Easy access to N-aryl, N-heteroarylbenzoxazolinones and 4-aza analogues via Diels-Alder cycloaddition reactions

Article abstract of DOI:10.1016/j.tetlet.2004.08.162

An improved method for the synthesis of N-aryl, N- heteroarylbenzoxazolinones and their 4-aza analogues is described. The process involves the Diels-Alder cycloaddition of benzoxazinic or pyridoxazinic dienic systems with dienophiles as a key step.

Full text of DOI:10.1016/j.tetlet.2004.08.162

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8257–8259
Easy access to N-aryl, N-heteroarylbenzoxazolinones and
4-aza analogues via Diels–Alder cycloaddition reactions
Franck Lepifre, Christophe Buon, Pierre-Yves Roger,
*
´
Pascal Bouyssou and Gerard Coudert
´
´
´
Institut de Chimie Organique et Analytique associe au CNRS, UMR 6005, Universite dÕOrleans,
´
BP 6759, 45067 Orleans Cedex 02, France
Received 2 July 2004; revised 27 August 2004; accepted 30 August 2004
Abstract—An improved method for the synthesis of N-aryl, N-heteroarylbenzoxazolinones and their 4-aza analogues is described.
The process involves the Diels–Alder cycloaddition of benzoxazinic or pyridoxazinic dienic systems with dienophiles as a key step.
Ó 2004 Elsevier Ltd. All rights reserved.
The benzoxazolinone moiety is present in a considerable
number of derivatives exhibiting various biological
activities.1 The nitrogen atom generally bears substi-
tuted linear or branched alkyl chains. On the other
hand, N-arylbenzoxazolinones are rarely reported in
the literature. In fact, their synthesis from appropriate
hydroxydiarylamines2 or by aromatic nucleophilic sub-
stitutions3 is quite easy but not versatile enough nor sat-
isfactory in terms of molecular diversity. Furthermore,
the preparation of such aza analogues as 3-aryloxaz-
olo[4,5-b]pyridine-2(3H)-ones, obtained by a 1,3-dipolar
cycloaddition reaction of pyridine N-oxides with aryliso-
cyanates, gives very poor yields.4
cal activity, we used a Diels–Alder reaction involving
dienic systems 7 and 8 as a key step. These derivatives,
which possess a benzoxazinic or pyridoxazinic subunit,
were easily obtained in high yield via palladium-cata-
lysed cross-coupling reactions from the corresponding
lactams.5
We think that 7 and 8, depending on which N-protecting
carbamate is chosen, could constitute ideal precursors
for the direct synthesis of N-aryl, N-heteroarylbenzoxaz-
olinones and their 4-aza analogues via a Diels–Alder
reaction. Indeed, it was possible to observe first the
cycloadduct ring opening (spontaneously or in the pres-
ence of a base with an ultimate air oxidation step),
which led to the formation of the N-aryl or N-hetero-
aryl ring. This was followed by the formation of the
In the course of a work devoted to the synthesis of com-
plex heteropolycyclic derivatives with potential biologi-
O
O
N
O
H
O
X
N
X
N
X
O
O
O
O
R
R
7 (X = CH)
8 (X = N)
9 (X = CH)
10 (X = N)
= electrowithdrawing group
Scheme 1.
Keywords: Benzoxazolinones; Benzoxazines; Pyridoxazines; Diels–Alder cycloaddition.
*
Corresponding author. Fax: +33 238 41 72 81; e-mail: gerard.coudert@univ-orleans.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.162

8258
F. Lepifre et al. / Tetrahedron Letters 45 (2004) 8257–8259
oxazolinone moiety via an intramolecular attack of the
carbamate by the phenolic leaving group (Scheme 1).
Depending on the nature of the dienophile and dienic
systems, the number of benzoxazolinones or 4-aza ana-
O
X
N
O
O
c
O
O
N
O
N
7a (X = CH) (83%)
8a (X = N) (84%)
O
P
a
b
O
X
N
H
O
X
O
X
O
O
O
O
O
O
O
d
1 (X = CH)
2 (X = N)
3 (X = CH) (98%)
4 (X = N) (80%)
5 (X = CH) (92%)
6 (X = N) (90%)
X
N
O
O
O
7b (X = CH) (80%)
8b (X = N) (81%)
Scheme 2. Synthesis of dienic systems: (a) n-BuLi, ClCOOPh, THF, À78°C; (b) LDA, ClP(O)(OPh)2, THF, À78°C; (c) vinyltributyltin, Pd(PPh3)4,
LiCl, THF, reflux; (d) benzo[b]furylboronic acid, PdCl2(PPh3)2, Na2CO3 2M, THF, reflux.
Table 1. Synthesis of benzoxazolinones 9a,b and pyridoxazolinones 10a,b
O
O
Dienophile : 3 éq.
O
X
N
R
N
X
Closed vessel
O
O
Ar
9a,b (X = CH)
10a,b (X = N)
7a,b (X = CH)
8a,b (X = N)
R
Dienophile
Ar
Products
X
Temp (°C)
Time (h)
Yield (%)c,d
9a–1
10a–1
10a–1
CH
N
95
70
20
3
2
85
85
85
MeOOC
COOMe
N
96
MeOOC
COOMe
9a–2
10a–2
CH
N
70
70
1
1
90a,b
70b
O
O
O
O
O
9b–1
10b–1
CH
N
95
95
24
5
60
41
MeOOC
COOMe
O
MeOOC
COOMe
a After treatment by triethylamine in dichloromethane.
b Diels–Alder reaction performed in the presence of toluene.
c Isolated yields.
d All isolated compounds afforded satisfactory elemental analysis and spectral data.

F. Lepifre et al. / Tetrahedron Letters 45 (2004) 8257–8259
8259
3. (a) Gogoleva, I. A.; Ivanova, S. N.; MelÕnikov, N. N.;
Shvetsov-Shilovskii, N. I. Khim. Geterotsikl. 1967, 4, 746–
749; (b) Moreno-Manas, M.; Sanchez-Ferrando, F.; Valle,
S. J. Heterocycl. Chem. 1985, 22, 1577–1579.
logues obtained can vary greatly. Taking a phenyl car-
bamate as the N-protecting group seemed to be the most
appropriate choice to reach our goal.
4. (a) Hisano, T.; Matsuoka, T.; Ichikawa, M. Org. Prep.
Proced. Int. 1974, 6, 239, 245, 249; (b) Hamana, M.; Noda,
H.; Aoyama, M. Heterocycles 1974, 2, 167–170; (c) Yosh-
ida, M.; Ishiguro, Y.; Yamamori, T.; Aoyama, M.; Endo,
T.; Noda, H.; Funakoshi, K.; Saeki, S.; Hamana, M.
Heterocycles 1979, 12, 167; (d) Hisano, T.; Ichikawa, M.;
Matsuoka, T.; Hagiwara, H.; Muraoka, K.; Komori, T.;
Harano, K.; Ida, Y.; Christensen, A. T. Chem. Pharm. Bull.
1979, 27, 2261–2272; (e) Matsuoka, T.; Shinada, M.;
Suematsu, F.; Harano, K.; Hisano, T. Chem. Pharm. Bull.
1984, 32(6), 2077–2090; (f) Harano, K.; Suematsu, F.;
Matsuoka, T.; Hisano, T. Chem. Pharm. Bull. 1984, 32(2),
543–552.
5. (a) Buon, C.; Bouyssou, P.; Coudert, G. Tetrahedron Lett.
1999, 40(4), 701–702; (b) Lepifre, F.; Buon, C.; Rabot, R.;
Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40(35),
6373–6376; (c) Buon, C.; Chacun-Lefevre, L.; Rabot, R.;
Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56(4), 605–
614; (d) Lepifre, F.; Buon, C.; Bouyssou, P.; Coudert, G.
Heterocycl. Commun. 2000, 6(5), 397–402; Lepifre, F.;
Buon, C.; Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57,
6969–6975.
We prepared 3-substituted benzoxazines 7a,b and 3-sub-
stituted pyridoxazines 8a,b via Stille or Suzuki coupling
reactions following the synthetic approach we previ-
ously described5 (Scheme 2).
Vinylphosphates 5 and 6 were thus obtained in two steps
from commercially available lactams 1 and 2, respec-
tively, in 90% and 72% yields. These derivatives were
then engaged in palladium-catalysed cross-coupling
reactions following the conditions reported in Scheme 2.
The four different dienic systems were then engaged,
most of the time without using any solvents, in Diels–
Alder reactions using dimethylacetylene dicarboxylate
or 1,4-benzoquinone as typical dienophiles.6 The
expected reactions effectively occurred and the benz-
oxazolinones 9a,b and pyridoxazolinones 10a,b were
obtained in fair to good yields (Table 1).
In some cases (e.g., product 9a–2) the intermediate
cycloadduct was isolated and it was necessary to add
first some dichloromethane at room temperature, then
a few drops of triethylamine to observe the completion
of the reaction. In the aza-series the cycloadducts were
more sensitive and opened spontaneously yielding to
the required derivatives. With dienes 7b and 8b each
bearing a benzofuran subunit, the Diels–Alder reaction
was obviously more difficult to complete, the reaction
took longer and the yields were lower than in the other
cases.
6. Standard procedure: Phosphate 5 (501mg, 1mmol) and
tributyl(vinyl)tin (634mg, 2mmol) were dissolved in
THF (3mL). Tetrakis(triphenylphosphine)palladium(0)
(58mg, 0.05mmol) and lithium chloride (127mg, 3mmol)
were added and the reaction was refluxed for 2h. After
concentration the reaction mixture was diluted with ethyl
acetate, washed with saturated aqueous solution of sodium
chloride, dried over MgSO4, filtered and concentrated. The
crude product was purified by flash chromatography on
silica gel with petroleum ether/ethyl acetate (6/4) to
give the desired product 7a (232mg, 83%) as a yellow
solid. Mp 70–72°C; 1H NMR (250MHz, CDCl3): d ppm
5.16 (dd, 1H, CH2 vinyl, Jcis = 11Hz, Jgem = 1Hz), 5.41 (dd,
1H, CH2 vinyl, Jtrans = 17.5Hz, Jgem = 1Hz), 6.31 (dd, 1H,
CH vinyl, Jcis = 11Hz, Jtrans = 17.5Hz), 6.77 (s, 1H, H2),
6.97–7.38 (m, 8H), 7.62 (m, 1H); 13C NMR (62.9MHz,
In conclusion, this paper describes an efficient synthesis
of N-aryl, N-heteroarylbenzoxazolinones and 4-aza ana-
logues. Considering the diversity of the accessible dienic
and dienophile systems our method allows an easy ac-
cess to a great variety of heterocycles, which offer high
potentialities for medicinal chemistry or agrochemical
applications.
CDCl3):
d ppm 113.20 (CH2), 116.65 (CH), 121.95
(2CH), 124.4 (CH), 125.35 (C), 125.80 (CH), 126.30
(CH), 127.20 (CH), 128.25 (CH), 128.80 (C), 129.85
(2CH), 140.25 (CH), 151.30 (C), 152.50 (C). MS:
m/z = 280 (M+1).
Dienic compound 7a (187mg, 0.67mmol) and dimethyl-
acetylene dicarboxylate (250lL, 2.0mmol) were mixed then
heated at 95°C for 3h in a closed vessel. After cooling to
room temperature, the mixture was directly purified by
flash chromatography (petroleum ether/ethyl acetate: 7/3)
to afford N-arylbenzoxazolinone 9a–1 (186mg, 85%) as a
white solid. Mp 85°C; 1H NMR (250MHz, CDCl3): d ppm
3.94 and 3.95 (2s, 6H, 2CH3O), 7.13–7.32 (m, 4H), 7.81 (dd,
1H, H5, J5,6 = 8.5Hz, J3,5 = 2Hz), 7.91–7.97 (m, 2H, H3
and H6); 13C NMR (62.9MHz, CDCl3): d ppm 53.00
and 53.05 (2CH3); 109.45 (CH), 110.70 (CH), 123.95
(CH), 124.35 (CH), 124.65 (CH), 130.70 (CH), 126.85
(CH), 130.00 (C),131.10 (C),133.90 (C), 136.30 (C), 142.75
(C), 152.55 (C), 166.90 (C), 167.00 (C). MS: m/z = 328
(M+1).
In this context, further studies directed towards the
synthesis of such derivatives are in progress in our
laboratory and will be reported in due course.
References and notes
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