Efficient synthesis of novel 4-substituted urazoles

Article abstract of DOI:10.1081/SCC-120004270

The efficient synthesis of several new and novel 4-substituted triazolidindiones (urazoles) starting from isocyanates, amines, anilines and carboxylic acids is reported.

Full text of DOI:10.1081/SCC-120004270

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EFFICIENT SYNTHESIS OF NOVEL 4-SUBSTITUTED
URAZOLES
Thomas Little a , Joseph Meara a , Fuqiang Ruan a , Minh Nguyen a & Maher Qabar a
a Molecumetics, 2023 120th Ave., N.E. Suite 400, Bellevue, WA, 98005-2199, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: Thomas Little, Joseph Meara, Fuqiang Ruan, Minh Nguyen & Maher Qabar (2002): EFFICIENT SYNTHESIS OF
NOVEL 4-SUBSTITUTED URAZOLES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:11, 1741-1749
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SYNTHETIC COMMUNICATIONS, 32(11), 1741–1749 (2002)
EFFICIENT SYNTHESIS OF NOVEL
4-SUBSTITUTED URAZOLES
Thomas Little, Joseph Meara, Fuqiang Ruan,
*
Minh Nguyen, and Maher Qabar
Molecumetics, 2023 120th Ave. N.E. Suite 400,
Bellevue, WA 98005-2199, USA
ABSTRACT
The efficient synthesis of several new and novel 4-substituted
triazolidindiones (urazoles) starting from isocyanates, amines,
anilines and carboxylic acids is reported.
Recently we have reported our work in the area of synthesis of
b-strand mimetic libraries using our most recent triazolopyridazine-based
b-strand mimetic.[1] Our approach to the synthesis of the b-sheet mimetic
template, on solid phase, is depicted in Scheme 1.
The triazolopyridazine template is synthesized by a highly efficient
hetero-Diels-Alder in a key diversity-introducing step. This is a convergent
synthesis that involves reaction of a resin-linked diene[2] with the hetero
Diels-Alder dienophile, in this case the 1,2,4-triazoledione[3] obtained by
bis(trifluoroacetoxy)iodobenzene (PhI(OTFA)2)-mediated oxidation of the
corresponding 4-substituted 1,2,4-triazolidindione (urazole).
An important component in the synthesis of these templates is the
4-substituted-urazoles. However there are only few commercially available
*Corresponding author.
1741
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1742
LITTLE ET AL.
Scheme 1.
urazoles. In this communication, we disclose the efficient synthesis of a wide
range of novel and synthetically useful urazoles.
In general, substituted urazoles were prepared starting with an isocya-
nate, an amine or an aniline. Reaction of an isocyanate with methyl carba-
zate in tetrahydrofuran at room temperature overnight led to the
precipitation of the intermediate substituted hydrazino carboxylate, which
was usually isolated by filtration (Scheme 2). On occasions where the prod-
uct did not precipitate, the product was simply obtained upon solvent eva-
poration. Most of the time this intermediate was pure enough to take to the
next step without further manipulation.
Alternatively, if the starting material is an amine or aniline, methyl
carbazate was first treated with carbonyldiimidazole followed, after 15 min,
by the addition of the amine or aniline to furnish the hydrazino carboxylate
(Scheme 3). If the product did not precipitate, simple flash chromatography
afforded the pure intermediate.
The typical method for closing the ring to prepare the urazole is to
treat the substituted hydrazino carboxylate with potassium hydroxide in
water at reflux (Scheme 4).[4]
Scheme 2.

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NOVEL 4-SUBSTITUTED URAZOLES
1743
Scheme 3.
Scheme 4.
The product is then isolated by acidification of the aqueous layer with
concentrated hydrochloric acid to pHꢀ1 to precipitate the urazole and
filtration. Although this method works well with most urazoles, we found
that in some cases it did not lead to product formation. For example,
treatment of compound 1 with KOH in water at reflux led mainly to the
formation of the hydrazino derivative 2 and not to the expected product 3
(Scheme 5). It seems that under this condition decarboxylation proceeds
faster than cyclization.
However, we found that cyclization can be affected by treatment of the
substituted hydrazinocarboxylate with freshly made sodium ethoxide in
ethanol at reflux. The desired product was then obtained following acidifi-
cation with concentrated HCl as described above. A more general and
milder protocol calls for the treatment of the substituted hydrazinocarbox-
ylate with potassium carbonate in an aqueous or alcoholic solvent (MeOH
or tBuOH) at reflux.[5] Although the reaction is slower under these con-
ditions, it is cleaner and sometimes the yield is better.
Scheme 5.

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1744
LITTLE ET AL.
The practicality of this chemistry afforded us many of these urazoles in
100-g scale in a short period of time with no chromatographic purification
involved. When working on a large scale, however, we found it more con-
venient not to isolate the intermediate hydrazinocarboxylate, but rather to
expose the crude, after solvent evaporation, to the cyclization conditions.
At occasions when neither amine nor isocyanate were available, a
carboxylic acid derivative was employed. The carboxylate group was
easily transformed into an isocyanate using the standard procedure.[6]
Treatment with methyl carbazate (Scheme 6, racemic starting material), as
described above, afforded the hydrazinocarboxylate and subsequently the
corresponding urazole.
It is noteworthy that protected a-amino acids also undergo the cycli-
zation to the urazoles (see Table 1).[7] However amino acids such as glutamic
acid did not yield any desired product, as exemplified by hydrazinocarbox-
ylate 16 (Scheme 7). Instead decomposition and/or recovery of starting
material were the predominant outcomes.
We applied two easy and convenient methods to quickly verify the
formation of the urazole. In one test (a colormetric test) we treated the
urazole in dichloromethane with iodosobenzene diacetate (PhI(OAc)2 or
PhI(OTFA)2) reagent, which oxidizes urazole to the triazolinedione. If a
red or purple color is obtained, then the urazole has been formed.[8] In
the second (a spectroscopic) we’ve recorded the HNMR in deuterated
DMSO. In this solvent, the urazole ring hydrogens appear consistently at
ꢀ10 ppm and integrate to two hydrogens.
Scheme 6.
Scheme 7.

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NOVEL 4-SUBSTITUTED URAZOLES
1745
Table 1.
Urazole
(Yield)
Entry
Starting Material
Solvent
Base
1
2
3
4
5
6
7
8
4-Nitrophenylisocyanate
4-Aminomethyl pyridine
2,4-Dichlorobenzylamine
4-(Trifluoromethoxy)aniline
1-Aminomethylnaphthalene
2-Butylaniline
H2O
H2O
H2O
H2O
MeOH
H2O
H2O
K2CO3
KOH
KOH
K2CO3
K2CO3
KOH
4 (74%)
5 (66%)
6 (67%)
7 (97%)
8 (64%)
9 (94%)
10 (100%)
11 (55%)
4-t-Butylaniline
KOH
K2CO3
3-Aminopropanoicacid
t-butyl ester
Phenylalanine-OH
tBu-glutamic acid
Phenyl-2-aminoethyl sulfone
tBuOH
9
10
11
EtOH
EtOH
MeOH
K2CO3
K2CO3
NaOCH3
12 (91%)
13 (0%)
14 (58%)
Inspection of the table indicates that a wide variety of urazoles could
be prepared in moderate to excellent yields (55–100%). Furthermore, sev-
eral of the urazoles incorporate additional functionality (see Entries 1, 8 and
9 in Table 1 and Scheme 6) that permit further derivatization on solid phase.
This is a key feature to introduce diversity at that end of the molecule in our
templated libraries.
In summary, by using the above-mentioned simple and convenient pro-
tocols, we have prepared many new and novel urazoles (numerous urazoles
were not disclosed) on a large scale (several urazoles were prepared on 100þ g
scale) and in high purity and yield. This allowed the preparation of libraries of
tens of thousands of compounds based on our b-strand template.
EXPERIMENTAL SECTION
General
THF was freshly distilled. MeOH (certified ACS) and DMF
1
(Omnisolv) were used as is. The H and 13C NMR spectra were recorded

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1746
LITTLE ET AL.
on a Varian Unity 500 spectrometer, and the DMSO peaks at d 2.5 ppm
(1H NMR) and 39.5 ppm (13C NMR) served as an internal standard. The
mass spectra were obtained using a Fisons VG Quattro spectrometer. Flash
column chromatography was done using Merck’s silica gel 60. Analytical
thin layer chromatography was done on silica gel 60 F254. Melting points
(m.p.) are uncorrected and were recorded using an electrothermal digital
melting point apparatus model IA9100.
General Procedure for Substituted Hydrazinocarboxylates
From isocyanates (1–120 g scale): Methyl hydrazinocarboxylate (1.0
equiv.) was dissolved in anhyd. THF (approx. 1.0 ml/mmol) with stirring
under an inert atmosphere. The isocyanate (1.0 equiv.) was gradually added
over 1 min and the mixture stirred at room temp. overnight. The product
was collected by filtration or by simple evaporation to dryness.
From amines and anilines (1–120 g scale): Methyl hydrazinocarboxy-
late (1.0 equiv.) was dissolved in anhyd. THF (approx. 1.0 ml/mmol) or
DMF (when using HCl salts) with stirring under an inert atmosphere.
Carbonyldiimidazole (1.0 equiv.) was added in portions over 2–3 min
and this mixture was stirred at room temp. for 15 min. The amine or
aniline (1.0 equiv.) was added followed by triethyl amine (1.0 equiv. for
when HCl salts are used) and this mixture was stirred at room temp.
overnight. The product was collected by filtration or by evaporation to
dryness followed by column chromatography using 2–10% MeOH/CH2Cl2
as the mobile phase.
From carboxylic acids (1–20 g scale): The starting material was
dissolved in CH2Cl2 with stirring. Diphenylphosphorylazide (1.0 equiv.)
and triethyl amine (1.0 equiv.) were added and the mixture stirred for
2 h at room temp. Following evaporation to dryness, the mixture was
refluxed in 1,2-dichloroethane for 30 min and cooled to room temp.
Methyl hydrazinocarboxylate (1.0 equiv.) was added and the mixture was
refluxed for an additional 30 min. After cooling to room temp., the product
was collected by filtration or by evaporation to dryness followed by column
chromatography.
General Procedure for 4-Substituted-1,2,4-triazolidine-3,5-diones
Method A: The substituted hydrazinocarboxylate was refluxed in aqu-
eous 4N KOH (approx. 0.5 ml/mmol) for 2.0 h. After cooling to room
temp., the mixture was stirred in ice water bath and the pH was adjusted

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NOVEL 4-SUBSTITUTED URAZOLES
1747
to approx. 1–2 with the slow addition of conc. HCl. The product was
collected by filtration, washed with H2O and dried.
Method B: The substituted hydrazino carboxylate was stirred in the
appropriate solvent followed by the addition of 2.0 equiv. of K2CO3 or
sodium ethoxide. This mixture was refluxed from 30 min to 16 h until TLC
indicated the reaction was complete. The mixture was evaporated to dry-
ness and the residue dissolved in H2O and cooled in an ice water bath. The
pH was adjusted to approx. 1–2 with the slow addition of conc. HCl. The
product was collected by filtration, washed with H2O and dried.
Method C (One pot procedure): Methyl hydrazino carboxylate (1.0
equiv.) was dissolved in THF with stirring under an inert atmosphere. CDI
(1.0 equiv.) was added in portions over a 2–3 min period and this mixture
was stirred at room temp. for 15 min. The amine (1.0 equiv.) was added
and stirring was continued at room temp. overnight. After evaporation
to dryness, the residue was either refluxed in 4N KOH or
MeOH/K2CO3 until the reaction was complete. It was then worked up
in the usual manner.
Note: In instances where the product has basic (ex. pyridyl) or acid
sensitive (ex. Boc) functionalities the pH was adjusted to 6.5–7.0. In certain
cases when the reaction mixture was acidified the product oiled out of
solution. The reaction mixture was then extracted with 3 volumes of ethyl
acetate. The combined organic layers were washed with brine, dried over
Na2SO4 and evaporated to dryness. CH2Cl2 was added and the product was
collected by filtration and dried. In cases where the product is not of suffi-
cient purity, recrystallization from a minimal amount of hot ethyl acetate or
stirring in CH2Cl2 with filtration can be used.
4-[2-(Phenyl)benzyl]-1,2,4-triazolidine-3,5-dione (3): (>97% pure)
1
m.p. ¼ 185–187; H NMR (DMSO-d6) d 4.49 (s 2H), 7.08 (dd, 1H), 7.21
(dd, 1H), 7.3–7.5 (m, 7H), 10.22 (s, 2H); 13C NMR (DMSO-d6) d 39.2,
125.9, 127.2, 127.3, 127.7, 128.4, 129.2, 130.0, 133.7, 139.9, 140.5, 154.8;
IR (cmꢁ1) 3060, 1771, 1678, 1475.
4-(4-Nitrophenyl)-1,2,4-triazolidine-3,5-dione (4): (>93% pure)
1
m.p. ¼ 265–267; H NMR (DMSO-d6) d 7.87 (d, 2H), 8.32 (d, 2H), 10.78
(s, 2H); 13C NMR (DMSO-d6) d 124.1, 125.4, 138.0, 145.4, 152.1; IR (cmꢁ1
3184, 1782, 1685, 1343.
)
4-(4-Pyridinylmethyl)-1,2,4-triazolidine-3,5-dione (5): (>98% pure)
1
m.p. ¼ 268–270 (dec); H NMR (DMSO-d6) d 4.57 (s, 2H), 7.21 (d, 2H),
8.51 (d, 2H), 10.34 (s, 2H); 13C NMR (DMSO-d6) d 40.4, 122.1, 145.4,
149.8, 154.4; IR (cmꢁ1) 2783, 1766, 1708, 1211
4-(2,4-Dichlorobenzyl)-1,2,4-triazolidine-3,5-dione (6): (>95% pure)
m.p. ¼ 227–229; 1H NMR (DMSO-d6) d 4.59 (s, 2H), 7.17 (d, 1H),
7.42 (dd, 1H), 7.64 (d, 1H), 10.34 (s, 2H); 13C NMR (DMSO-d6)

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1748
LITTLE ET AL.
d 38.8, 127.5, 128.8, 129.9, 132.7, 132.9, 154.3; IR (cmꢁ1) 3048, 1766, 1680,
1467.
4-[4-(Trifluoromethoxy)phenyl]-1,2,4-triazolidine-3,5-dione (7): (>98%
pure) m.p. ¼ 224–226; 1H NMR d (DMSO-d6) d 7.47 (d, 2H), 7.60 (d,
2H), 10.58 (s, 2H); 13C NMR (DMSO-d6) d (117.0, 119.0, 121.1, 123.1,
quartet CF3), 121.5, 127.7, 131.0, 147.0, 153.0; IR (cmꢁ1) 3106, 1692,
1510, 1432.
4-(1-Naphthylmethyl)-1,2,4-triazolidine-3,5-dione (8): (>98% pure)
1
m.p. ¼ 201–204; H NMR (DMSO-d6) d 5.00 (s, 2H), 7.32 (d, 1H), 7.46
(m, 1H), 7.52–7.58 (m, 2H), 7.87 (d, 1H), 7.94 (d, 1H), 8.27 (d, 1H), 10.27
(s, 2H); 13C NMR (DMSO-d6) d 39.6, 123.3, 125.3, 125.7, 126.0, 126.5,
128.0, 128.6, 130.5, 131.6, 133.3, 154.8; IR (cmꢁ1) 3052, 1665, 1487, 1109.
4-(2-Butylphenyl)-1,2,4-triazolidine-3,5-dione (9): (>98% pure)
1
m.p. ¼ 173–175; H NMR (DMSO-d6) d 0.83 (t, 3H), 1.20–1.45 (m, 2H),
1.40–1.45 (m, 2H), 2.43 (t, 2H), 7.19 (dd, 1H), 7.27–7.31 (m, 1H), 7.27–7.29
(m, 2H), 10.4 (s, 2H); 13C NMR (DMSO-d6) d 13.7, 22.0, 30.5, 31.8, 126.7,
129.2, 129.5, 129.9, 130.1, 140.9, 153.9; IR (cmꢁ1) 3040, 1747, 1677, 1463.
4-(4-tert-Butylphenyl)-1,2,4-triazolidine-3,5-dione (10): (>98% pure)
1
m.p. ¼ 282–284; H NMR (DMSO-d6) d 1.29 (s, 9H), 7.32 (d, 2H), 7.47
(d, 2H), 10.40 (s, 2H); 13C NMR (DMSO-d6) d 31.1, 34.5, 125.6, 125.7,
129.3, 150.1, 153.5; IR (cmꢁ1) 3075, 1774, 1685, 1363.
tert-Butyl 3-(3,5-dioxo-1,2,4-triazolidin-4-yl)propanoate (11): (>98%
1
pure) m.p. ¼ 178–179; H NMR (DMSO-d6) d 1.36 (s, 9H), 2.48 (t, 2H),
3.54 (t, 2H), 10.06 (s, 2H); 13C NMR (DMSO-d6) d 27.6, 33.2, 34.4, 80.2,
154.6, 169.6; IR (cmꢁ1) 3125, 1770, 1692, 1475.
(2S)-2-(3,5-Dioxo-1,2,4-triazolidin-4-yl)-3-phenylpropanoic acid (12):
1
(>98% pure) m.p. ¼ 227–229; H NMR (DMSO-d6) d 3.22–3.38 (m, 2H
overlapping H2O), 4.74 (dd, 1H), 7.16–7.29 (m, 5H), 10.04 (s, 2H);
13C NMR (DMSO-d6) d 33.1, 53.1, 126.6, 128.3, 128.8, 137.3, 154.4,
170.2; IR (cmꢁ1) 3192, 1724, 1677, 1471.
4-[2-(Phenylsulfonyl)ethyl]-1,2,4-triazolidine-3,5-dione (14): (>98%
pure) m.p. ¼ 183–186; 1H NMR (DMSO-d6)
d 3.63–3.68 (m, 4H),
7.66–7.93 (m, 5H), 10.2 (s, 2H); 13C NMR (DMSO-d6) d 32.6, 51.2, 127.8,
129.5, 134.1, 138.3, 154.0; IR (cmꢁ1) 3048, 1719, 1677, 1486.
Benzyl-trans-4-(3,5-dioxo-1,2,4-triazolidin-4-yl)cyclohexyl carbamate
(15): (>90% pure contains <10% of the cis isomer; this ratio of
t : c reflects the ratio of the isomers in the commercial precursors)
1H NMR (DMSO-d6) d 1.35–1.38 (m, 2H), 1.44–1.51 (m, 2H), 1.87–1.89
(m, 2H), 2.27–2.34 (m, 2H), 3.55 (s, 1H), 3.64–3.70 (s, 1H), 5.00 (s, 2H),
7.24–7.37 (m, 6H), 9.92 (s, 2H); 13C NMR (DMSO-d6) d 23.7, 28.9, 44.8,
50.0, 65.2, 127.7, 127.9, 128.3, 137.2, 154.8, 155.7; IR (cmꢁ1) 3176, 1763,
1681, 1456.

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NOVEL 4-SUBSTITUTED URAZOLES
ACKNOWLEDGMENT
1749
The author thanks Professor Michael Kahn at University of
Washington (Seattle, WA) for stimulating discussions.
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7. Various b-amino acids also undergo this cyclization with minor
variation on the synthetic protocol (Mark Blaskovich and Jean-
Laurent Paparin manuscript in preparation)
8. The formation of the triazoledione can also be quantified by UV/VIS
spectroscopy measurement.
Received in the USA June 23, 2001

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