A facile and efficient iodination of 5,6-di(arylamino)pyridine-2,3-diones

Article abstract of DOI:10.3184/174751912X13272462962072

A simple and efficient method for the iodination of 5,6-di(arylamino) pyridine-2,3-diones using iodine with ethanol at room temperature is described. Notable advantages include mild reaction condition, no need for a catalyst, short reaction time, simple practical procedure, giving excellent yield of the product. Iodopyridines have important medical applications as drug or diagnostic aids and radiolabelled compounds.

Full text of DOI:10.3184/174751912X13272462962072

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 103
FEBRUARY, 103–104
A facile and efficient iodination of 5,6-di(arylamino)pyridine-2,3-diones
Wenlin Xie,* Ying Zhou, Chuangping Xiao, Ling Xie, Xufu Tang and Renyuan Liu
Key Laboratory ofTheoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan Provincial University Key Laboratory of
QSAR/QSPR , School of Chemistry and Chemical Engineering, Hunan University of Science andTechnology, Xiangtan 411201, P. R. China
A simple and efficient method for the iodination of 5,6-di(arylamino)pyridine-2,3-diones using iodine with ethanol at
room temperature is described. Notable advantages include mild reaction condition, no need for a catalyst, short
reaction time, simple practical procedure, giving excellent yield of the product. Iodopyridines have important
medical applications as drug or diagnostic aids and radiolabelled compounds.
Keywords: iodination, iodine, pyridine-2,3-dione, aromatic-amine, radiolabelled compounds
Iodo substituents offer various functionalities because of their
excellent reactivity.1 The iodine may be replaced by lithium
or magnesium, the organometallic intermediate may then be
converted into a functionalised derivative by reaction with a
suitable electrophile.2–4 Consequently, substituents can be
easily functionalised through cross-coupling reactions in the
synthesis of many interesting natural products and bioactive
material.5,6 Iodopyridines are used in medicine as drug or diag-
nostic aids and radiolabelled compounds.7 While iodopyridines
are versatile intermediates, their limited commercial availabil-
ity requires that they be synthesised from readily available
precursors. One of the most common methods for the prepara-
tion of iodopyridines involves lithiation of activated pyridines
followed by quenching with iodine.8 The major disadvantage
of this protocol is that sensitive functional groups are not
well tolerated leading to either competing side reactions or
decomposition of either the starting materials or products.9
Therefore, the development of new, efficient synthetic method
of iodopyridines is very important. We report here a facile
and efficient protocol for the direct iodination of 5,6-
di(arylamino)pyridine-2,3-diones with iodine (Scheme 1).
spectrum of 2a showed a molecular ion peak at m/z 446
([M+H]+), which indicated the addition of iodine to the
5,6-di(arylamino)pyridine-2,3-diones. The 1H NMR spectrum
of 2a demonstrated the presence of a singlet of two methyl
protons of benzene ring at δ 2.41, several multiplets in the
range of δ 6.85–7.27 assigned as aromatic protons of benzene
ring, and two singlets at δ 8.31 and 8.92 were assigned to the
two NH respectively. An important characteristic feature in the
1H NMR spectra of 2a was the disappearance of the signals
at δ 5.93 for 4-H of pyridine ring, which was present in the
spectra of the intermediate 5,6-di(p-methylanilino)pyridine-
2,3-dione,10 thus suggesting the iodination of compound 1 had
taken place at the 4-position of the pyridine and not at the
aromatic ring. The 13C NMR spectrum of the product 2a
revealed the presence of two methyl carbons at δ 20.9 and
21.2, and two carbonyl carbons at δ 151.5 and. 171.0.
In conclusion, a simple and convenient method for the direct
iodination of 5,6-di(arylamino)pyridine-2,3-diones has been
developed. The major advantages of this method include no
catalyst, mild conditions, simple operation and short reaction
time with excellent yield.
Experimental
Results and discussion
Melting points were determined in the open capillaries and were
uncorrected. IR spectra were recorded on a PE-2000 spectrometer in
KBr pellets and reported in cm−1. All NMR spectra were recorded on
a Bruker AV-II 500 MHz NMR spectrometer, operating at 500 MHz
for 1H, and 125 MHz for 13C, TMS was used as an internal reference
for 1H and 13C chemical shifts and CDCl3 was used as solvent. Mass
spectra were collected on a Bruker ESQUIRE electrospray/ion trap
instrument. Elemental analysis was determined with a Perkin-Elmer
240c elemental analysis instrument. All starting materials were
commercial except 5,6-di(arylamino)pyridine-2,3-diones 1, which
was prepared according to a literature procedure.10
The 4-iodo-5,6-5,6-di(arylamino)pyridine-2,3-diones 2 were
synthesised by direct iodination of 5,6-di(arylamino)pyridine-
2,3-diones 1 with iodine without a catalyst at room tempera-
ture. The intermediate product 5,6-di(arylamino)pyridine-
2,3-diones were prepared by the Michael oxidation. where
addition of aromatic amine with 3-hydroxypyridin-2(1H)-ones
is carried out in the presence of oxidant NaIO3 at room
temperature. The reaction did not require catalysis and an
excellent yield could be obtained. The structure of the formed
products was supported based on the elemental analysis and
spectral data (IR, NMR and MS). The IR spectrum of 2a
revealed the presence of two carbonyl stretching vibration
bands at 1719 and 1655 cm−1, the absorption peak at 3431 cm−1
indicated the presence of N-H stretching vibration. The mass
Iodination of 5,6-di(arylamino)pyridine-2,3-diones derivatives;
general procedure
5,6-Di(arylamino)pyridine-2,3-diones compounds 1 (1 mmol) and
iodine (0.305 g, 1.2 mmol) were dissolved in anhydrous ethanol
Scheme 1 Synthetic of 4-iodo-5,6-di(arylamino)pyridine-2,3-diones.
* Correspondent. E-mail: xwl2003zsu@yahoo.com.cn

104 JOURNAL OF CHEMICAL RESEARCH 2012
(20 mL). The mixture was stirred at room temperature. The progress
of the reaction was monitored by TLC. After completion of the reac-
tion, the solvent was removed under reduced pressure to yield a crude
solid. The obtained solid was dissolved in ethyl acetate (50 mL),
washed by sodium thiosulfate (0.5 mol L−1, 50 mL × 3), and then
dried by anhydrous magnesium sulfate. The crude product is
recrystallised from ethanol/acetone to afford the corresponding 2.
4-Iodo-5,6-di(p-methylanilino)pyridine-2,3-dione (2a): Yield (87.5%);
yellow powder, m.p. 123.6–125.4 °C. IR (KBr, cm−1): 3431, 3214,
1719, 1655, 1574, 1507; 1H NMR (500 MHz, CDCl3) δ: 2.41 (s, 6H,
2CH3), 6.85–7.27 (m, 8H, ArH), 8.31 (s, 1H, NH), 8.92 (s, 1H, NH);
13C NMR (125 MHz, CDCl3) δ: 20.9, 21.2, 78.4, 120.3, 126.5, 129.3,
130.8, 133.4, 136.3, 137.1, 140.9, 141.0, 147.1, 151.5, 171.0; MS
(ESI) m/z 446.3 (M+H)+. Anal. Calcd for C19H16IN3O2: C, 51.25; H,
3.62; N, 9.44. Found: C, 51.53; H, 3.80; N, 9.59%.
4-Iodo-5,6-di(p-chloroanilino)pyridine-2,3-dione (2b): Yield (83.5%),
red powder, m.p. 128.9–130.1 °C. IR (KBr, cm−1): 3436, 3221, 1719,
1655, 1552, 1484; 1H NMR (500 MHz, CDCl3) δ: 6.93 (d, J = 9 Hz,
2H, ArH), 7.13 (d, J = 8.5 Hz, 2H, ArH), 7.40 (d, J = 8.5 Hz, 2H,
ArH), 7.45 (d, J = 8.0 Hz, 2H, ArH), 8.41 (s, 1H, NH), 8.78 (s, 1H,
NH); 13C NMR (125 MHz, CDCl3) δ: 79.6, 116.3, 122.0, 127.7, 128.9,
129.8, 130.2, 131.7, 134.5, 142.1, 147.1, 151.4, 170.9; MS (ESI) m/z
486.1 (M+H)+. Anal. Calcd for C17H10Cl2IN3O2: C, 42.00; H, 2.07; N,
8.64. Found: C, 42.18; H, 2.23; N, 8.56%.
138.8, 140.7, 141.1, 143.9, 147.0, 151.5, 171.0; MS (ESI) m/z 446.3
(M+H)+. Anal. Calcd for C19H16IN3O2: C, 51.25; H, 3.62; N, 9.44.
Found: C, 51.56; H, 3.50; N, 9.63%.
4-Iodo-5,6-di(m-chloroanilino)pyridine-2,3-dione (2g): Yield (83.5%),
red powder, m.p. 107.0–110.3 °C. IR (KBr, cm−1): 3422, 3217, 1718,
1656, 1587, 1552; 1H NMR (500 MHz, CDCl3) δ: 6.86 (d, J = 7.5 Hz,
1H, PhH), 6.99 (s, 1H. PhH), 7.09 (d, J = 8.0 Hz, 1H, PhH), 7.20 (s,
1H, PhH), 7.25 (d, J = 3.5 Hz, 1H, PhH), 7.29 (d, J = 8 Hz, 1H, PhH),
7.36 (t, J = 8 Hz, 1H, PhH), 7.41 (t, J = 8 Hz, 1H, PhH), 8.76
(m,1H,NH).13C NMR (125 MHz, CDCl3) δ: 81.1, 118.6, 120.7, 124.3,
126.3, 126.3, 127.0, 129.7, 131.3, 134.4, 135.8, 137.1, 141.5, 144.5,
146.9, 151.2, 171.0; MS (ESI) m/z 486.1 (M+H)+. Anal. Calcd for
C17H10Cl2IN3O2: C, 42.00; H, 2.07; N, 8.64. Found: C, 42.28; H, 2.18;
N, 8.75%.
4-Iodo-5,6-di(m-methoxyanilino)pyridine-2,3-dione (2h): Yield
(91.5%), orange powder, m.p. 156.8-158.9 °C. IR (KBr, cm−1): 3444,
3237, 1717, 1655, 1594, 1557; 1H NMR (500 MHz, CDCl3) δ: 3.838
(s, 6H, 2CH3), 6.514 (t, J = 7.5 Hz, 2H, PhH), 6.731 (s, 1H, PhH),
6.807 (t, J = 7.5 Hz, 2H, PhH), 6.863 (d, J = 8 Hz, 1H, PhH), 7.313
(t, J = 8 Hz, 1H, PhH), 7.371 (t, J = 8.5 Hz, 1H, PhH), 8.34 (s, 1H,
NH), 8.85 (s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ: 55.4, 55.5,
79.7, 106.3, 111.9, 112.1, 112.2, 112.9, 118.8, 129.4, 131.2, 136.9,
141.2, 144.9,147.1, 151.3, 159.9, 161.1, 171.1; MS (ESI) m/z 478.3
(M+H)+. Anal. Calcd for C19H16IN3O4: C, 47.82; H, 3.38; N, 8.80.
Found: C, 47.98; H, 3.56; N, 8.95%.
4-Iodo-5,6-di(p-fluoroanilino)pyridine-2,3-dione (2c): Yield (84.3%),
Yellow powder, m.p. 185.3–187.2 °C. IR (KBr, cm−1): 3438, 3234,
1727, 1662, 1573, 1499; 1H NMR (500 MHz, CDCl3) δ: 6.95–7.21 (m,
8H, PhH), 8.33 (s, 1H, NH), 8.82 (s, 1H, NH); 13C NMR (125 MHz,
CDCl3) δ: 79.0, 115.7, 115.9, 117.2, 117.4, 122.1, 122.2, 128.6, 128.7,
132.0, 132.0, 139.5, 139.5, 141.3, 147.1, 151.2, 159.9, 160.5, 161.8,
162.5, 170.9; MS (ESI) m/z 454.2 (M+H)+. Anal. Calcd for
C17H10F2IN3O2: C, 45.06; H, 2.22; N, 9.27. Found: C, 45.19; H, 2.38;
N, 9.49%.
4-Iodo-5,6-di(p-methoxyanilino)pyridine-2,3-dione (2i): Yield
(85.5%), yellow powder, m.p. 113.7–114.9 °C. IR (KBr, cm−1): 3426,
1
3235, 1714, 1657, 1567, 1506; H NMR (500 MHz, CDCl3) δ: 3.85
(s, 3H), 3.86 (s, 3H), 6.93–7.27 (m, 8H, PhH), 8.40 (s, 1H);13C NMR
(125 MHz, CDCl3) δ: 55.4, 55.5, 77.5, 113.8, 115.5, 122.0, 128.4,
128.7, 136.3, 140.5, 147.2, 151.6, 158.0, 158.5, 173.2; MS (ESI) m/z
478.3 (M+H)+. Anal. Calcd for C19H16IN3O4: C, 47.82; H, 3.38; N,
8.80. Found: C, 48.01; H, 3.55; N, 8.62%.
4-Iodo-5,6-di(o-methoxyanilino)pyridine-2,3-dione (2d): Yield
(80.1%), red powder, m.p. 179.8–181.9 °C. IR (KBr, cm−1): 3444,
3211, 1708, 1654, 1559, 1498; 1H NMR (500 MHz, CDCl3) δ: 3.85 (s,
6H, CH3O), 6.92 (d, J = 3 Hz, 2H, PhH), 6.93 (d, J = 2 Hz, 2H, PhH),
6.99 (d, 1H, PhH), 7.00 (d, 1H, PhH), 7.13 (d, 1H, PhH), 7.15 (s, 1H,
PhH), 8.41 (s, 1H, NH), 8.94 (s, 1H, PhH); 13C NMR (125 MHz,
CDCl3) δ: 55.7, 55.8, 78.1, 111.1, 112.2, 120.0, 121.7, 122.7, 124.7,
127.4, 127.8, 128.3, 132.1, 140.8, 147.2, 148.8, 151.7, 154.2, 171.0;
MS (ESI) m/z 478.3 (M+H)+. Anal. Calcd for C19H16IN3O4: C, 47.82;
H, 3.38; N, 8.80. Found: C, 48.01; H, 3.56; N, 8.91%.
We are grateful for financial support from the Key Laboratory
of Theoretical Chemistry and Molecular Simulation of Minis-
try of Education (No. LKF0905) and Science and Technology
Project of Hunan Province (No. 2011SK3122).
Received 23 November 2011; accepted 12 January 2012
Paper 1101001 doi: 10.3184/174751912X13272462962072
Published online: 23 February 2012
4-Iodo-5,6-di(m-methylanilino)pyridine-2,3-dione (2e): Yield (90.3%),
red powder, m.p. 181.6–182.2 °C. IR (KBr, cm−1): 3445, 3239, 1721,
1670, 1566, 1498; 1H NMR (500 MHz, CDCl3) δ: 2.39 (s, 6H, 2CH3),
6.76 (d, J = 11.5 Hz, 2H, PhH), 7.00 (d, J = 6.5 Hz, 2H, PhH),
7.08 (d, J = 8.0 Hz, 1H, PhH), 7.13 (d, J = 8.0 Hz, 1H, PhH), 7.32 (t,
J = 5.5 Hz, 1H, PhH), 7.35 (t, J = 7.5 Hz, 1H, PhH), 8.32 (s, 1H, NH),
8.91 (s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ: 21.3, 21.4, 79.1,
117.2, 120.7, 123.4, 126.9, 127.0, 127.7, 128.5, 130.0, 135.7, 138.7,
140.4, 141.0, 143.6, 147.1, 151.5, 171.1; MS (ESI) m/z 446.3 (M+H)+.
Anal. Calcd for C19H16IN3O2: C, 51.25; H, 3.62; N, 9.44. Found: C,
51.53; H, 3.80; N, 9.21%.
References
1
2
3
4
M.B. Smith and J. March, Advanced organic chemistry, 5th edn, Wiley,
New York, 2001.
M. Schlosser, Organometallics in synthesis: A Manual, ed. M. Schlosser,
2nd edn, Wiley, Chichester, 2002, p. 95 and 134–136.
F. Trecourt, G. Breton, V. Bonnet, F. Mongin and F. Marsais, Tetrahedron,
2000, 56, 1349.
T. Iida, T. Wada, K. Tomimoto and T. Mase, Tetrahedron Lett., 2001, 42,
4841.
5
6
7
R.H. Seevers and R.E. Counsell, Chem. Rev., 1982, 82, 574.
K.C. Nicolaou, Angew. Chem., Int. Ed. Engl., 1993, 32, 1377.
N.D. Heindel, H.D. Burnes, T. Honds and L.W. Brandy, eds, Chemistry of
radiopharmaceuticals, Masson, New York, 1997.
P. Gros and Y. Fort, Eur. J. Org. Chem., 2002, 20, 3375.
M. Schlosser, F. Mongin, Chem. Soc. Rev., 2007, 36, 1161.
4-Iodo-5,6-di(o-methylanilino)pyridine-2,3-dione (2f): Yield (81.9%),
orange powder, m.p. 113.5–116.9 °C. IR (KBr, cm−1): 3436, 3207.23,
1
1728, 1659, 1559,1505; H NMR (500 MHz, CDCl3) δ: 2.17 (s, 3H,
8
9
CH3), 2.30 (s, 3H, CH3), 6.83 (d, 1H, PhH), 7.19–7.21 (m, 2H, PhH),
7.25–7.33 (m, 5H, PhH); 13C NMR (125 MHz, CDCl3) δ: 21.2, 21.3,
78.6, 117.3, 120.9, 123.4, 126.6, 127.1, 127.9, 128.2, 130.1, 136.2,
10 W.L. Xie, G.W. Xiao and L.Q. Gu, Chinese J. Org. Chem., 2008, 28,
1123.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.