50 (m, CH2O); 3.65 (dd, J ¼ 11.1, 5.7, CH2N). ESI-MS: 443 (22, [M þ H]þ) for 81Br, 441
(45, [M þ H]þ for 81Br/79Br), 439 (22, [M þ H]þ for 79Br), 243 (100). HR-ESI-MS: 438.1330 ([M þ H]þ,
C12H13Br2N2Oþ6 ; calc. 438.9140).
Ethyl 3-Chloro-2-diazo-3-oxopropanoate (15) [14]. To a stirred soln. of triphosgene (6.50 g,
21.9 mmol) in anh. benzene (30 ml) at 08, anh. pyridine (200 ml) was added causing the formation of a
white precipitate. To this suspension, diazoacetate (5.70 ml, 54.3 mmol) was added at such a rate that the
temp. of the mixture did not rise above 108. After 20 h at r.t., the soln. was filtered through Celite and
concentrated under reduced pressure. Bulb-to-bulb distillation of residue provided 15 (3.05 g, 79%).

Helvetica Chimica Acta – Vol. 96 (2013)
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1
Yellow oil. B.p. 90 – 958 (<1 mbar). H-NMR (300 MHz, CDCl3): 4.30 (q, J ¼ 7.2, CH2); 1.29 (t, J ¼ 7.2,
Me).
Ethyl 2-[(4-Nitrophenyl)amino]ethyl 2-Diazopropanedioate (16). A soln. of 15 (353 mg, 2 mmol) in
CH2Cl2 (3 ml) was added dropwise to a stirred soln. of 8 (364 mg, 2 mmol) and Et3N (306 ml, 2.2 mmol)
in CH2Cl2 (10 ml) at 08. After 20 h at r.t., the solvent was evaporated under reduced pressure. The residue
was purified by FCC (AcOEt/hexane, 2 :1) to afford 16 (390 mg, 61%). Yellow crystals. M.p. 105 – 1088.
IR (ATR): 3358, 2961, 2136, 1746, 1593, 1531, 1463, 1337, 1295, 1184, 1146, 1072, 834, 750, 698, 599.
1H-NMR (300 MHz, CDCl3): 8.09 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 6.60 (d, J ¼ 9.2, HꢀC(2), HꢀC(6)); 5.08
(s, NH); 4.50 (t, J ¼ 5.4, CH2O); 4.32 (q, J ¼ 7.1, MeCH2); 3.57 (dd, J ¼ 11.0, 5.6, NHCH2); 1.33 (t, J ¼ 7.1,
Me). 1H-NMR (300 MHz, (D6)DMSO): 8.00 (d, J ¼ 9.3, HꢀC(3), HꢀC(5)); 7.35 (t, J ¼ 5.9, NH); 6.70 (d,
J ¼ 9.3, HꢀC(2), HꢀC(6)); 4.31 (t, J ¼ 5.5, CH2O); 4.20 (q, J ¼ 7.2, MeCH2); 3.50 (dd, J ¼ 11.1, 5.6,
NHCH2); 1.21 (t, J ¼ 7.1, Me ) . 13C-NMR (75 MHz, (D6)DMSO): 14.1 (Me); 41.0 (CH2N); 61.1
(MeCH2); 63.3 (CH2O); 64.8 (CN2); 110.9 (C(2), C(6)); 126.2 (C(3), C(5)); 135.9 (C(4)); 154.4 (C(1));
156.0 (CH2CH2OCO); 160.2 (COO). ESI-MS: 323.1 (58, [M þ H]þ), 165.1 (100). HR-ESI-MS: 323.0991
([M þ H]þ, C13H15N4Oþ6 ; calc. 323.0992).
Ethyl 4-(4-Nitrophenyl)-2-oxomorpholine-3-carboxylate (5b). To a stirred soln. of 16 (0.97 g,
3 mmol) in CH2Cl2 (30 ml), Rh2(OAc)4 (7 mol-%) was added, and the mixture was stirred for 4 d at r.t.
The solvent was evaporated under reduced pressure, and residue was purified by FCC (AcOEt/hexane;
2 :1) to furnish 5b (354 mg, 40%). Yellow oil. IR (ATR): 3380, 2922, 1751, 1594, 1497, 1465, 1376, 1322,
1277, 1227, 1194, 1110, 1065, 1015, 980, 944, 831, 752, 712, 693, 655, 629, 579. 1H-NMR (300 MHz, CDCl3):
8.20 (d, J ¼ 9.5, HꢀC(3), HꢀC(5)); 6.73 (d, J ¼ 9.4, HꢀC(2), HꢀC(6)); 5.19 (s, CH); 4.59 – 4.77 (m,
CH2O); 4.36 (ddd, J ¼ 14.3, 7.1, 2.1, MeCH2); 3.75 – 3.80 (m, CH2N); 1.36 (t, J ¼ 7.2, Me). 13C-NMR
(75 MHz, CDCl3): 14.0 (Me); 42.8 (CH2N); 62.3 (CH); 63.6 (MeCH2); 65.1 (CH2O); 111.2 (C(2), C(6));
126.1 (C(3), C(5)); 139.6 (C(4)); 151.0 (C(1)); 163.0 (CH2CH2OCO); 166.6 (COO). ESI-MS: 295.1 (100,
[M þ H]þ). HR-ESI-MS: 295.0941 ([M þ H]þ, C13H15N2Oþ6 ; calc. 295.0930).
4-Phenylmorpholin-3-one (19) [18]. To a stirred soln. of 17 (12.54 ml, 100 mmol) in EtOH (12.75 ml)
and H2O (38.25 ml), 18 (23.88 ml, 300 mmol) and 45% soln. of NaOH (6.2 equiv.) were added
concurrently at such a rate that the temp. remained between 358 and 458, and pH between 12 and 12.5.
After 1 h at r.t., the mixture was stirred on an ice bath for 30 min. The precipitate was filtered off, washed
with H2O, and dried to constant mass at 508 to yield 19 (11.87 g, 67%). White crystals. M.p. 113 – 1158
([18]: 1148). 1H-NMR (300 MHz, (D6)DMSO): 7.38 – 7.40 (m, HꢀC(2), HꢀC(3), HꢀC(5), HꢀC(6));
7.26 – 7.30 (m, HꢀC(4)); 4.21 (s, CH2CO); 3.98 (t, J ¼ 5.1, CH2O); 3.74 (t, J ¼ 5.1, CH2N).
4-(4-Nitrophenyl)morpholin-3-one (20) [18]. Conc. HNO3 (4 ml) was added dropwise to a stirred
soln. of 19 (10 g, 56.5 mmol) in conc. H2SO4 (24 ml) at ꢀ 58 over 1 h. The mixture was stirred at ꢀ 58 for
another h and then diluted with brine (75 ml). The obtained soln. was neutralized with 25% NH3 soln.,
diluted with acetone (150 ml), and heated to 408. The org. phase was separated in separatory funnel,
concentrated to ca. 25% of its volume under reduced pressure and cooled to 5 – 108. The precipitate was
filtered off, washed with cold acetone, and dried to afford 20 (5.25 g, 42%). Light-brown crystals. M.p.
148 – 1518 ([18]: 1528). 1H-NMR (300 MHz, CDCl3): 8.27 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 7.77 (d, J ¼ 9.2,
HꢀC(2), HꢀC(6)); 4.28 (s, CH2CO); 4.00 – 4.03 (m, CH2O); 3.84 – 3.88 (m, CH2N).
Ethyl 3-[(2-Hydroxyethyl)(phenyl)amino]-3-oxopropanoate (22). A soln. of 21 (5.79 ml, 45 mmol)
in CH2Cl2 (10 ml) was added dropwise to a stirred soln. of 17 (5.01 ml, 40 mmol) and Et3N (6.68 ml,
48 mmol) in CH2Cl2 (80 ml) at 08. After 24 h at r.t., the mixture was washed successively with 1m HCl
(2 ꢁ 50 ml) and brine (1 ꢁ 50 ml). The org. phase was dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by FCC (AcOEt/hexane; 3 :1) to yield 22 (3.41 g, 34%).
Colorless oil. IR (ATR): 3397, 2983, 1735, 1643, 1593, 1494, 1401, 1368, 1321, 1242, 1154, 1074, 1052, 1027,
946, 849, 771, 701, 663, 558. 1H-NMR (400 MHz, (D6)DMSO): 7.34 – 7.48 (m, HꢀC(2), HꢀC(3), HꢀC(4),
HꢀC(5), HꢀC(6)); 4.73 (t, J ¼ 5.6, OH); 3.98 (q, J ¼ 7.1, MeCH2); 3.69 (t, J ¼ 6.5, CH2N); 3.46 (q, J ¼ 6.2,
CH2OH); 3.12 (s, COCH2CO); 1.11 (t, J ¼ 7.1, Me ) . 13C-NMR (100 MHz, (D6)DMSO): 13.9 (Me); 41.8
(COCH2CO); 51.1 (CH2N); 57.7 (CH2OH); 60.4 (MeCH2); 128.0 (C(4)); 128.3 (C(2), C(6)); 129.6
(C(3), C(5)); 142.1 (C(1)); 165.3 (NCO); 167.3 (COO). ESI-MS: 252.1 (100, [M þ H]þ). HR-ESI-MS:
252.1232 ([M þ H]þ, C13H18NOþ4 ; calc. 252.1236).

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Helvetica Chimica Acta – Vol. 96 (2013)
Ethyl 2-Diazo-3-[(2-hydroxyethyl)(phenyl)amino]-3-oxopropanoate (6). To a soln. of 22 (2.84 g,
11.3 mmol) and Et3N (1.57 ml, 11.3 mmol) in MeCN (30 ml) TsN3 (23 [19]; 2.40 g, 11.3 mmol) was added
dropwise, and the mixture was stirred for 15 h at r.t. The solvent was evaporated under reduced pressure.
The residue was purified by FCC (AcOEt/hexane; 2 :1) to, yield 6 (1.38 g, 44%). Yellow oil. IR (ATR):
3434, 2982, 2115, 1717, 1628, 1591, 1493, 1436, 1387, 1287, 1171, 1115, 1075, 1033, 896, 845, 748, 698, 680,
618, 595, 574, 528. 1H-NMR (400 MHz, (D6)DMSO): 7.37 – 7.42 (m, HꢀC(2), HꢀC(3), HꢀC(5),
HꢀC(6)); 7.25 – 7.29 (m, HꢀC(4)); 4.79 (t, J ¼ 5.6, OH); 3.92 (q, J ¼ 7.1, MeCH2); 3.78 (t, J ¼ 6.4, CH2N);
3.51 (q, J ¼ 6.2, CH2OH); 1.03 (t, J ¼ 7.1, Me ) . 13C-NMR (100 MHz, (D6)DMSO): 14.0 (CH2Me); 52.6
(CH2N); 57.8 (CH2OH); 60.9 (MeCH2); 65.4 (CN2); 126.5 (C(2), C(6)); 126.6 (C(4)); 129.1 (C(3),
C(5)); 142.6 (C(1)); 159.4 (NCO); 161.4 (COO). ESI-MS: 278.1 (100, [M þ H]þ). HR-ESI-MS: 278.1136
([M þ H]þ, C13H16N3Oþ4 ; calc. 278.1141).
Ethyl 3-Oxo-4-phenylmorpholine-2-carboxylate (4) [14]. Compound 6 (985 mg, 3.55 mmol) was
dissolved in CH2Cl2 (35 ml). Rh2(OAc)4 (12 mol-%) was added, and the mixture was stirred for 48 h at
r.t. The residue obtained after solvent removal was purified by FCC (CH2Cl2/MeOH; 49 :1) to furnish 4
(541 mg, 61%). Colorless oil. IR (ATR): 2982, 1740, 1663, 1595, 1494, 1470, 1427, 1376, 1316, 1257, 1191,
1
1150, 1123, 1098, 1025, 949, 852, 761, 695, 609, 561. H-NMR (400 MHz, (D6)DMSO): 7.38 – 7.46 (m,
HꢀC(2), HꢀC(3), HꢀC(5), HꢀC(6)); 7.28 – 7.32 (m, HꢀC(4)); 4.94 (s, CH); 4.17 – 4.25 (m, MeCH2, 1 H
of CH2N); 4.06 (td, J ¼ 12.0, 5.1, 1 H of CH2N); 3.81 (t, J ¼ 5.1, CH2O); 1.23 (t, J ¼ 7.1, Me ) . 13C-NMR
(100 MHz, (D6)DMSO): 13.9 (CH2 Me); 48.9 (CH2O); 61.3 (CH2 Me); 62.1 (CH2N); 76.7 (CH); 125.3
(C(2), C(6)); 126.7 (C(4)); 128.9 (C(3), C(5)); 141.3 (C(1)); 162.6 (NCO); 167.3 (COO). ESI-MS: 250.1
(100, [M þ H]þ). HR-ESI-MS: 250.1071 ([M þ H]þ, C13H16NO4þ ; calc. 250.1079).
Methyl 3-[(4-Nitrophenyl)amino]-3-oxopropanoate (25). A soln. of 10 (3.22 ml, 30 mmol) in CH2Cl2
(10 ml) was added dropwise to a stirred soln. of 24 (4.14 g, 30 mmol) and Et3N (5.01 ml, 36 mmol) in
CH2Cl2 (80 ml) at 08. After 24 h at r.t., the mixture was washed successively with 1m HCl (2 ꢁ 30 ml) and
brine (2 ꢁ 30 ml). The org. phase was dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was taken up in 100 ml of Et2O and filtered to afford 25 (5.28 g, 74%). Beige crystals.
M.p. 147 – 1508. IR (ATR): 3314, 3094, 1721, 1665, 1618, 1596, 1570, 1507, 1426, 1337, 1246, 1197, 1171,
1
1112, 1000, 971, 906, 857, 826, 790, 751, 692, 614, 583, 533. H-NMR (400 MHz, (D6)DMSO): 10.79 (s,
NH); 8.23 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 7.82 (d, J ¼ 9.2, HꢀC(2), HꢀC(6)); 3.68 (s, Me); 3.57 (s,
COCH2CO). 13C-NMR (100 MHz, (D6)DMSO): 43.6 (CH2); 52.1 (Me); 118.8 (C(2), C(6)); 125.0 (C(3),
C(5)); 142.4, 144.8 (C(1), C(4)); 165.0 (NCO); 167.7 (COO). ESI-MS: 239.1 (92, [M þ H]þ), 139.0 (100).
HR-ESI-MS: 239.0664 ([M þ H]þ, C10H11N2O5þ ; calc. 239.0668).
N,N-Diethylethanaminium (2-Diazo-3-methoxy-3-oxopropanoyl)(4-nitrophenyl)azanide (26). To a
soln. of 25 (5.24 g, 22 mmol) and Et3N (3.06 ml, 22 mmol) in MeCN (50 ml), 23 [19] (4.69 g, 22 mmol)
was added dropwise, and the mixture was stirred for 15 h at r.t. The mixture was concentrated under
reduced pressure. The crude product was recrystallized from MeOH/Et2O to give 26 (4.74 g, (59%).
Yellow crystals. M.p. 115 – 1178. IR (ATR): 2993, 2952, 2601, 2440, 2361, 1693, 1604, 1514, 1498, 1452,
1
1404, 1337, 1307, 1287, 1181, 1111, 1059, 975, 941, 901, 854, 837, 817, 783, 763, 750, 726, 690. H-NMR
(400 MHz, (D6)DMSO): 9.00 (s, (MeCH2)3NHþ); 8.42 (d, J ¼ 9.4, HꢀC(3), HꢀC(5)); 8.30 (d, J ¼ 9.4,
HꢀC(2), HꢀC(6)); 3.64 (s, Me); 3.11 (q, J ¼ 7.3, (MeCH2)3NHþ); 1.17 (t, J ¼ 7.3, (MeCH2)3NHþ).
13C-NMR (100 MHz, (D6)DMSO): 8.6 (Me); 45.7 (CH2); 49.5 (Me); 116.6 (CN2); 117.2 (C(3), C(5));
124.9 (C(2), C(6)); 143.1 (C(1)); 143.4 (C(4)); 159.7 (ꢀNCO); 162.7 (COO). ESI-MS: 265.1 (100, [M þ
H]þ). ESI-MS (neg.): 263.0 (100, [M ꢀ H]ꢀ). HR-ESI-MS: 265.0581 ([M þ H]þ, C10H9N4O5; calc.
265.0573). HR-ESI-MS (neg.): 263.0409 ([M ꢀ H]ꢀ, C10H7N4O5ꢀ ; calc. 263.0416).
General Procedure for the Preparation of Compounds 28, 31, and 32. To a soln. of 26 in THF (0.1m),
the corresponding alcohol (5 equiv. of 27 or 1.5 equiv. of 29, or 1.25 equiv. of 30) was added. The mixture
was stirred for 2 – 3 d at 668, and then the solvent was evaporated under reduced pressure. The residue
was purified by FCC (CH2Cl2/MeOH, 49 :1) to afford 28 and 31, or, recrystallized from MeOH, 32.
Methyl 2-Diazo-3-[(2-hydroxyethyl)(4-nitrophenyl)amino]-3-oxopropanoate (28). Yield: 734 mg
(36%). Pale-yellow crystals. M.p. 173 – 1778. IR (ATR): 3449, 3115, 3079, 1703, 1671, 1594, 1523, 1476,
1434, 1384, 1345, 1264, 1234, 1200, 1146, 1117, 1072, 1051, 963, 934, 884, 855, 808, 772, 749, 728, 694, 626,
604, 544. 1H-NMR (400 MHz, (D6)DMSO): 8.45 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 8.27 (d, J ¼ 9.2, HꢀC(2),
HꢀC(6)); 5.01 (t, J ¼ 6.2, OH); 4.76 (t, J ¼ 5.2, CH2N); 3.88 (dd, J ¼ 10.7, 5.8, CH2OH); 3.82 (s, Me).

Helvetica Chimica Acta – Vol. 96 (2013)
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13C-NMR (100 MHz, (D6)DMSO): 51.5 (Me); 57.5 (CH2N); 58.9 (CH2OH); 108.6 (CN2); 120.9 (C(2),
C(6)); 125.2 (C(3), C(5)); 139.8 and 146.0 (C(1), C(4)); 155.3 (NCO); 158.8 (COO). ESI-MS: 309.1
(100, [M þ H]þ). HR-ESI-MS: 309.0831 ([M þ H]þ, C12H13N4Oþ6 ; calc. 309.0835).
Methyl 2-Diazo-3-[(3-hydroxypropyl)(4-nitrophenyl)amino]-3-oxopropanoate (31). Yield: 420 mg
(26%). Pale-orange crystals. M.p. 158 – 1618. IR (ATR): 3418, 3117, 2953, 2872, 1676, 1590, 1517, 1477,
1453, 1383, 1338, 1314, 1296, 1223, 1189, 1152, 1114, 1057, 1006, 924, 897, 859, 813, 770, 749, 683. 1H-NMR
(400 MHz, (D6)DMSO): 8.45 (d, J ¼ 9.3, HꢀC(3), HꢀC(5)); 8.28 (d, J ¼ 9.3, HꢀC(2), HꢀC(6)); 4.76 (t,
J ¼ 7.1, CH2N); 4.71 (s, OH); 3.83 (s, Me); 3.53 (t, J ¼ 5.7, CH2OH); 2.02 – 2.11 (m, CH2CH2CH2).
13C-NMR (100 MHz, (D6)DMSO): 31.6 (CH2CH2CH2); 51.5 (Me); 52.5 (CH2N); 57.5 (CH2OH); 108.6
(CN2); 120.9 (C(2), C(6)); 125.1 (C(3), C(5)); 139.9, 146.0 (C(1), C(4)); 155.2 (NCO); 158.7 (COO).
ESI-MS: 323.1 (100, [M þ H]þ). HR-ESI-MS: 323.1000 ([M þ H]þ, C13H15N4Oþ6 ; calc. 323.0992).
Methyl 2-Diazo-3-{[2-(hydroxymethyl)benzyl](4-nitrophenyl)amino}-3-oxopropanoate (32). Yield:
184 mg (24%). Pale-yellow crystals. M.p. 215 – 2178. IR (ATR): 3374, 3051, 2957, 2879, 1704, 1666, 1593,
1
1512, 1469, 1383, 1345, 1204, 1147, 1109, 1061, 1016, 939, 856, 748, 690, 620, 582. H-NMR (400 MHz,
(D6)DMSO): 8.45 (d, J ¼ 9.3, HꢀC(3), HꢀC(5)); 8.25 (d, J ¼ 9.3, HꢀC(2), HꢀC(6)); 7.46 (d, J ¼ 7.5,
HꢀC(3’)); 7.35 (dt, J ¼ 7.5, 1.5, 1 H of HꢀC(4’)/HꢀC(5’)); 7.27 (dt, J ¼ 7.4, 1.4, 1 H of HꢀC(4’)/HꢀC(5’));
7.10 (d, J ¼ 7.6, HꢀC(6’)); 6.02 (s, CH2N); 5.29 (t, J ¼ 5.4, OH); 4.68 (d, J ¼ 5.3, CH2OH); 3.76 (s, Me).
13C-NMR (100 MHz, (D6)DMSO): 51.6 (Me); 54.7 (CH2N); 61.0 (CH2OH); 109.0 (CN2); 121.0 (C(2),
C(6)); 125.1 (C(3), C(5)); 126.9, 127.5, 127.8, 128.1 (C(3’), C(4’), C(5’), C(6’)); 131.5, 139.8 (C(1’), C(2’));
139.9 (C(1)); 146.0 (C(4)); 155.1 (NCO); 158.6 (COO). ESI-MS: 385.1 (100, [M þ H]þ). HR-ESI-MS:
385.1138 ([M þ H]þ, C18H17N4Oþ6 ; calc. 385.1148).
Methyl 2-Diazo-3-[(4-nitrophenyl)amino]-3-oxopropanoate (33). To a soln. of 25 (2.38 g, 10 mmol)
and 23 [19] (2.13 g, 10 mmol) in MeCN (50 ml), DBU (2.25 ml, 15 mmol) was added dropwise, and the
mixture was stirred for 15 h at r.t. The solvent was evaporated under reduced pressure. The residue was
dissolved in CH2Cl2 (75 ml) and washed with 10% citric acid soln. (3 ꢁ 50 ml). The org. phase was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The crude product was recrystallized from
MeOH to afford 33 (1.92, 73%). Pale-yellow crystals (stored in closed container at 2 – 88!). M.p. 178 –
1808. IR (ATR): 3274, 3220, 3087, 2963, 2144, 1683, 1655, 1608, 1601, 1553, 1503, 1440, 1410, 1329,
1278, 1247, 1200, 1172, 1110, 949, 854, 819, 783, 751, 726, 685, 535. 1H-NMR (400 MHz, (D6)DMSO): 9.98
(s, NH); 8.24 (d, J ¼ 9.2, HꢀC(3), HꢀC(5)); 7.88 (d, J ¼ 9.3, HꢀC(2), HꢀC(6)); 3.87 (s, Me). 13C-NMR
(100 MHz, (D6)DMSO): 52.9 (Me); 68.7 (CN2); 119.5 (C(2), C(6)); 125.0 (C(3), C(5)); 142.7 and 143.8
(C(1), C(4)); 159.0 (NCO); 163.7 (COO). ESI-MS: 265.1 (68, [M þ H]þ). HR-ESI-MS: 265.0566 ([M þ
H]þ, C10H9N4Oþ5 ; calc. 265.0573).
Methyl 2-(2-Bromoethoxy)-3-[(4-nitrophenyl)amino]-3-oxopropanoate (34). Compound 33 and 2-
bromoethanol (27; 1 equiv.) were dissolved in CH2Cl2 (0.065m). Rh2(OAc)4 (7 mol-%) was added, and
the mixture was stirred for 15 h at r.t. After removal of undissolved Rh2(OAc)4, which was dried and
successfully reused, the solvent was evaporated under reduced pressure. The residue was purified by FCC
(AcOEt/hexane; 1:2) to afford 34 (1.05 g, 46%). Pale-yellow crystals. M.p. 128 – 1338. IR (ATR): 3295,
3108, 1744, 1696, 1618, 1596, 1559, 1507, 1437, 1410, 1377, 1344, 1293, 1255, 1231, 1169, 1109, 1065, 978, 941,
918, 857, 841, 774, 749, 688, 628, 610, 567. 1H-NMR (400 MHz, (D6)DMSO): 10.73 (s, NH); 8.25 (d, J ¼
9.3, HꢀC(3), HꢀC(5)); 7.92 (d, J ¼ 9.3, HꢀC(2), HꢀC(6)); 4.90 (s, CH); 3.97 (t, J ¼ 5.8, CH2O); 3.74 (s,
Me); 3.68 (t, J ¼ 5.8, BrCH2). 13C-NMR (100 MHz, (D6)DMSO): 31.4 (CH2Br); 52.5 (Me); 70.5 (CH2O);
79.7 (CH); 119.7 (C(2), C(6)); 124.9 (C(3), C(5)); 142.9, 144.1 (C(1), C(4)); 165.0 (NCO); 167.3 (COO).
ESI-MS: 363.0 (92, [M þ H]þ for 81Br), 361.0 (100, [M þ H]þ for 79Br). HR-ESI-MS: 361.0045 ([M þ
H]þ, C12H14BrN2Oþ6 ; calc. 361.0035).
Methyl 4-(4-Nitrophenyl)-3-oxomorpholine-2-carboxylate (3a). To a soln. of 34 (964 mg, 2.67 mmol)
in MeCN (30 ml), K2CO3 (368 mg, 2.67 mmol) was added, and the resulting suspension was heated at 828
for 2 h. After solvent removal, the residue was dissolved in CH2Cl2 (60 ml) and washed with H2O (2 ꢁ
30 ml). The org. phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by FCC (CH2Cl2/AcOEt; 19 :1) to yield 3a and a side-product5). Prolongation of
reaction time did not give 3a. Yield: 195 mg (26%). Yellow crystals. M.p. 132 – 1358. IR (ATR): 3111,
2957, 1743, 1660, 1607, 1590, 1513, 1490, 1472, 1432, 1377, 1343, 1319, 1291, 1255, 1225, 1201, 1151, 1126,
1103, 1032, 984, 968, 938, 856, 815, 752, 700, 606, 534. 1H-NMR (400 MHz, (D6)DMSO): 8.30 (d, J ¼ 9.2,

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Helvetica Chimica Acta – Vol. 96 (2013)
HꢀC(3), HꢀC(5)); 7.75 (d, J ¼ 9.2, HꢀC(2), HꢀC(6)); 5.07 (s, CH); 4.21 – 4.26 (m, CH2N); 4.08 – 4.13
(m, CH2N); 3.92 – 3.95 (m, CH2O); 3.75 (s, Me). 13C-NMR (100 MHz, (D6)DMSO): 48.2 (CH2O); 52.6
(Me); 62.0 (CH2N); 76.6 (CH); 124.2 (C(3), C(5)); 125.3 (C(2), C(6)); 144.8, 146.8 (C(1), C(4)); 163.1
(NCO); 167.6 (COO). ESI-MS: 281.1 (100, [M þ H]þ). HR-ESI-MS: 281.0775 ([M þ H]þ, C12H13N2O6þ ;
calc. 281.0774).
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[1] U. Trstenjak, J. Ilas, D. Kikelj, Synthesis 2012, 44, 3551.
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[2] U. Trstenjak, J. Ilas, D. Kikelj, Eur. J. Med. Chem. 2013, 64, 302.
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Received February 13, 2013