A transformation of N-alkylated anilines to N-aryloxamates

Article abstract of DOI:10.1002/hlca.201200603

Transformation of N-alkylated anilines to N-aryloxamates was studied using ethyl 2-diazoacetoacetate as an alkylating agent and dirhodium tetraacetate (Rh₂(OAc)₄) as the catalyst. The general applicability of the reaction as a synthetic method for N-aryloxamates was studied with a number of substituted N-alkylated anilines. The results revealed that the oxamate was formed by a radical reaction with molecular O₂ and Rh ₂(OAc)₄ as initiator. Copyright

Full text of DOI:10.1002/hlca.201200603

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Helvetica Chimica Acta – Vol. 96 (2013)
A Transformation of N-Alkylated Anilines to N-Aryloxamates
by Xiao-He Zhu, Xin Zhang, Hong-Xing Xin, and Hong Yan*
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, P. R.
China (e-mail: hongyan@bjut.edu.cn)
Transformation of N-alkylated anilines to N-aryloxamates was studied using ethyl 2-diazoacetoa-
cetate as an alkylating agent and dirhodium tetraacetate (Rh2(OAc)4) as the catalyst. The general
applicability of the reaction as a synthetic method for N-aryloxamates was studied with a number of
substituted N-alkylated anilines. The results revealed that the oxamate was formed by a radical reaction
with molecular O2 and Rh2(OAc)4 as initiator.
Introduction. – N-Aryloxamates (¼2-(arylamino)-2-oxoacetates) have been broad-
ly used as 1,2-dielectrophiles and selective inhibitors of the sperm-specific lactate
dehydrogenase isozyme-C4 [1]. Therefore, a new synthetic method for the preparation
of oxamates is of great interest. The existing methods for the synthesis of oxamates are
carbonylation of amino aldehydes using ZrO2 [2], reaction of NH3 with diketones [3]
and aniline with diethyl oxalate [4], oxidation of dithiooxamide [5], and hydrolysis of
a-functionalized nitriles [6]. It is, therefore, anticipated that the transformation of N-
alkylanilines to N-aryloxamates will serve as an attractive method for the synthesis of
oxamates.
From the N-alkylation of anilines 1, using ethyl 2-diazoacetoacetate and
Rh2(OAc)4, in addition to compounds 2, N-aryloxamates 3 were obtained as main
by-products. This product can be produced by the oxidation of 2 with O2 in the
presence of Rh2(OAc)4 in a likely radical process [7]. The formation of the oxamates 3
prompted us to examine the generality of the reaction from the perspective of using it
as a synthetic method for the preparation of oxamates (Scheme 1).
Results and Discussion. – Compounds 2 were prepared by the N-alkylation of
anilines with ethyl 2-diazoacetoacetate catalyzed by Rh2(OAc)4 in refluxing benzene.
The resulting mixtures were filtered over silica gel, eluting with AcOH/petroleum
ether, and significant amounts of by-products 3 were always obtained, sometimes in
equal amounts as 2. The transformation of 2 to N-aryloxamates 3 occured via oxidation
of 2 in the presence of Rh2(OAc)4. Assuming that O2 participates in the reaction
leading to 3, the preparation of 3a was studied under different gas-bubbling conditions
to demonstrate the role of molecular O2 in the reaction. The test reactions were
performed with 2a and Rh2(OAc)4 in refluxing benzene only, and with air, O2, or N2
flow rate of 2 l/h. The results are compiled in Table 1. The yield of 3a was 18.1% in
refluxing benzene, but it significantly increased to 41.7% in the presence of air. The
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 96 (2013)
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Scheme 1. Transformation of N-Alkylated Anilines to N-Aryloxamates
yield further increased to 49.4% in an atmosphere of O2, and no oxamate formation
was observed in an atmosphere of N2. The more molecular O2 with the opportunity to
participate in the reaction was present, the more 3a was formed, indicating that
molecular O2 was an essential reagent in the reaction.
Table 1. Effect of Gas Supply on the Yield of 3aa)
Entry
Gas additive
Yield [%]
1
2
3
4
–
18.1
41.7
49.4
Nil
Air
O2
N2
a) Compound 2a (2 mmol), Rh2(OAc)4 (0.005 mmol); and dry benzene (10 ml) reflux, gas bubbling (2 l/
h).
To confirm that Rh2(OAc)4 participated in the transformation of 2a to 3a, 2a was
reacted in the presence of molecular O2 in refluxing benzene without Rh2(OAc)4 for
24 h. Interestingly, 3a was not detected in the reaction mixture. This result revealed that
Rh2(OAc)4 was necessary for the transformation of N-alkylanilines to N-aryloxamates.
Next, the reaction was performed with different amounts of Rh2(OAc)4. The results
are collected in Table 2. When the amount of Rh2(OAc)4 was reduced to 2.5 ꢀ
10ꢁ4 equiv., the yields of 3a remained constant at 49%. Obviously, Rh2(OAc)4 acted
as the initiator in this free-radical reaction [7], and it cannot be replaced by other
radical initiators, such as azobiisobutyronitrile (AIBN) or I2.
The synthesis of 3a was simplified by introducing O2 into the mixture of aniline 1a,
ethyl 2-diazoacetoacetate, and Rh2(OAc)4 in benzene. The resulting mixture was
heated to reflux, until 1a was converted into 3a, as monitored by TLC, in 39.4% yield.
The general applicabelity of the reaction as a synthetic method for the preparation of
N-aryloxamates was further studied with a number of substituted anilines under the
same conditions (i.e., 2.5 ꢀ 10ꢁ4 equiv. of Rh2(OAc)4 in the presence of molecular O2
(2 l/h)). The results are compiled in Table 3.

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Helvetica Chimica Acta – Vol. 96 (2013)
Table 2. Effect of the Amount of Rh2(OAc)4 on the Yield of 3aa)
Entry
Equiv.
Yield [%]
1
2
3
2.5 ꢀ 10ꢁ3
2.5 ꢀ 10ꢁ4
2.5 ꢀ 10ꢁ5
49.4
49.3
38.6
a) Compound 2a (2 mmol), dry benzene (10 ml), and Rh2(OAc)4 (0.005 mmol); reflux, 0.5 h, O2
bubbling (2 l/h).
Table 3. Yields of Oxamates 3a – 3ka)
Entry
Product
X
Time [min]
Yield [%]
This work
Conventional method
1
2
3
4
5
6
7
8
9
3a [4]
3b [4]
3c [4]
3d [4]
3e [4]
3f [4]
3g [4]
3h [4]
3i [8]
3j [9]
3k [10]
H
4-Me
3-Me
4-NO2
3-NO2
4-MeO
4-Cl
80
100
100
60
60
100
70
70
70
50
60
39.4
45.1
47.6
66.8
64.0
49.3
68.4
71.6
69.2
65.6
68.7
64
35
37
41
64
88
75
87
54
63
59
3-Cl
4-EtOCO
2,5-F2
3,5-(CF3)2
10
11
a) 1 Compound (2 mmol), ethyl 2-diazoacetoacetate (5.0 mmol), dry benzene (10 ml), and Rh2(OAc)4
(2.5 ꢀ 10ꢁ4 equiv.); reflux, O2 bubbling (2 l/h).
This method afforded 3 in less than 100 min at reflux temperature, whereas
conventional methods [4] required temperatures of 1158 and times of up to 5.5 h with
aniline and diethyl oxalate. The efficiency of the preparation of 3b and 3c was also
increased, as the yield was 45.1 and 47.6% by the reported method, and 35 and 37% for
the conventional method, respectively. However, the yield of 3f (49.3%) was lower
than the yield of 88% reported in [4]. The explanation of the lower yields needs further
studies.
The mechanism of the transformation of 2 to 3 is presumed to be an oxidation of 2
by O2 via a free-radical mechanism, as outlined in Scheme 2, and similar to the 2,3-
cleavage of acetylacetone to acetate and methylglyoxal (¼2-oxopropanal [11]. The
transition-metal ions play a key role in oxygen activation, to form a transition metalꢁO2
.
.
complex and a free peroxide radical [12]. The cat.OO abstracts H from 2 to give
cat.OOH, leading to a C-centered radical 2’. The addition of O2 gives 2’’, which
.
abstracts H from cat.OOH or 2 to generate hydroperoxide 3’. Finally, 3’ undergoes
nucleophilic attack of the HO group to the adjacent C¼O group to form 3.

Helvetica Chimica Acta – Vol. 96 (2013)
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Scheme 2. Proposed Mechanism of Transformation of 2 to 3
Conclusions. – The transformation of N-alkylanilines into N-aryloxamates was
accomplished in the presence of Rh2(OAc)4 using molecular O2. The general
applicability of the reaction as a synthetic method for N-aryloxamates was evaluated
with a series of substituted anilines. The potential application of the reaction as a
synthetic method for oxamates is remarkable and may serve as an alternative in the
synthesis of oxamates.
This work was financially supported by the Key Projects in the National Science & Technology Pillar
Program during the Twelfth Five-Year Plan Period (No. 2012ZX10001007-008-002) and Scientific and
Technological Innovation Platform of Beijing Local Colleges and Universities (No. JJ015790201202).
Experimental Part
General. All chemicals and reagents were purchased from commercial sources and were used
without further purification. All reactions were monitored by TLC (silica-gel plates; Merck 60 F254).
Column chromatography (CC): silica gel (Merck, 230 – 400 mesh). M.p.: X-5 apparatus; uncorrected.
NMR Spectra: Bruker-Avance II400 instrument (400 MHz) in CDCl3; d rel. to Me4Si, in ppm, J in Hz.
General Procedure for the Preparation of 3. A mixture of aniline 1 (2.0 mmol), Rh2(OAc)4
(0.005 mmol), and 10 ml of dry benzene was heated to reflux. A soln. of ethyl 2-diazoacetoacetate
[13] (5.0 mmol) in 10 ml of benzene was added dropwise to the refluxing mixture in the presence of
molecular O2, which was bubbled into the mixture at a rate of 2 l/h. The resulting mixture was heated at
reflux temperature until 1 was consumed. After cooling to r.t., the volatiles were removed in vacuo, and
the residue was purified by CC (petroleum ether/AcOEt) to give 3 in yields in the range of 39.4 – 69.2%.

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Helvetica Chimica Acta – Vol. 96 (2013)
Ethyl 2-Oxo-2-(phenylamino)acetate (3a) [4]. Yield: 221.0 mg (39.4%). Colorless solid. M.p. 71 –
1
728. H-NMR: 1.35 (t, J ¼ 7.2, Me); 4.35 (q, J ¼ 7.2, CH2); 7.17 – 7.23 (m, 3 arom. H); 7.48 – 7.52 (m, 2
arom. H); 8.85 (s, NH).
Ethyl 2-[(4-Methylphenyl)amino]-2-oxoacetate (3b) [4]. Yield: 186.9 mg (45.1%). Colorless solid.
M.p. 69 – 718. 1H-NMR: 1.43 (t, J ¼ 7.2, Me); 2.34 (s, Me); 4.42 (q, J ¼ 7.2, CH2); 7.18 (d, J ¼ 8.0, 2 arom.
H); 7.53 (d, J ¼ 8.0, 2 arom. H); 8.86 (s, NH).
Ethyl 2-[(3-Methylphenyl)amino]-2-oxoacetate (3c) [4]. Yield: 197.3 mg (47.6%). Colorless solid.
M.p. 58 – 598. 1H-NMR: 1.42 (t, J ¼ 7.2, Me); 2.36 (s, Me); 4.41 (q, J ¼ 7.2, CH2); 7.00 – 7.45 (m, 4 arom. H);
9.38 (s, NH).
Ethyl 2-[(4-Nitrophenyl)amino]-2-oxoacetate (3d) [4]. Yield: 318.2 mg (66.8%). Colorless solid.
M.p. 144 – 1458. 1H-NMR: 1.44 (t, J ¼ 7.2, Me); 4.45 (q, J ¼ 7.2, CH2); 7.86 (d, J ¼ 8.8, 2 arom. H); 8.27 (d,
J ¼ 8.8, 2 arom. H); 9.27 (s, NH).
Ethyl 2-[(3-Nitrophenyl)amino]-2-oxoacetate (3e) [4]. Yield: 304.9 mg (64.0%). Colorless solid.
M.p. 96 – 988. 1H-NMR: 1.45 (t, J ¼ 7.2, Me); 4.60 (q, J ¼ 7.2, CH2); 7.56 – 7.60 (m, 1 arom. H); 8.05 – 8.10
(m, 2 arom. H); 8.53 (s, 1 arom. H); 9.19 (s, NH).
Ethyl 2-[(4-Methoxyphenyl)amino]-2-oxoacetate (3f) [4]. Yield: 264.7 mg (49.3%). Colorless solid.
1
M.p. 112 – 1138. H-NMR: 1.40 (t, J ¼ 7.2, Me); 3.75 (s, Me); 4.35 (q, J ¼ 7.2, CH2); 6.85 (dd, J ¼ 8.4, 2
arom. H); 7.50 (dd, J ¼ 8.4, 2 arom. H); 8.90 (s, NH).
Ethyl 2-[(4-Chlorophenyl)amino]-2-oxoacetate (3g) [4]. Yield: 356.9 mg (68.4%). Colorless solid.
M.p. 146 – 1488. 1H-NMR: 1.41 (t, J ¼ 7.2, Me); 4.41 (q, J ¼ 7.2, CH2); 7.34 (d, J ¼ 8.8, 2 arom. H); 7.61 (d,
J ¼ 8.8, 2 arom. H); 8.95 (s, NH).
Ethyl 2-[(3-Chlorophenyl)amino]-2-oxoacetate (3h) [4]. Yield: 371.5 mg (71.6%). Colorless solid.
M.p. 1108. 1H-NMR: 1.50 (t, J ¼ 7.2, Me); 4.45 (q, J ¼ 7.2, CH2); 7.28 – 7.31 (m, 1 arom. H); 7.34 – 7.36 (m, 1
arom. H); 7.52 – 7.53 (m, 1 arom. H); 7.75 (s, 1 arom. H); 9.10 (s, NH).
Ethyl 4-[(2-Ethoxy-1,2-dioxoethyl)amino]benzoate (3i) [8]. Yield: 367.1 mg (69.2%). Colorless
solid. M.p. 130 – 1318. 1H-NMR: 1.40 (t, 3 H, J ¼ 7.2, Me); 1.44 (t, J ¼ 7.2, Me); 4.37 (q, J ¼ 7.2, CH2); 4.43
(q, J ¼ 7.2, CH2); 7.73 (d, J ¼ 8.8, 2 arom. H); 8.06 (d, J ¼ 8.8, 2 arom. H); 9.05 (s, NH).
Ethyl 2-[(2,5-Difluorophenyl)amino]-2-oxoacetate (3j) [9]. Yield: 291.5 mg (65.6%). Colorless
solid. M.p. 44.5 – 45.38. 1H-NMR: 1.46 (t, J ¼ 7.2, Me); 4.46 (q, J ¼ 7.2, CH2); 6.21 – 6.29 (m, 2 arom. H);
7.11 – 7.13 (m, 1 arom. H); 8.21 – 8.23 (m, 1 arom. H); 9.15 (s, NH).
Ethyl 2-{[3,5-Bis(trifluoromethyl)phenyl]amino}-2-oxoacetate (3k) [10]. Yield: 303.9 mg (68.7%).
Colorless solid. M.p. 88 – 908. 1H-NMR: 1.45 (t, J ¼ 7.2, Me); 4.35 (q, J ¼ 7.2, CH2); 7.41 (s, 1 arom. H); 7.87
(s, 2 arom. H); 9.11 (s, NH).
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Received November 6, 2012