Synthesis of alkyl N-(4-nitrophenyl)-3/2-oxomorpholine-2/3-carboxylates by rhodium(II) acetate catalyzed O-H and N-H carbene insertion

Article abstract of DOI:10.1016/j.tetlet.2013.04.049

The synthesis of methyl N-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate and ethyl N-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate, via rhodium(II) acetate catalyzed intermolecular O-H and intramolecular N-H carbene insertion, is described. The products represent new and versatile building blocks for the synthesis of bioactive compounds of pharmaceutical interest.

Full text of DOI:10.1016/j.tetlet.2013.04.049

Tetrahedron Letters 54 (2013) 3341–3343
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of alkyl N-(4-nitrophenyl)-3/2-oxomorpholine-2/3-carboxylates
by rhodium(II) acetate catalyzed O–H and N–H carbene insertion
⇑
Uroš Trstenjak, Janez Ilaš, Danijel Kikelj
ˇ
University of Ljubljana, Faculty of Pharmacy, Aškerceva 7, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of methyl N-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate and ethyl N-(4-nitrophenyl)-
2-oxomorpholine-3-carboxylate, via rhodium(II) acetate catalyzed intermolecular O–H and intramolecu-
lar N–H carbene insertion, is described. The products represent new and versatile building blocks for the
synthesis of bioactive compounds of pharmaceutical interest.
Received 12 February 2013
Revised 28 March 2013
Accepted 12 April 2013
Available online 27 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Morpholin-3-one
Morpholin-2-one
Diazotization
a-Diazocarbonyl compounds
Rh2(OAc)4 catalysis
The morpholin-3-one (1) and morpholin-2-one (2) skeletons
and their derivatives are important synthons for the preparation
of bioactive compounds.1 In the course of our medicinal chemistry
program, aimed at producing dual antithrombotic compounds with
highly overlapping factor Xa inhibitor and fibrinogen receptor
antagonist pharmacophores,2 protected isomeric 4-(4-nitro-
phenyl)-3-oxomorpholine-2-carboxylate 3 and 4-(4-nitrophenyl)-
2-oxomorpholine-3-carboxylate 4 (Fig. 1) were required as key
intermediates in order to functionalize the parent morpholin-
3-one moiety of the lead compound with a negatively charged
carboxylate group (Fig. 2). 2,4-Disubstituted morpholin-3-ones
and 3,4-disubstituted morpholin-2-ones are generally prepared
by either one- or two-bond cyclization reactions1,3–7 or by direct
functionalization of N-substituted morpholin-2/3-ones with
electrophilic reagents at the 2- or 3-position.8–13
O
N
COOEt
O
O
O
N
COOR
O
O
N
O
N
H
1
O
O
COOR
5
O
O
O
NO2
NO2
N
H
3
4
N
COOEt
3a: R = Me
4a: R = Et
2
COOBn
6
Figure 1. Envisaged 3/2-oxomorpholine-2/3-carboxylates 3a and 4a and related
compounds.
Ethyl 3-oxo-4-phenylmorpholine-2-carboxylate (5),14 which
closely resembles 3-oxo-morpholine-2-carboxylate 3, is the only
known 4-phenylmorpholin-3-one derivative bearing a protected
carboxylate group. Compound 5 was prepared by rhodium(II)
acetate catalyzed intramolecular O–H insertion of the carbenoid
intermediate obtained by decomposition of diazo-N-(2-hydroxy-
ethyl)-N-phenylmalonamide ethyl ester.14 No isomeric 2-oxomorph-
oline-3-carboxylate resembling 4 is known in the literature, and an
attempt to prepare structurally related ethyl N-benzyloxycar-
bonyl-2-oxomorpholine-3-carboxylate (6) via an Rh2(OAc)4-cata-
lyzed N–H insertion reaction failed.15
We report herein the rhodium(II) acetate catalyzed syntheses of
isomeric methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxyl-
ate (3a) and ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxyl-
ate (4a) (Fig. 1), which are versatile new building blocks for the
synthesis of bioactive compounds of pharmaceutical interest. They
can be functionalized easily at the aromatic nitro group, and they
are key intermediates in the synthesis of factor Xa-inhibitor riva-
roxaban analogues with potential dual antithrombotic activity.2
Although 3-oxomorpholine-2-carboxylates 3 and 5 differ solely
in the p-nitro substituent on the phenyl ring, direct transfer of the
methodology for synthesizing 5, which comprises O1–C2 bond
formation by intramolecular insertion of a carbene generated from
a
-diazoester 7 into the O–H bond of the N-(2-hydroxyethyl) moiety
⇑
Corresponding author. Tel.: +386 1 4769 561; fax: +386 1 4258 031.
E-mail address: danijel.kikelj@ffa.uni-lj.si (D. Kikelj).
(Fig. 3),14 proved to be unsuccessful in our hands for preparing 3.16
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.049

3342
U. Trstenjak et al. / Tetrahedron Letters 54 (2013) 3341–3343
O
O
O
R
Cl
OEt
18
Et3N, CH2Cl2,
N2
N
OH
NH
O
O
N
O
N2
O
OEt
Rh2(OAc)4,
CH2Cl2,
rt, 15 h
O
O
COOEt
°
0
C → rt, 20 h
NH
N
O
61%
40%
N
O
O
NH2
NH
O
O
S
NO2
NO2
4a
Cl
NH
O
S
NO2
19
N
17
Scheme 2. Synthesis of ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate
(4a).
O
N
COOR'
O
O
N
O
R =
or
R' = H, alkyl
heating, intramolecular carbene insertion into the O–H bond did
not take place. Moreover, the reduced derivative 9, the correspond-
ing phthalimido protected derivative 10, the homologous methyl
2-diazo-3-[(3-hydroxypropyl)(4-nitrophenyl)amino]-3-oxopro-
panoate (11), and methyl 2-diazo-3-{[2-(hydroxymethyl)benzyl]
(4-nitro-phenyl)amino}-3-oxopropanoate (12) could not be cy-
clized by rhodium(II) acetate promoted intramolecular carbene
insertion into the O–H bond. This suggests that the synthetic strat-
egy used for preparing 514 (Fig. 3, top) is not generally applicable
to the synthesis of N-aryl-3-oxomorpholine-2-carboxylates.
COOR'
Figure 2. Evolution of dual antithrombotic compounds requesting development of
synthesis of 3 and 4.
HO
O
N
COOEt
O
O
O
(OAc)4, CH2Cl2, rt
[ref. 14]
Rh2
N
OEt
N2
Therefore, we explored alternative methods for the synthesis of 3
and found that intermolecular insertion of a carbene, which was
generated by decomposition of a-diazomalonate 15, into the O–H
7
5
bond of 2-bromoethanol, prior to the cyclization step, enabled suc-
cessful synthesis of 3a from 4-nitroaniline (13) (Scheme 1). Thus,
methyl 3-[(4-nitrophenyl)amino]-3-oxopropanoate (14), which
was prepared by acylation of 4-nitroaniline with ethyl malonyl chlo-
ride, was subjected to a diazo-transfer reaction using tosyl azide in
the presence of 1,8- diazabicycloundec-7-ene (DBU) to give methyl
2-diazo-3-[(4-nitrophenyl)amino]-3-oxopropanoate (15), which
afforded methyl 2-(2-bromoethoxy)-3-[(4-nitrophenyl)amino]-
3-oxopro-panoate (16)17 on stirring with 2-bromoethanol in the
presence of rhodium(II) acetate at room temperature. Finally, 16
gave methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate
(3a)18 via intramolecular nucleophilic substitution.
no reaction with:
HO
O
HO
HO
O
O
O
O
O
N
N
OMe
N
OMe
OMe
N2
O
N2
N2
HN
HO
NO2
NH2
8
9
N
O
HO
10
HO
O
O
O
N
O
In an attempt to access isomeric 4-(4-nitrophenyl)-2-
oxomorpholine-3-carboxylate 4, we combined our earlier observa-
tion that O-acylation of 2-[(4-nitrophenyl)amino]ethanol (17) is
preferred over N-acylation, with expected rhodium(II)-catalyzed
N
OMe
OMe
N2
N2
N–H insertion of a carbene generated from
a-diazomalonate 19.
Thus, O-acylation of 17 with ethyl 3-chloro-2-diazo-3-oxopropan-
oate (18)14 in the presence of triethylamine gave 1-ethyl 3-{2-[(4-
nitrophenyl)amino]ethyl}-2-diazomalonate (19), which afforded
4a via rhodium(II) acetate catalyzed intramolecular N–H carbene
insertion (Scheme 2).19
NO2
NO2
11
12
Figure 3. Attempted intramolecular carbene insertion into the O-H bond.
We did not study the reaction scope with different substituents
on the morpholinone and phenyl rings because the p-nitro group
was indispensable for synthetic elaboration of 3 and 4 toward
When 8 was treated with rhodium(II) acetate in dichloromethane,
benzene, tetrahydrofuran or water at room temperature, or with
methyl malonyl
chloride,
Et3N, CH2Cl2,
O
N
COOMe
O
O
O
O
O
O
O
2-bromoethanol,
Rh2(OAc)4, CH2Cl2,
rt, 15 h
tosyl azide,
DBU, MeCN,
rt, 2 h
NH2
K2CO3, MeCN,
reflux, 1 h
HN
OMe
HN
OMe
HN
OMe
Br
0 °C → rt, 2 h
N2
O
74%
73%
46%
26%
NO2
NO2
NO2
NO2
NO2
13
14
15
16
3a
Scheme 1. Synthesis of methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a).

U. Trstenjak et al. / Tetrahedron Letters 54 (2013) 3341–3343
3343
15. Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985, 50, 5223–5230.
16. Compound 3 could not be obtained by nitration of 5. Attempts to prepare 3 by
potential dual antithrombotic compounds, and because the pres-
ence of other substituents on both rings was expected to decrease
factor Xa-inhibitory and fibrinogen receptor antagonistic activity.
Alternative rhodium ligands were not studied because it is known
that some of them, for example, with a perfluorocarboxamide, pro-
mote aromatic C–H insertion.14
introduction of an ethoxycarbonyl group at position
2
of 4-(4-
nitrophenyl)morpholin-3-one using ethyl chloroformate or diethyl carbonate
with lithium diisopropylamide, sodium hydride, or sodium ethoxide as the
base, were not successful.
17. Methyl 2-(2-bromoethoxy)-3-[(4-nitrophenyl)amino]-3-oxopropanoate (16).
Methyl 2-diazo-3-[(4-nitrophenyl)amino]-3-oxopropanoate (15) (1.68 g,
6.35 mmol) and 2-bromoethanol (447 lL, 6.35 mmol) were dissolved in
In conclusion, we have developed successful strategies for the
rhodium(II) acetate catalyzed preparation of methyl 4-(4-nitro-
phenyl)-3-oxomorpholine-2-carboxylate (3a) starting from 4-nitro-
aniline, and ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate
(4a) starting from 2-[(4-nitrophenyl)amino]ethanol. Both compounds
can serve as versatile new building blocks for the synthesis of bioac-
tive compounds of pharmaceutical interest.
dichloromethane (100 mL). Rh2(OAc)4 (7 mol %) was added and the reaction
mixture was stirred at room temperature for 15 h. After removal of
undissolved Rh2(OAc)4, solvent was evaporated under reduced pressure.
Residue was purified by flash column chromatography using EtOAc/hexane
(1:2) as eluant to afford 16. Yield: 1.05 g (46%); pale yellow crystals, mp 128–
133 °C. 1H NMR (400 MHz, DMSO-d6) d 3.68 (t, 2H, J = 5.8 Hz, CH2Br), 3.74 (s,
3H, CH3), 3.97 (t, 2H, J = 5.8 Hz, OCH2), 4.90 (s, 1H, CH), 7.92 (d, 2H, J = 9.3 Hz,
Ar-H2,H6), 8.25 (d, 2H, J = 9.3 Hz, Ar-H3,H5), 10.73 (br s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d 31.37 (CH2Br), 52.53 (CH3), 70.51 (OCH2), 79.66 (CH),
119.65 (Ar-C2,6), 124.92 (Ar-C3,5), 142.88 and 144.05 (Ar-C1,4), 165.04 (NCO),
167.26 (COO). MS (EI) m/z (%): 363.0 ([M+H]+, 92) for 81Br, 361.0 ([M+H]+, 100)
for 79Br. HRMS (ESI) calcd for C12H14BrN2O6 361.0035, found 361.0045. 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,
Acknowledgment
This work was supported by the Slovenian Research Agency
(Grant P1-0208).
628, 610, 567 cmÀ1
18. Methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a). Methyl 2-(2-
bromoethoxy)-3-[(4-nitrophenyl)amino]-3-oxopropanoate (16) (964 mg,
.
Supplementary data
2.67 mmol) was dissolved in acetonitrile (30 mL). K2CO3 (368 mg,
2.67 mmol) was added and the resulting suspension refluxed for 2 h. After
solvent removal, residue was dissolved in dichloromethane (60 mL) and
washed with water (2 Â 30 mL). The organic phase was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by
flash column chromatography using dichloromethane/EtOAc (19:1) as eluant,
yielding 3a. According to TLC prolongation of reaction time at reflux did not
give 3a. Yield: 195 mg (26%); yellow crystals, mp 132–135 °C. 1H NMR
(400 MHz, DMSO-d6) d 3.75 (s, 3H, CH3), 3.92–3.95 (m, 2H, OCH2), 4.08–4.13
(m, 1H, NCH2), 4.21–4.26 (m, 1H, NCH2), 5.07 (s, 1H, CH), 7.75 (d, 2H, J = 9.2 Hz,
Ar-H2,H6), 8.30 (d, 2H, J = 9.2 Hz, Ar-H3,H5). 13C NMR (100 MHz, DMSO-d6) d
48.23 (OCH2), 52.60 (CH3), 61.99 (NCH2), 76.58 (CH), 124.22 (Ar-C3,5), 125.25
(Ar-C2,6), 144.78 and 146.78 (Ar-C1,4), 163.07 (NCO), 167.56 (COO). MS (EI) m/z
(%): 281.1 ([M+H]+, 100). HRMS (ESI) calcd for C12H13N2O6 281.0774, found
281.0775. IR (ATR) 3111, 2957, 1743, 1660, 1607, 1590, 1513, 1490, 1472,
1432, 1377, 1343, 1319, 1291, 1255, 1225, 1201, 1151, 1126, 1103, 1032, 984,
Supplementary data (NMR spectra of compounds 3a, 4a, 15, 16
and 19) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.04.049.
References and notes
1. Trstenjak, U.; Ilaš, J.; Kikelj, D. Synthesis 2012, 44, 3551–3578.
2. Trstenjak, U.; Ilaš, J. Kikelj. D Eur. J. Med. Chem. 2013, 64, 302–313.
3. Aparicio, D. M.; Teran, J. L.; Roa, L. F.; Gnecco, D.; Juarez, J. R.; Orea, M. L.;
Mendoza, A.; Flores-Alamo, M. S.; Micouin, L. Synthesis 2011, 2310–2320.
4. Nisihida, H.; Saitoh, F.; Hirabayashi, T.; Chackalamannil, S.; Chan, T. Y.; Chelliah,
M.; Clasby, M.; Dwyer, M. P.; Greenlee, W. J.; Xia, Y. WO2010065717, 2010;
Chem. Abstr. 2010, 153, 62269.
5. Kashima, C.; Harada, K. J. Chem. Soc., Perkin Trans. 1988, 6, 1521–1526.
6. Nelson, T. D.; Rosen, J. D.; Brands, K. M. J.; Craig, B.; Huffman, M. A.; McNamara,
J. M. Tetrahedron Lett. 2004, 45, 8917–8920.
7. Zhang, Q. Y.; Xu, J. M.; Chen, W. Q.; Wu, Q.; Lin, X. F. Synlett 2008, 679–682.
8. Nechev, L. V.; Dobrev, A.; Ivanov, C. Bulg. Chem. Commun. 1992, 25, 509–513.
9. Yamanaka, T.; Ohki, H.; Ishida, J.; Toda, A.; Harayama, Y.; Makino, T.; Kunikawa,
S.; Mizuno, H.; Ohtake, H. WO2010139986, 2008; Chem. Abstr. 2008, 149,
576837.
10. Allen, A. J.; Hemrick-Luecke, S.; Sumner, C. R.; Wallace, O. B. WO2005060949,
2005; Chem. Abstr. 2005, 143, 115550.
11. Owen, D. R.; Bull, D. J.; Bunnage, M. E.; Glossop, M. S.; Maguire, R. J.; Strang, R.
S. Bioorg. Med. Chem. Lett. 2010, 20, 92–96.
12. Dobrev, A.; Nechev, L.; Ivanov, C.; Bon, M. J. Chem. Res., Synop. 1999, 3, 188–189.
13. Roehrig, S.; Jeske, M.; Akbaba, M.; Rosentreter, U.; Boyer, S.; Fischer, K.;
Pohlmann, J.; Tuch, A.; Perzborn, E.; Gerdes, C.; Schlemmer, K. H.; Burkhardt,
N.; Allerheiligen, S.; Nell, P.; Arndt, S.; Lobell, M. WO2006061116, 2006; Chem.
Abstr. 2006, 145, 62922. .
968, 938, 856, 815, 752, 700, 606, 534 cmÀ1
19. Ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate (4a). To
.
a
stirred
solution of 1-ethyl 3-{2-[(4-nitrophenyl)amino]ethyl} 2-diazomalonate (19)
(0.97 g, 3 mmol) in dichloromethane (30 mL) Rh2(OAc)4 (7 mol %) was added
and reaction mixture was stirred for 4 days at room temperature. Solvent was
evaporated under reduced pressure and residue purified by flash column
chromatography using EtOAc/hexane (2:1) as eluant to afford 4a. Yield:
354 mg (40%); yellow oil. 1H NMR (400 MHz, CDCl3) d 1.36 (t, 3H, J = 7.2 Hz,
CH2CH3), 3.75–3.80 (m, 2H, NCH2), 4.36 (ddd, 2H, J = 14.3 Hz, 7.1 Hz, 2.1 Hz,
CH2CH3), 4.59–4.77 (m, 2H, CH2O), 5.19 (s, 1H, CH), 6.73 (d, 2H, J = 9.4 Hz, Ar-
H2,H6), 8.20 (d, 2H, J = 9.5 Hz, Ar-H3,H5). 13C NMR (100 MHz, CDCl3) d 14.04
(CH3), 42.82 (NCH2), 62.33 (CH), 63.64 (CH2CH3), 65.09 (CH2O), 111.20 (Ar-C2,6),
126.05 (Ar-C3,5), 139.63 (Ar-C4), 150.98 (Ar-C1), 163.04 (CH2CH2OCO), 166.56
(COO). MS (EI) m/z (%): 295.1 ([M+H]+, 100), 279.1 (40), 165.1 (42). HRMS (ESI)
calcd for C13H15N2O6 295.0930, found 295.0941. 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 cmÀ1
.
14. Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem, T. J.; Marino, J. P., Jr.; Padwa,
A. J. Org. Chem. 1994, 59, 2447–2455.