Synthesis of methyl N-aryl oxamate using soluble polymer support

Article abstract of DOI:10.1080/00397910500408357

A variety of methyl N-aryl oxamates were synthesized using poly(ethylene glycol) (PEG) as a soluble polymer support and a monoproctection group with excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500408357

Synthetic Communicationsw, 36: 611–619, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500408357
Synthesis of Methyl N-Aryl Oxamate Using
Soluble Polymer Support
Guichun Yang
Faculty of Chemistry and Material Science, Hubei University,
Wuhan, Hubei, China
Haiqing Zhang
Faculty of Chemistry and Material Science, Hubei University,
Wuhan, Hubei, China and Faculty of Chemical Engineering, Resources
and Environment, Wuhan University of Science and Technology,
Wuhan, Hubei, China
Yanling Huang and Zuxing Chen
Faculty of Chemistry and Material Science, Hubei University,
Wuhan, Hubei, China
Abstract: A variety of methyl N-aryl oxamates were synthesized using poly(ethylene
glycol) (PEG) as a soluble polymer support and a monoproctection group with
excellent yields.
Keywords: Methyl N-aryl oxamate, soluble polymer support, synthesis
The oxalyl group has been reported in a variety of biologically active series. In
particular, oxamic acid esters have been found to be potent, orally active anti-
allergy agents.[1–4] It is typically made using traditional solution-phase
synthesis, which treats the requisite arylamines with an alkyloxalyl chloride
in the presence of a base. The purification of products for further modification
is difficult.
Received in Japan July 7, 2005
Address correspondence to Guichun Yang, Faculty of Chemistry and Material
Science, Hubei University, Wuhan, Hubei 430062, China. Fax: þ86(27)88663043;
E-mail: ygc33@tom.com
611

612
G. Yang et al.
Liquid-phase synthetic approaches using soluble polymer support couple
the advantages of homogeneous solution chemistry (high reactivity, lack of
diffusion phenomena, and ease of analysis) with those of solid-phase
methods (use of excessive reagents, easy workup, and easy purification of
products).[5,6] Poly(ethylene glycol) (PEG) is among the most studied
soluble polymers for organic synthesis.[7–9] PEG support is soluble in most
organic solvents such as DMF, dichloromethane, acetonitrile, and toluene.
However, it has a strong tendency to precipitate in certain solvents such as
diethyl ether, isopropyl alcohol, and cold ethanol. Hence purification is
performed by simple precipitation, filtration, and washing of the polymer
matrix. UV, IR, and NMR could be used readily to analyze the configuration
of the polymer-supported intermediates and products without preliminary
cleavage of the growing structure.
Keeping these facts in mind, in continuation of our efforts to utilize
soluble polymer-supported systems in organic synthesis,[10–14] we report
herein the new method of synthesizing methyl N-aryl oxamate using PEG
as soluble polymer support. The synthetic route is illustrated in Scheme 1.
We anchored oxalyl chloride on PEG to yield a novel PEG-bound reactive
acid chloride, one of which oxalyl groups was protected by PEG. PEG was
used as a soluble polymer support and monoprotection group.
Considering the balance between loading capacity and the solubility
profile of the resulting polymer derivatives, we chose dihydroxy PEG of
molecular weight 3400 as support. PEG reacted with excess of oxalyl
chloride in dried CH2Cl2 to give PEG-bound acid chloride 1 through ester
linkage. The reaction proceeds to completion as evidenced by the disappear-
ance of absorption for the hydroxy at 3469 cm21 in the IR spectrum. Then,
PEG-bound acid chloride was treated with various aromatic amines at rt to
give PEG-bound oxamic acid ester 3. The appearances of absorption for
acylamide and aryl group in IR spectrum are clear evidence for the
formation of 3. Treatment of 3 with 1% KCN in methanol resulted in a very
efficient cleavage from PEG support to provide the corresponding crude
product 4, which was purified by chromatography.
Scheme 1.

Synthesis of Methyl N-Aryl Oxamate
613
To establish the scope of this reaction, a variety of arylamines was inves-
tigated. Table 1 includes representatire examples.
It is note worthy that the reaction is easily carried out using PEG as a
soluble polymer support and monoprotection group. The PEG-bound inter-
mediates were easily isolated and purified by simple precipitating, filtering,
and washing with Et2O to remove the unreacted low molecular materials
and by-products, avoiding tedious workup procedures, in contrast to using
conventional, nonpolymeric reagent methods. TLC could be used to detect
the low molecular reagent and by-product to confirm their complete
removal. The configuration of PEG-bound product was easily analyzed with
routine analytical methods (UV, IR, NMR) without following the cleave-
and-analysis technique, or spectral analysis technique, in contrast to
insoluble polymers as polymer supports.
In summary, we have successfully developed the new liquid-phase com-
binatorial synthesis of methyl N-aryl oxamate from oxalyl chloride and
arylamine using PEG as soluble polymer support in excellent yields.
EXPERIMENTAL
All organic solvents and bases were dried by standard methods. PEG and
PEG-bound compounds were melted at 808C in a vacuum for 30 min before
use to remove traces of moisture. IR spectra were recorded on a IR
spectrum one (PE) spectrometer; 1H NMR (600 MHz) and 13C NMR
(150 MHz) spectra were recorded on a Varian Unity Inova 600 spectrometer
in CDCl3 using TMS as internal standard. Elemental analyses were done on
a PE 2400 CHN analyzer. Melting points were measured on a WRS-1A
digital melting-point apparatus and are uncorrected.
Preparation of PEG-Bound Acid Chloride 1
A solution of PEG (12.00 g, 6.96 mmol) in CH2Cl2 (40 mL) was added
dropwise to an ice-cold solution of oxalyl chloride (2.44 mL, 14 mmol) in
CH2Cl2 (15 mL) and the mixture was stirred at rt for 3 h. The resulting
mixture was concentrated to remove the solvent and excess of oxalyl
chloride; the residue, PEG-bound acid chloride, was used to proceed to the
next reaction.
General Procedure for Preparation of PEG-Bound N-Aryl
Oxamate Esters 3
PEG-bound acid chloride 1 (3.00 g) was redissolved in CH2Cl2 (15 mL) and
added dropwise to a solution of arylamine (5.22 mmol) and triethylamine

614
G. Yang et al.
Table 1. Synthesis of methyl N-aryl oxamate using PEG as soluble polymer support
Product 4
Substrate (ArNH2) 2
Mp (8C)
Yield (%)a
89
4a
106.6–108.2
4b
4c
78.4–79.7
92
93
147.0–147.4
4d
4e
4f
102.1–102.6
75.2–76.0
93.1–94.5
78.4–79.8
52.3–53.6
95
94
95
94
96
4g
4h
4i
4j
147.5–148.1
164.9–166.4
98
92
4k
4l
86.8–88.0
90
91
164.2–164.8
4m
124.2–125
90
(continued)

Synthesis of Methyl N-Aryl Oxamate
615
Table 1. Continued
Product 4
Substrate (ArNH2) 2
Mp (8C)
Yield (%)a
4n
160.6–161.9
91
4o
104.7–106.4
97
aIsolated yields.
(0.36 mL, 2.16 mmol) in CH2Cl2 at rt with stirring. After 4 h, the resulting
mixture was washed with H2O and the aqueous phase was extracted with
CH2Cl2 (30 mL ꢀ 3). Combined organic layer was dried with anhydrous
MgSO4, filtered, concentrated, and precipitated with cold Et2O (300 mL).
The precipitate was filtered, washed with cold Et2O (30 mL ꢀ 3), and dried
under vacuum to afford 3.
General Procedure for Preparation of Methyl N-Aryl Oxamate 4
Compound 3 was treated with 1% KCN in CH3OH at rt for 5 h. After removing
CH3OH, the residue was redissolved in CH2Cl2 (3 mL); the detached PEG was
precipitated by adding cold Et2O and removed by filtering. Then, the
combined filtrate was evaporated to give crude product, which was purified
by column chromatography on silica gel (EtOAc–n-hexane, 1:3) to give the
desired pure product 4.
Data
4a: Methyl N-phenyl oxamate. IR: 3342 (NH), 1729 (CO), 1698 (CONH)
1
cm21; H NMR: d ¼ 3.979 (s, 3 H, CO2CH3), 7.202 (m, 1 H, ArH), 7.400
(m, 2 H, ArH), 7.651 (m, 2 H, ArH), 8.864 (s, 1 H, NH); 13C NMR:
d ¼ 54.583, 120.305 (2 C), 126.095, 129.738 (2 C), 136.669, 154.013,
161.958; anal. calcd. for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.15; H, 5.12; N, 7.78.
4b: Methyl N-(2-methylphenyl) oxamate. IR: 3383 (NH), 1727 (CO), 1678
(CONH) cm21
;
1H NMR: d ¼ 2.330 (s, 3 H, Ar-CH3), 3.978 (s, 3 H,
CO2CH3), 7.132 (m, 1 H, ArH), 7.226 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.270
(m, 1 H, ArH), 8.020 (d, 1 H, J ¼ 7.8 Hz, ArH), 8.819 (s, 1 H, NH);
13C NMR: d ¼ 17.954, 54.541, 122.193, 126.431, 127.491, 128.910,

616
G. Yang et al.
131.088, 134.674, 154.055, 162.076; anal. calcd for C10H11NO3: C, 62.17; H,
5.74; N, 7.25. Found: C, 62.06; H, 5.68; N, 7.09.
4c: Methyl N-(4-methylphenyl) oxamate. IR: 3338 (NH), 1726 (CO),
1
1696 (CONH) cm21; H NMR: d ¼ 2.342 (s, 3 H, Ar-CH3), 3.970 (s, 3 H,
CO2CH3), 7.189 (d, 2 H, J ¼ 8.4 Hz, ArH), 7.535 (d, 2 H, J ¼ 8.4 Hz,
ArH), 8.827 (s, 1 H, NH); 13C NMR: d ¼ 21.455, 54.534, 120.252
(2 C), 130.211 (2 C), 134.136, 135.883, 153.883, 162.038; anal. calcd
for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C, 61.98; H, 5.79; N,
7.33.
4d: Methyl (2,3-dimethylphenyl) oxamate. IR: 3240 (NH), 1741 (CO), 1682
1
(CONH) cm21; H NMR: 2.205 (s, 3 H, Ar-CH3), 2.317 (s, 3 H, Ar-CH3),
3.978 (s, 3 H, CO2CH3), 7.065 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.145 (t, 1 H,
J ¼ 7.8 Hz, ArH), 7.718 (d, 1 H, J ¼ 7.8 Hz, ArH), 8.802 (s, 1 H, NH);
13C NMR: d ¼ 13.960, 21.032, 54.465, 121.014, 126.637, 128.487,
128.681, 134.334, 138.088, 154.341, 162.198; anal. calcd for C11H13NO3:
C, 63.76; H, 6.32; N, 6.76. Found: C, 63.54; H, 6.70; N, 6.84.
4e: Methyl (2,4-dimethylphenyl) oxamate. IR: 3342 (NH), 1738 (CO), 1691
(CONH) cm21
;
1H NMR: d ¼ 2.286 (m, 6 H, Ar-CH3), 3.974 (s, 3 H,
COOCH3), 7.047 (m, 2 H, ArH), 7.828 (m, 1 H, ArH), 8.743 (s, 1 H, NH).
13C NMR: d ¼ 17.904, 21.375, 31.377, 54.450, 122.430, 127.976, 129.135,
131.767, 132.080, 136.306, 154.089, 162.168; anal. calcd for C11H13NO3:
C, 63.76; H, 6.32; N, 6.76. Found: C, 64.01; H, 6.45; N, 6.58.
4f: Methyl (3,4-dimethylphenyl) oxamate. IR: 3341 (NH), 1743 (CO), 1685
1
(CONH) cm21; H NMR: d ¼ 2.271 (s, 3 H, Ar-CH3), 2.298 (s, 3 H, Ar-
CH3), 3.992 (s, 3 H, CO2CH3), 7.147 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.407 (d, 2
H, J ¼ 7.8 Hz, ArH), 8.795 (s, 1 H, NH); 13C NMR: d ¼ 19.773, 20.376,
54.476, 117.780, 121.491, 130.665, 134.407, 134.613, 138.065, 153.849,
162.099; anal. calcd. for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.81; H, 6.28; N, 6.84.
4g: Methyl (2,6-dimethylphenyl) oxamate. IR: 3337 (NH), 1740 (CO), 1688
(CONH) cm21
;
1H NMR: d ¼ 2.249 (s, 6 H, Ar-CH3), 3.990 (s, 3 H,
CO2CH3), 7.147 (m, 3 H, ArH), 8.398 (s, 1 H, NH); 13C NMR: d ¼ 18.942
(2 C), 54.438, 128.559 (2 C), 128.922 (2 C), 132.499, 135.501, 154.787,
161.851; anal. calcd. for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.57; H, 6.19; N, 6.30.
4h: Methyl (2,5-dimethylphenyl) oxamate. IR: 3344 (NH), 1739 (CO), 1689
(CONH) cm21
;
1H NMR: d ¼ 2.279 (s, 3 H, Ar-CH3), 2.340 (s, 3 H,
Ar-CH3), 3.977 (s, 3 H, CO2CH3), 6.938 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.089
(d, 1 H, J ¼ 7.8 Hz, ArH), 7.823 (s, 1 H, ArH), 8.765 (s, 1 H, NH);

Synthesis of Methyl N-Aryl Oxamate
617
13C NMR: d ¼ 17.507, 21.619, 54.469, 122.826, 125.878, 127.228, 130.875,
134.456, 137.321, 154.032, 162.160; anal. calcd. for C11H13NO3: C, 63.76; H,
6.32; N, 6.76. Found: C, 63.61; H, 6.39; N, 6.80.
4i: Methyl (4-propionylphenyl) oxamate. IR: 3344 (NH), 1725 (CO), 1705
1
(CONH) cm21; H NMR: d ¼ 1.412 (t, 3 H, J ¼ 7.2 Hz, CH2CH3), 3.963
(s, 3 H, CO2CH3), 4.032 (m, 2 H, J ¼ 7.2 Hz, OCH2 CH3), 6.900 (d, 2 H,
J ¼ 9.0 Hz, ArH), 7.554 (d, 2 H, J ¼ 9.0 Hz, ArH), 8.777 (s, 1 H, NH);
13C NMR: d ¼ 15.253, 54.431, 64.169, 115.396, 121.854 (2 C), 129.707,
153.765, 157.079, 162.114; anal. calcd. for C11H13NO4: C, 59.19; H, 5.87;
N, 6.27. Found: C, 59.22; H, 5.67; N, 6.14.
4j: Methyl (4-bromophenyl) oxamate. IR: 3346 (NH), 1743(CO), 1688
(CONH) cm21
;
1H NMR: d ¼ 3.983 (s, 3 H, CO2CH3), 7.508 (d, 2 H,
J ¼ 8.4 Hz, ArH), 7.561 (d, 2 H, J ¼ 8.4 Hz, ArH), 8.864 (s, 1 H, NH);
13C NMR: d ¼ 54.713, 118.932, 121.823 (2 C), 132.782 (2 C), 135.726,
154.013, 161.725; anal. calcd. for C9H8BrNO3: C, 41.89; H, 3.12; N, 5.43.
Found: C, 41.82; H, 3.07; N, 5.59.
4k: Methyl (2-chlorophenyl) oxamate. IR: 3366 (NH), 1736(CO), 1682
1
(CONH) cm21; H NMR: d ¼ 3.999 (s, 3 H, CO2CH3), 7.141 (m, 1 H,
ArH), 7.336 (m, 1 H), 7.435 (d, 1 H, J ¼ 7.8 Hz, ArH), 8.453 (d, 1 H,
J ¼ 8.4 Hz, ArH), 9.476 (s, 1 H, NH); 13C NMR: d ¼ 54.736, 121.709,
123.955, 126.496, 128.418, 129.784, 133.606, 154.039, 161.451; anal.
calcd. for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.56. Found: C, 50.77; H,
3.81; N, 6.42.
4l: Methyl (4-chlorophenyl) oxamate. IR: 3349 (NH), 1745 (CO), 1688
(CONH) cm21
;
1H NMR: d ¼ 3.985 (s, 3 H, CO2CH3), 7.362 (d, 2 H,
J ¼ 9.0 Hz, ArH), 7.620 (d, 2 H, J ¼ 9.0 Hz, ArH), 8.892 (s, 1 H, NH);
13C NMR: d ¼ 54.486, 121.268 (2 C), 129.572 (2 C), 130.956, 134.961,
153.751, 161.479; anal. calcd. for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.56.
Found: C, 50.52; H, 3.63; N, 6.73.
4m: Methyl (2,5-dichlorophenyl) oxamate. IR: 3344 (NH), 1725 (CO), 1705
1
(CONH) cm21; H NMR: d ¼ 4.007 (s, 3 H, CO2CH3), 7.119 (m, 1 H,
ArH), 7.346 (d, 1 H, J ¼ 8.6 Hz, ArH), 8.516 (d, 1 H, J ¼ 8.6 Hz, ArH),
9.452 (s, 1 H, NH); 13C NMR: d ¼ 54.804, 121.617, 122.033, 126.446,
130.463, 134.262, 134.464, 154.047, 161.199; anal. calcd. for C9H7Cl2NO3:
C, 43.58; H, 2.84; N, 5.65. Found: C, 43.63; H, 3.05; N, 5.49.
4n: Methyl (3,4-dichlorophenyl) oxamate. IR: 3342 (NH), 1731 (CO), 1696
(CONH) cm21
;
1H NMR: d ¼ 3.988 (s, 3 H, CO2CH3), 7.436 (d, 1 H,
J ¼ 8.4 Hz, ArH), 7.477 (d, 1 H, J ¼ 8.4 Hz, ArH), 8.859 (s, 1 H, NH);
13C NMR: d ¼ 55.287, 119.534, 122.006, 127.463, 128.916, 132.167,

618
G. Yang et al.
134.269; anal. calcd. for C9H7Cl2NO3: C, 43.58; H, 2.84; N, 5.65. Found: C,
44.06; H, 2.91; N, 5.76.
4o: Methyl (naphthalen-5-yl) oxamate. IR: 3390 (NH), 1712 (CO), 1705
1
(CONH) cm21; H NMR: d ¼ 4.024 (s, 3 H, CO2CH3), 7.549 (m, 3 H,
ArH), 7.754 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.888 (t, 2 H, J ¼ 7.2 Hz, ArH),
8.168 (d, 1 H, J ¼ 7.2 Hz, ArH), 9.411 (s, 1 H, NH); 13C NMR:
d ¼ 54.644, 120.049, 120.374, 126.198, 126.522, 126.789, 127.007,
127.228, 129.406, 131.111, 134.437, 154.585, 162.145; anal. calcd. for
C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C, 68.33; H, 4.95; N, 6.40.
ACKNOWLEDGMENT
This work is supported by the National Natural Sciences Fundation of China
(No: 20372019).
REFERENCES
1. Sellstedt, J. H.; Guinosso, C. J.; Begany, A. J.; Bell, S. C.; Rosenthale, M. Oxanilic
acid, a new series of orally active antiallergic agents. J. Med. Chem. 1975, 18 (9),
926–933.
2. Wright, J. B.; Hall, C. M.; Johnson, H. G. N, N0-(phenylene)dioxamic acids and
their esters as antiallergy agents. J. Med. Chem. 1978, 21 (9), 930–935.
3. Klaubert, D. H.; Sellstedt, J. H.; Guinosso, C. J.; Capetola, R. J.; Bell, S. C.
N-(Aminophenyl) oxamic acids and esters as potent, orally active antiallergy
agents. J. Med. Chem. 1981, 24 (6), 742–748.
4. Hargrave, K. D.; Hess, F. K.; Oliver, J. T. N-(4-Substituted-thiazolyl)oxamic acid
derivatives, a new series of potent, orally active antiallergy agents. J. Med. Chem.
1983, 26 (8), 1158–1163.
5. Wentworth, J.; Janda, K. D. Liquid-phase chemistry: Recent advances in soluble
polymer-supported catalysts, reagents and synthesis. Chem. Commun. 1999, 19,
1917–1924.
6. Toy, P. H.; Janda, K. D. Soluble polymer-supported organic synthesis. Acc. Chem.
Res. 2000, 33 (18), 546–554.
7. Yeh, W. B.; Lin, M. J.; Sun, C. M. Liquid-phase parallel synthesis of tetrahydro-b-
carbolines. Tetrahedron Lett. 2003, 44, 4923–4926.
8. Oikawa, M.; Ikoma, M.; Sasaki, M. Alkoxyacetyl (AAc) group as a useful linker
for organic synthesis on poly(ethylene glycol) support. Tetrahedron Lett. 2004, 45,
2371–2375.
9. Yeh, W. B.; Sun, C. M. Soluble polymer-supported synthesis of thioxotetrapyrimi-
dinone by focused microwave irradiation. J. Comb. Chem. 2004, 6, 279–282.
10. Chen, Z. X.; Yang, G. C.; Zhang, Z. J.; Wang, D. Synthesis of a library of N-p-
hydroxyl benzoyl thioureas using a poly(ethylene glycol) support. Synthesis
2001 (10), 1483–1486.
11. Yang, G. C.; Chen, Z. X.; Zhang, Z. J.; Qiu, X. L. Novel synthesis of monoethers of
hydroquinone and resorcinol on soluble polymer-supports. Synth. Commun. 2002,
32 (23), 3637–3642.

Synthesis of Methyl N-Aryl Oxamate
619
12. Chen, Z. X.; Yang, G. C.; Zhang, Z. J. Soluble polymer-supported synthesis of
tertiary amines. Synth. Commun. 2003, 33 (5), 729–734.
13. Zhang, H. Q.; Yang, G. C.; Chen, J. N.; Chen, Z. X. Synthesis of thiophene deriva-
tives on soluble polymer-support using Gewald reaction. Synthesis 2004 (18),
3055–3059.
14. Chen, Z. X.; Yue, G. Z.; Lu, C. F.; Yang, G. C. Synthesis of library of
indolizines using poly(ethylene glycol) as soluble support. Synlett 2004 (7),
1231–1234.