Potassium cyanate as an amino-dehydroxylating agent: Synthesis of aminooxypyrrole mono, dicarboxylic acid esters, and carbonitrile

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Potassium Cyanate as an Amino-dehydroxylating Agent:
Synthesis of Aminooxypyrrole Mono, Dicarboxylic Acid
Esters, and Carbonitrile
Fabrice Jourdan a , Jens T. Kaiser b & David J. Lowe a
a John Innes Centre, Department of Biological Chemistry, Colney, Norwich, UK
b Max Planck Institut für Biochemie, Martinsried, Germany
Available online: 17 Aug 2006
To cite this article: Fabrice Jourdan, Jens T. Kaiser & David J. Lowe (2003): Potassium Cyanate as an Amino-dehydroxylating
Agent: Synthesis of Aminooxypyrrole Mono, Dicarboxylic Acid Esters, and Carbonitrile, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:13, 2235-2241
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2235–2241, 2003
Potassium Cyanate as an
Amino-dehydroxylating Agent: Synthesis of
Aminooxypyrrole Mono, Dicarboxylic Acid
Esters, and Carbonitrile
2
1
Fabrice Jourdan,1, Jens T. Kaiser, and David J. Lowe
*
1John Innes Centre, Department of Biological
Chemistry, Colney, Norwich, UK
2Max Planck Institut fur Biochemie,
Martinsried, Germany
INTRODUCTION
In the vast area of heterocyclic chemistry, the search for new small
polyfunctionalized heterocyclic rings constitutes a key step towards the
synthesis of larger systems. Amongst these intermediate heterocycles,
ortho amino esters are electrophilic and nucleophilic centre containing
reagents that have been widely used for further cyclization reactions
such as the annelation of a pyridine,[1] pyrimidine,[2] diazepine,[3] benzox-
*Correspondence: Fabrice Jourdan, John Innes Centre, Department of Biological
Chemistry, Colney, Norwich, NR4 7UH, UK; Fax: (44) (01603) 450 018;
E-mail: fabrice.jourdan@bbsrc.ac.uk.
2235
DOI: 10.1081/SCC-120021502
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2236
Jourdan, Kaiser, and Lowe
azine or benzothiazine,[4] benzodiazepine,[5] benzoxazepines,[6] and pyra-
zine[7] ring. Thus, aiming at preparing new heterobicyclic derivatives as
potential Xanthine Oxidase inhibitors, we were particularly interested in
synthesizing new 4-amino-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic
acid esters.
RESULTS
During the preparation of new potential inhibitors of xanthine
oxidase, we have incidentally found that potassium cyanate can be
used as a reagent for the amino-dehydroxylation of various hydroxy-
pyrroles such as 1a–d, 3a–d, and 5a–d (Sch. 1 and Table 1).
The preparation of the 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3
-carboxylic acid esters 1a–d, 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-
2,3-dicarboxylic acid esters 3a–d, and 4-hydroxy-5-oxo-2,5-dihydro-1H-
pyrrole-3-carbonitrile 5a–d followed methods previously described in the
Lit.[8–10] When subjected to reaction with potassium cyanate in refluxing
acetic acid and water the hydroxypyrroles 1a–d, 3a–d, and 5a–d gave the
corresponding aminopyrroles 2a–d, 4a–d, and 6a–d in 50 to 82% yields.
The best yields were obtained when refluxing the hydroxypyrroles in a 5/1
(v/v) mixture of water and acetic acid. The aminopyrrole carboxylic acid
esters 2a–d and carbonitriles 6a–d have been described before and were
prepared by aminodehydroxylation of their respective hydroxypyrroles
with ammonium formate in refluxing ethanol[11] or 2-ethoxyethanol.[l2]
On the other hand, this is the first preparation of the 4-amino-5-oxo-2,5-
dihydro-1H-pyrrole-2,3-dicarboxylic acid esters 4a–d (see Table 2 for
NMR data). The derivatives 4a–d couldn’t be prepared in satisfactory
yield with ammonium salts in refluxing ethanol, 2-ethoxyethanol, or
Scheme 1.

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Aminooxypyrrole Mono, Dicarboxylic Acid Esters, and Carbonitrile
2237
Table 1. Percentage yields for the amino-dehydroxylation of the
4-hydroxypyrroles.
Reactant Product
R1
R2
R3
Yield (%)
1a
1b
1c
1d
3a
3b
3c
3d
5a
5b
5c
5d
2a
2b
2c
2d
4a
4b
4c
4d
6a
6b
6c
6d
CH3
(CH3)2CHCH2
Benzyl
H
H
H
H
COOEt65
COOEt52
COOEt76
COOEt82
Phenyl
CH3
COOEtCOOEt
(CH3)2CHCH2 COOEtCOOEt
59
50
65
72
Benzyl
Phenyl
CH3
COOEtCOOEt
COOEtCOOEt
H
H
H
H
CN
CN
CN
CN
63
51
62
69
(CH3)2CHCH2
Benzyl
Phenyl
acetic acid. Moreover, small amounts (up to 8–10%) of 2a–d were
obtained together with 4a–d when 3a–d was refluxed in acetic acid or
2-ethoxyethanol.
To the best of our knowledge, the present communication is the first
report of the use of cyanate salts for a direct conversion of an enol to an
enamine. This procedure provides an alternative route to the standard
ones using hexamethyldisilazane[13] (HMDS), high-pressure ammonia,[14]
or ammonium salts.[11,12,15] A possible mechanism for this reaction might
involve an in situ hydrolysis of potassium cyanate to ammonium acetate.
The current method can be applied to molecules containing many
different types of functional and protecting groups and might be suitable
in cases where the methods using ammonium salts[11,12,15] fail or give
unsatisfactory results as shown for the derivatives 4a–d.
EXPERIMENTAL
Yields expressed are for isolated pure compounds (flash chromatog-
raphy). Their characterization was obtained by a combination of
IR, NMR, MS, microanalysis, and/or direct comparison to authentic
material prepared with ammonium acetate. Infrared spectra were
recorded on a FTIR-8300 Shimadzu spectrometer in KBr with absorp-
tions in cmꢀ1. 1H and 13C NMR spectra were recorded on a JEOL JNM

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Jourdan, Kaiser, and Lowe
LA-400 spectrometer. Mass spectra were recorded on a Kratos MS25
spectrometer.
General Procedure
A solution of 1a–d, 3a–d, or 5a–d (2 mmol) and potassium cyanate
(1 equiv.) in 5 mL acetic acid and 25 mL water was refluxed for 3 h. After
cooling the solution to room temperature, an equivalent of potassium
cyanate was added and the solution refluxed for 3 h. This operation was
repeated until the reaction was complete as monitored by TLC. The
solvents were evaporated and the residual solid stirred in water. The
aqueous solution was made alkaline by addition of sodium hydroge-
nocarbonate, the organics were extracted with ethylacetate and the
organic layer washed with brine and water and dried over magensium
sulfate. After removal of ethyl acetate, the crude product was purified
using flash chromatography (hexane/ethyl acetate ranging from 2/1 to 1/1
ratio) to give the corresponding aminopyrroles 2a–d, 4a–d, or 6a–d.
4-Amino-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic acid
esters 4a. White crystals, m.p. 111ꢁC. IR: 3441 and 3319 (ꢀNH2), 1733,
1
1700 and 1688 (ꢀC¼O). H NMR (CDCl3) ꢁ: 5.76 (br, 2H, NH2), 4.64
(s, 1H, CH), 4.25 (tq, JH-H¼7.3 and 3.7 Hz, 2H, OCH2), 4.23
(JH-H¼7.3 and 3.7Hz, 2H, OCH2), 3.01 (s, 3H, CH3N), 1.29 (t, JH-H
¼
7.3 Hz, 3H, CH3), 1.27 (t, JH-H¼7.3 Hz, 3H, CH3). 13C NMR (CDCl3) ꢁ:
168.6 (CO), 165.6 (CO), 164.3 (CO), 147.1 (C4), 98.4 (C3), 62.6 (CH2O),
61.9 (CH2O), 59.9 (C2), 28.3 (CH3N), 14.4 (CH3), 14.1 (CH3). MS m/e
(%): 256 (Mþ, 13), 183 (100), 153 (5), 137 (98), 111 (64). Anal. calcd.
for C11H16N2O5: C, 51.56; H, 6.29; N, 10.93. Found: C, 51.73; H, 6.24;
N, 10.70.
4-Amino-1-isobutyl-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic
acid esters 4b. Lightyellow crysatls m.p. 78 ꢁC, IR: 3442 and 3317
1
(ꢀN H2), 1738, 1701 and 1689 (ꢀC¼O), H NMR (CDCl3) ꢁ: 5.91 (br,
2H, NH2), 4.73 (s, 1H, CH), 4.25 (tq, JH-H¼7.3 and 3.4 Hz, 2H,
OCH2), 4.23 (JH-H ¼ 7.3 and 3.4 Hz, 2H, OCH2), 3.58 (dd JH-H¼13.9
and 9.0 Hz, 1H, NCH2), 2.84 (dd JH-H¼13.9 and 6.4 Hz, 1H, NCH2),
1.98 (m, 1H, CH), 1.29 (t, JH-H¼7.3 Hz, 3H, CH3), 1.27 (t, JH-H
7.3 Hz, 3H, CH3), 0.94 (d, JH-H¼6.8 Hz, 3H, CH3), 0.86 (d, JH-H
¼
¼
6.6 Hz, 3H, CH3) 13C NMR (CDCl3) ꢁ: 168.6 (CO), 166.1 (CO), 164.4
(CO), 147.1 (C4), 98.5 (C3), 61.8 (CH2O), 61.4 (CH2O), 60.0 (C2), 49.2
(CH2N), 27.3 (CH), 20.1 (CH3), 19.7 (CH3), 14.4 (CH3), 14.1 (CH3). MS
m/e (%): 298 (Mþ, 15), 225 (100), 179, (56), 111 (5), 137 (98), 109 (22).

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Aminooxypyrrole Mono, Dicarboxylic Acid Esters, and Carbonitrile
2239
Anal. calcd. for C14H22N2O5: C, 56.36; H, 7.43; N, 9.39. Found: C, 56.31;
H, 7.34; N, 9.44.
4-Amino-1-benzyl-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic acid
esters 4c. White crystals, m.p. 102ꢁC. IR: 3418 and 3320 (ꢀNH2), 1747,
1
1707 and 1696 (ꢀC¼O). H NMR (CDCl3) ꢁ: 5.68 (br, 2H, NH2), 5.03
(d, JH-H¼14.9 Hz, 1H, 1CH2Ph), 4.56 (s, 1H, CH), 4.19 (JH-H¼7.0 and
3.7 Hz, 2H, OCH2), 4.16 (d, JH-H¼14.9 Hz, 1H, 1CH2Ph), 4.10
(JH-H ¼ 7.1 and 3.7 Hz, 2H, OCH2), 1.25 (t, JH-H¼7.0 Hz, 3H, CH3),
1.23 (t, JH-H¼7.1 Hz, 3H, CH3) 13C NMR (CDCl3) ꢁ: 168.6 (CO), 165.6
(CO), 164.4 (CO), 148.8 (C4), 135.5 (Ph), 128.7 (Ph), 128.5 (Ph), 128.0
(Ph), 99.0 (C3), 61.8 (CH2O), 60.3 (CH2O), 60.0 (C2), 45.7 (C H2N), 14.3
(CH3), 14.0 (CH3). MS m/e (%): 332 (Mþ, 16), 259 (100), 213 (67), 187,
(18), 177 (35), 149 (19), 135 (16), 106 (786). Anal. calcd. for C17H20N2O5:
C, 61.44; H, 6.07; N, 8.43. Found: C, 61.51; H, 6.00; N, 8.42.
4-Amino-1-phenyl-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic acid
esters 4d. Lightred crystals, m.p. 98 ꢁC. IR: 3441 and 3319 (ꢀNH2), 1746,
1
1720 and 1699 (ꢀC¼O). H NMR (CDCl3) ꢁ: 5.68 (br, 2H, NH2), 5.03
(d, JH-H¼14.9 Hz, 1H, 1CH2Ph), 4.56 (s, 1H, CH), 4.19 (JH-H¼7.0 and
3.7 Hz, 2H, OCH2), 4.16 (d, JH-H¼14.9 Hz, 1H, 1CH2Ph), 4.10 (JH-H¼7.1
and 3.7 Hz, 2H, OCH2), 1.27 (t, JH-H¼7.0 Hz, 3H, CH3), 1.25 (t, JH-
¼7.1 Hz, 3H, CH3); 13C NMR (CDCl3) ꢁ: 168.6 (CO), 165.6 (CO),
H
164.4 (CO), 148.8 (C4), 135.5 (Ph), 128.7 (Ph), 128.5 (Ph), 128.0 (Ph),
99.0 (C3), 61.8 (CH2O), 60.3 (CH2O), 60.0 (C2), 45.7 (CH2N), 14.3
(CH3), 14.0 (CH3) MS m/e (%): 318 (Mþ, 18), 245 (100), 199 (79), 171
(9), 143 (9), 104 (19), 77 (32). Anal. calcd. for C16H18N2O5: C, 60.37; H,
5.70; N, 8.80. Found: C, 60.23; H, 5.60; N, 8.71.
ACKNOWLEDGMENTS
We gratefully acknowledge the European Community (grant HPRN-
CT-1999-00084) and the BBSRC for financial support. We also wish to
thank Professor Chris Pickett for helpful discussions and suggestions.
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Received in the UK July 2, 2002

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