Regioselective preparation of 5-amino- and 6-amino-1,3-benzoxazole-4,7- diones from symmetrical diaminophenol and aminoresorcinol

Article abstract of DOI:10.1016/j.tetlet.2005.01.045

Regioisomeric 5-amino- and 6-amino- 1,3-benzoxazole-4,7-diones were prepared from 2,6-diamino-4-methoxyphenol and 2-amino-5-methoxyresorcinol, respectively. These symmetrical precursors have the property to be antisymmetrical to each other with respect to

Full text of DOI:10.1016/j.tetlet.2005.01.045

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1437–1440
Regioselective preparation of 5-amino- and
6-amino-1,3-benzoxazole-4,7-diones from symmetrical
diaminophenol and aminoresorcinol
*
´ ´
Laetitia Brehu, Anne-Cecile Fernandes and Olivier Lavergne
Ipsen Research Laboratories, Institut Henri Beaufour, 5 avenue du Canada, 91960 Les Ulis, France
Received 6 September 2004; revised 7 January 2005; accepted 11 January 2005
Abstract—Regioisomeric 5-amino- and 6-amino- 1,3-benzoxazole-4,7-diones were prepared from 2,6-diamino-4-methoxyphenol
and 2-amino-5-methoxyresorcinol, respectively. These symmetrical precursors have the property to be antisymmetrical to each other
with respect to their amino and hydroxy substituents.
Ó 2005 Elsevier Ltd. All rights reserved.
A series of compounds based on the 1,3-benzoxazole-
4,7-dione template (1, Fig. 1) has been prepared and
screened against dual specificity phosphatases CDC25.
These enzymes are involved in the regulation of the cell
cycle and their synthetic inhibitors are currently investi-
gated as cytostatic agents for oncological applica-
tions.1–3 Biological assays revealed that amines at
positions 5 and 6 were substituents of choice for an im-
proved activity. A few heterocyclic quinones such as 1
are reported in the literature. They are generally fused
within tricyclic or tetracyclic systems,4–13 and stand-
alone bicyclic structures as in 1 are encountered just
sporadically.14–16 The present communication discloses
the regioselective synthesis of 5- and 6-amino-1,3-benz-
oxazole-4,7-diones.
O
O
3
N
4
7
2
5
6
Ar
O
1
1
Figure 1.
ene]21 to the corresponding quinone 1a. Alternatively,
the rhodium catalyzed cycloaddition of 2-diazo-1,3-
cyclohexanedione (5) to diversely substituted nitriles
gave cyclohexenones such as 6b22 which were then aro-
matized to hydroxybenzoxazoles such as 4b by a bro-
mination–elimination23,24 sequence. These latter
phenolic intermediates were readily converted to quin-
ones such as 1 by oxidation with Fremyꢀs salt or
BTI.21 Further experimental details for Scheme 1 can
be found in the patent literature.25
As shown on Scheme 1, either an amino or a hydroxy
substituent can provide a handle to oxidize a given benz-
enoid to its corresponding quinone. The initial route to
benzoxazolediones 1 consisted in the condensation of 2-
amino-3-nitrophenol (2) with either carboxylic acids17,18
or orthoesters19 to give substituted nitrobenzoxazoles 3.
A subsequent reduction of the nitro group19 provided
aminobenzoxazoles such as 4a which were oxidized with
either Fremyꢀs salt [potassium nitrosodisulfonate,
(KO3S)2NO],20 or BTI [bis(trifluoroacetoxy)iodobenz-
We then turned our attention to the addition of amino
substituents to benzoxazolediones 1. Amines are known
to add in a 1,4-mode to quinones.26–28 In the case of
non-symmetrical molecules such as 5,8-quinolinedione,
two regioisomeric adducts are generally obtained in
varying ratios depending on the reaction conditions.29
In the present case, the addition of N,N-dimethylethyl-
enediamine to 3-bromophenylbenzoxalonedione 1c
gave in low yield a mixture of regioisomers 7 and 8 (6-
N and 5-N, respectively, as shown on Scheme 2), in a
1:1.9 ratio as measured by 1H NMR. Although the
Keywords: Benzoxazole; Quinone; Regioselectivity; Symmetry;
Antisymmetry.
*
Corresponding author. Tel.: +33 1 60 92 20 00; fax: +33 1 69 07 38
02; e-mail: olivier.lavergne@ipsen.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.045

´
L. Brehu et al. / Tetrahedron Letters 46 (2005) 1437–1440
1438
NO2
O
O
R
NH2
OH
N2
O
N
O
2
5
O
1a: R = H
1b: R = Cl
i
iv
iii
NO2
A
O
R
Cl
N
O
N
O
N
O
v
ii
3a
6b
4a: A = NH2, R = H
4b: A = OH , R = Cl
Scheme 1. Reagents and conditions: (i) PhC(OMe)3 (2 equiv), neat, PTSA (cat), 110 °C, 2 h, 82%; (ii) H2 (8 atm) 10%Pd/C (cat), MeOH, 70%; (iii)
BTI (2.2 equiv), MeCN/H2O, À5 °C, 30min, 1a: 42%, 1b: 67%; (iv) 2-Cl–C6H4CN (1.5 equiv), ((AcO)2Rh)2 (0.02 equiv) 60 °C, 1 h, 36%; (v) (a) Br2,
AcOH, rt, 27 h, 84%, (b) DBU (1.5 equiv), THF, 1.5 h, 87%.
O
O
O
O
O
O
H
N
N
N
O
N
O
N
O
i
+
N
N
H
Br
Br
Br
1c
7
8
Scheme 2. Reagents and conditions: (i) Me2NCH2CH2NH2 (2 equiv), CeCl3Æ7H2O (1 equiv), EtOH/THF, rt, 1 h, 19%.
regioisomers could be separated by chromatography, a
general regioselective preparation was desirable.
thioamides, either of commercial origin or derived from
commercial benzonitriles,35 by treatment with methyl
iodide in acetone.36
Aminated quinones can also be obtained by displace-
ment of the corresponding alkoxy substituents.30,31 Such
a process, which can be formally seen as a ꢁvinylogousꢀ
trans-esterification or a 1,4-addition–elimination, has
the merit of being regiospecific.31,32 Combining the
requirement of a methoxy group para to the nitrogen
and with the convenience of a symmetrical starting
material such as 5, aminoresorcinol 9 was identified as
a possible precursor for 6-amino-benzoxazoles such as
8. Conversely, diaminophenol 10 could lead to 5-amino-
benzoxazole 7 since both anilines and phenols can
be oxidized to quinones. These two tetra-substituted
benzenes, 9 and 10 are readily obtained by applying a
nitration and reduction sequence to commercially avail-
able starting material.33,34 Another refinement in this
method consisted in engaging thioimidate salts as acti-
vated carboxylic synthons in the condensation reaction
with either 9 or 10. These salts are readily obtained from
This new method was validated and applied to a lead
optimization program.37 The operating procedure is
exemplified here with 3-bromo-phenyl at position 2 of
the benzoxazole and N,N-dimethylethylenediamino at
position 5 or 6 (Scheme 3). Obtained by nitration and
subsequent reduction of the corresponding resorcinol
(Scheme 4),33 aminoresorcinol 9 was condensed with
bromophenylthioimidate 11 in refluxing ethanol to give
hydroxybenzoxazole 12. BTI oxidation furnished the ex-
pected methoxybenzoxazoledione 14, which was treated
in refluxing ethanol with N,N-dimethylethylenediamine
to give the desired 6-aminated benzoxazoledione 7.
As shown on Scheme 3, regioisomeric 5-amino-benz-
oxazoledione 8 was obtained similarly from diamino-
phenol 10, although the experimental procedure had
to be modified to accommodate the high instability of
10 to air. The condensation of 10 to 11 was therefore
performed under nitrogen, in the same vessel used for
the previous hydrogenation and without removal of
the palladium catalyst to avoid exposition to ambient
atmosphere. Furthermore, the dinitrophenol precursor
of 10, obtained by nitration of 2-hydroxy-5-methoxy-
benzoic acid (Scheme 5),34 must be considered as
shock-sensitive and, as such, should neither be dried
too thoroughly, nor triturated unduly. Taking these pre-
NH2
OH
NH2
10
OH
NH2
MeO
MeO
OH
9

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L. Brehu et al. / Tetrahedron Letters 46 (2005) 1437–1440
1439
procedure takes advantage of the symmetry found in
aminoresorcinol 9 and diaminophenol 10 which tends
to simplify their structure and availability. Interestingly
9 and 10 are also antisymmetrical to each other as the
amino and hydroxyl groups are interchanged between
their structures. Both compounds lead to benzoxazoledi-
ones structures because both phenols and anilines can be
oxidized to quinoid structures. No significant difference
in activity was observed between the two regioisomeric
products 7 and 8, either in respect to their inhibition
of CDC25 phosphatases or in their antiproliferative
effect. However, 6-amino-benzoxazoles such as 7 are
preferred for their safer and easier preparation.
OH
MeO
NH2
OH
NH2
OH
I
H2N+
MeS
MeO
MeO
NH2
9
10
ii
i
Br
11
OH
MeO
N
O
N
O
Br
Br
Br
Br
Br
Br
NH2
13
15
12
iii
iii
O
O
Spectral data: Compound 14 (6-OMe): IR (KBr) 1033,
1539, 1565, 1601, 1660, 1692. 1H NMR (d6-DMSO):
3.86 (br, 3H); 6.20(br, 1H); 7.59 (t, 1H); 7.89 (d, 1H);
8.13 (d, 1H); 8.23 (s, 1H). 13C NMR (d6-DMSO)
57.83; 106.65; 122.76; 126.70; 127.38; 129.87; 132.05;
135.77; 142.03; 148.17; 159.82; 163.26; 169.09; 180.09.
MeO
N
O
N
O
MeO
N
O
O
O
O
14
iv
iv
H
N
Compound 15 (5-OMe): IR (KBr) 1034, 1543, 1563,
1600, 1656, 1703. H NMR (d6-DMSO): 3.85 (br, 3H);
N
O
N
O
1
6.15 (br, 1H); 7.59 (t, 1H); 7.88 (d, 1H); 8.12 (d, 1H);
8.22 (s, 1H). 13C NMR (d6-DMSO): 57.62; 106.01;
122.73; 126.56; 127.40; 129.75; 132.03; 135.59; 139.64;
149.64; 160.35; 162.43; 174.45; 175.23.
N
N
H
O
O
7
8
Scheme 3. Reagents and conditions: (i) EtOH, rt, 2 h, 29%; (ii) EtOH,
rt, 16 h, 75% from dinitro precursor; (iii) BTI, MeCN/H2O, À5 °C,
20min, 14: 76%, 15: 8%); (iv) Me2NCH2CH2NH2, EtOH, reflux, 1 h,
7: 54%, 8: 38%.
Compound 7 (6-N): IR (KBr) 1046, 1531, 1576, 1599,
1635, 1693. H NMR (d6-DMSO): 2.18 (s, 6H); 2.47
1
(m, 2H); 3.25 (m, 2H); 5.39 (s, 1H); 7.40(br, 1H); 7.59
(t, 1H); 7.87 (d, 1H); 8.13 (d, 1H); 8.23 (s, 1H); 13C
NMR (d6-DMSO): 40.38; 45.08; 56.08; 95.68; 122.64;
126.65; 127.55; 129.83; 131.92; 135.57; 144.48; 146.65;
148.13; 163.59; 170.46; 177.85.
cautions into account, 5-aminated benzoxazoledione 8
was obtained via 5-methoxy-benzoxazoledione 15, thus
providing the counterpart of 6-amino compound 7.
The observation that BTI oxidation proceeded with
much lower yields on anilines such as 13 compared to
phenols such as 12 (5–15% vs 40–76%) may be related
to the higher instability of 10 compared to 9.
Compound 8 (5-N): IR (KBr) 1042, 1547, 1571, 1603,
1637, 1703. H NMR (d6-DMSO): 2.19 (s, 6H); 2.52
1
(m, 2H); 3.26 (m, 2H); 5.41 (s, 1H); 7.53 (br, 1H); 7.58
(t, 1H); 7.85 (d, 1H); 8.09 (d, 1H); 8.19 (s, 1H); 13C
NMR (d6-DMSO): 40.45; 45.12; 56.08; 95.05; 122.59;
126.23; 127.60; 129.48; 131.87; 135.12; 137.62; 148.97;
152.39; 161.32; 173.09; 176.06.
In summary, a novel strategy was developed to obtain
regioisomerically pure 5- and 6-aminated benzoxazoqui-
nones without chromatographic separation. This new
OH
OH
OH
NO2
OH
NH2
OH
i
ii
MeO
OH
MeO
MeO
9
Scheme 4. Reagents and conditions: (i) HNO3 (d 1.42, 1.3 equiv), AcOH/Ac2O, 5 °C, 1 h, 23%; (ii) H2 (1 atm) 10%Pd/C cat, EtOH, 70%.
MeO
COOH
OH
MeO
NO2
OH
MeO
NH2
OH
i
ii
NO2
NH2
10
Scheme 5. Reagents and conditions: (i) HNO3 (d 1.42, 2.4 equiv), AcOH, 10 °C, 2 h, 50%; (ii) H2 (1 atm) 10%Pd/C cat, EtOH.

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1440
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