Synthesis of 2H-1,5-benzodioxepin and 2,5-dihydro-1,6-benzodioxocin derivatives via ring-closing metathesis reaction

Article abstract of DOI:10.1016/j.tetlet.2004.01.125

The synthesis of various 2H-1,5-benzodioxepin and 2,5-dihydro-1,6- benzodioxocin derivatives is described. The key step involves the construction of seven- and eight-membered rings via ring-closing metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2004.01.125

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2631–2633
Synthesis of 2H-1,5-benzodioxepin and 2,5-dihydro-1,6-
benzodioxocin derivatives via ring-closing metathesis reaction
R. Mamouni,a,b M. Soukri,a,b S. Lazar,b M. Akssirab and G. Guillaumeta,*
aInstitut de Chimie Organique et Analytique, UMR CNRS 6005, Universitꢀe d’Orlꢀeans, BP 6759, 45067 Orlꢀeans Cedex 2, France
bLaboratoire de Chimie Bioorganique et Analytique, Universitꢀe Hassan II ––Mohammedia, BP 146, 20800 Mohammedia, Morocco
Received 4 December 2003; revised 26 January 2004; accepted 27 January 2004
Abstract—The synthesis of various 2H-1,5-benzodioxepin and 2,5-dihydro-1,6-benzodioxocin derivatives is described. The key step
involves the construction of seven- and eight-membered rings via ring-closing metathesis reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
The past few years have seen an intense interest in the
ring-closing metathesis (RCM) reaction. This type of
carbon–carbon bond formation has proven to be a very
powerful method for the synthesis of cyclic systems.1–5
applied to 1,2-bis(vinyloxy)benzenes to afford
benzo[1,4]dioxins.15 They also described the synthesis of
a series of N- and O-benzo-fused heterocycles using a
ruthenium-mediated isomerisation followed by RCM.16
This paper prompted us to disclose our success in the
RCM of other substrates containing electron-rich ole-
fins. Using simple precursors, we were able to synthesise
benzodioxepin and benzodioxocin derivatives.
However, amongst the large number of examples
described in reviews, relatively few utilise RCM for the
synthesis of benzo-fused bicyclic molecules.6–11 As part
of our ongoing interest in the synthesis of this class of
compounds, in particular substrates containing electron-
rich olefins such as benzodioxins12 and benzodioxe-
pins,13 we report here our preliminary results on a
general approach to a range of benzo-fused bicyclic
molecules using first- and second-generation GrubbsÕ
1,5-Benzodioxepins: Although the 2H-1,5-benzodioxe-
pin ring system constitutes a common structural ele-
ment in some natural products17 and is a similar feature
to that found in the antifungal Strobilurin G,18 the
synthesis of this type of molecules is rarely cited in the
literature.
catalysts
I
[(PCy3)2Cl2Ru@CHPh] and II [(IM-
esH2)(PCy3)Cl2Ru@CHPh],14 respectively, in the key
ring-closing step.
In continuation of our longstanding interest in the
preparation of fused oxygenated ring, we report an
interesting and efficient synthetic approach towards 1,5-
benzodioxepin compounds as illustrated in Scheme 1.
Very recently, van Otterlo et al. showed that the versa-
tile RCM reaction with ruthenium catalyst II can be
R1
R1
R1
1
R
R2
R2
O
O
O
O
R2
O
R2
O
(iii)
(i)
(ii)
80-86%
84-90%
OH
OH
4a-c
3a-c
1a-c
2a-c
Scheme 1. (a) R1 ¼ R2 ¼ H; (b) R1 ¼ OMe, R2 ¼ H; (c) R1 ¼ H, R2 ¼ Br. Reagents and conditions: (i) t-BuOK, DMSO, rt, 6 h; (ii) allyl bromide,
K2CO3, acetone, reflux, 10 h; (iii) catalyst (mol %) I or II (see Table 1), C6H6, 55 °C.
Keywords: 2H-1,5-Benzodioxepin; 2,5-Dihydro-1,6-benzodioxocin; Ring-closing metathesis.
* Corresponding author. Fax: +33-2-38-41-72-81; e-mail: gerald.guillaumet@univ-orleans.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.125

2632
R. Mamouni et al. / Tetrahedron Letters 45 (2004) 2631–2633
The starting materials, phenols 1a and 1b,19 were syn-
thesised by O-alkylation of the appropriate diols 5a and
5b with 1 equiv of allyl bromide in the presence of
K2CO3 in acetone at reflux, in 70% and 72% yield,
respectively. Compound 1c was obtained from 4-bromo-
2-(allyloxy)acetophenone20 by Baeyer–Villiger oxidation
followed by hydrolysis with aqueous NaOH 5% in eth-
anol.
disclosed the first route to this eight-membered ring
system using catechol and cis-1,4-dichloro-2-butene in
35–40% yield. However, this method has some limita-
tions since an inseparable side product is formed along
with the low yield of the desired compound. Recently,
Grubbs26 and Sarkar27 accessed this ring system using
RCM reaction using elaborate ruthenium catalysts.
Unfortunately only one benzodioxocin derivative was
described and the ruthenium catalysts used are not
28
Isomerisation21 of phenols 1a–c was carried out by
treatment with 8 equiv of t-BuOK in DMSO for 6 h at
room temperature to give phenols 2a–c in 84–90% yield
as a mixture of E- and Z-isomers. Subsequent treatment
of these substrates with 1 equiv of allyl bromide in the
presence of potassium carbonate in acetone at reflux
afforded compounds 3a–c in excellent yield.
€
commercially available. Later, Konig reported the
synthesis of this eight-membered ring systems via an
RCM reaction of 1,2-dihydroxybenzene diallyl ether 6a
using GrubbsÕ catalyst I. However, a mixture of cyclic
and acyclic products was obtained in an overall yield of
only 35%.
In the present work, we report our initial investigations
on the application of RCM with catalysts I or II as the
key cyclisation step in the synthesis of benzodioxocin
derivatives. Our strategy is based on the preparation of
various 1,2-diallyloxybenzenes 6a–f and 2,3-diallyloxy-
naphthalene 6g by alkylation of phenols 5a–f and
naphthol 5g followed by the cyclisation of these com-
pounds under the RCM conditions.
The treatment of 3a and 3c gave no cyclised products
with catalyst I. In contrast, in the presence of catalyst II
(10%), the reaction proceeded smoothly (in 6 h) to give
4a22 and 4c in 53% and 82% yield, respectively. How-
ever, cyclisation of 3b via RCM in the presence of cat-
alyst I (20%) for 17 h afforded 4b in 80% yield, while the
use of catalyst II (10%) for 6 h increased the yield to 98%
(Table 1).
The ethers 6a–g were obtained by treatment of the
appropriate diols 5a–g with 2 equiv of allyl bromide in
the presence of K2CO3 in acetone at reflux (Scheme 2).
The key metathesis reaction was carried out by varying
different parameters such as quantity of catalyst, sol-
vent, reaction time and temperature. After screening
several reaction conditions, we found that the cyclisa-
tion forming the eight-membered rings 7a–g22 is possible
by using various proportions of commercially available
GrubbsÕ catalyst I at 55 °C in benzene.
These results constitute a novel approach for the syn-
thesis of the 1,5-benzodioxepin structure using an allyl-
ation/isomerisation/RCM procedure. The desired com-
pounds were readily formed and this methodology
should stimulate further exploration of the properties of
this class of organic molecules. To the best of our
knowledge, this study represents the first use of RCM to
synthesise benzodioxepin derivatives.
1,6-Benzodioxocins: The eight-membered ring analogues
are also interesting and show potential pharmacological
activity23 and industrial applications.24 So far, to the
best of our knowledge, only a few reports describe the
synthesis of 2,5-dihydro-1,6-benzodioxocin. Schroth25
It is interesting to point out that the quantity of catalyst
and the time of reaction depend on the substrate. In the
cases of 6d and 6e, an almost 2-fold ratio of catalyst I
(15%) was necessary to reach completion of the reaction.
Also, we have noted that the RCM of compounds 6a
and 6g was even slower and required a higher amount
(20%) of catalyst I to complete the reaction whereas,
only 10% of catalyst II was required to produce 6a in
60% yield (Table 2). In contrast, we found that 8% of
catalyst I was sufficient to complete the RCM reaction
of 6b, 6c and 6f in satisfactory yield.
Table 1. Synthesis of 2H-1,5-benzodioxepin derivatives 4a–c
Substrate
Catalyst (mol %) Time (h)
Product Yielda (%)
3a
3a
3b
3b
3c
3c
I (10)
II (10)
I (20)
II (10)
I (10)
II (10)
17
6
4a
4a
4b
4b
4c
4c
––b
53c
80
17
6
98
17
6
––b
82
In summary, we have successfully applied the RCM
reaction using the commercially available GrubbsÕ cat-
alysts I and II to prepare a diversity of 2H-1,5-benzo-
dioxepins and 2,5-dihydro-1,6-benzodioxocins in good
yield. In these reactions, GrubbsÕ ruthenium carbene
a Yield in isolated product after silica gel chromatography.
b The starting material 3a or 3c was recovered.
c The low yield is due to the lower reactivity of substrate 3a.
R1
R1
R1
O
R2
R3
OH
OH
R2
R2
R3
O
O
(i)
(ii)
R3
O
70-97%
7a-g
6a-g
5a-g
Scheme 2. (a) R1 ¼ R2 ¼ R3 ¼ H; (b) R1 ¼ OMe, R2 ¼ R3 ¼ H; (c) R1 ¼ H, R2 ¼ NO2, R3 ¼ H; (d) R1 ¼ H, R2 ¼ Br, R3 ¼ H; (e) R1 ¼ H,
R2 ¼ CHO, R3 ¼ H; (f) R1 ¼ F, R2 ¼ R3 ¼ H; (g) R1 ¼ H, R2, R3 ¼ fused benzene ring. Reagents and conditions: (i) allyl bromide, K2CO3,
acetone, reflux, 18–24 h; (ii) catalyst (mol %) I or II (see Table 2), C6H6, 55 °C.

R. Mamouni et al. / Tetrahedron Letters 45 (2004) 2631–2633
Table 2. Synthesis of 2,5-dihydro-1,6-benzodioxocin derivatives 7a–g
2633
18. (a) Williams, R. M.; Cushing, T. D. Tetrahedron Lett.
1990, 31, 6325; (b) Hagmann, W. K.; Dorn, C. P.;
Frankshun, R. A.; OÕGrady, L. A.; Bailey, P. J.; Rackhm,
A.; Dougherty, H. J. Med. Chem. 1986, 29, 1436.
19. The determination of the structure of 1b was ensured by
transforming 1b into 1b0 via Claisen and Cope rearrange-
ments. We observed, in particular, the disappearance of
coupling between of H4 and H6. 2D RMN experiments
(HMBC, HMQC) of compound 4b confirmed the struc-
ture of 1b.
Substrate
Catalyst (mol %) Time (h)
Product Yielda (%)
6a
6a
6b
6c
6d
6e
6f
I (20)
II (10)
I (8)
17
17
17
12
17
17
12
17
7a
7a
7b
7c
7d
7e
7f
50b
60
68
71
69
62
70
56b
I (8)
I (15)
I (15)
I (8)
6g
I (20)
7g
OMe
OMe
a Yield in isolated product after silica gel chromatography.
b The low yields are due to lower reactivity of the substrates 6a and 6g.
OH
OH
O
240-250˚C
78%
OH
1b
1b'
complex II shows enhanced RCM activity compared to
its parent I.
20. Nelson, W. L.; Burke, T. R. J. Med. Chem. 1979, 22, 1088,
and references cited therein.
21. de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira,
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22. All new compounds were fully characterised and gave
satisfactory spectroscopic data. A representative example,
2H-1,5-benzodioxepin 4a: 3a (1.05 mmol) in C6H6 (5 mL)
was added to a solution of 10 mol % catalyst II in CH2Cl2.
The reaction mixture was stirred at 55 °C for 6 h. The pure
4a was obtained by flash chromatography (AcOEt/petro-
leum, 1:9) in 53% yield. 1H NMR (CDCl3, 250 MHz) d
4.56 (dt, 2H, J ¼ 1:9, 4.0 Hz, CH2CH@CH), 4.85–5.00 (m,
1H, CH2CH@CH), 6.50 (dt, 1H, J ¼ 2, 7.3 Hz,
CH2CH@CH), 6.95–7.15 (m, 4H, Harom). MS (m=z) 149
(M+1). A representative example, 7-methoxy-2,5-dihydro-
1,6-benzodioxocin 7b: following the procedure described
for 4a but substituting catalyst II by 8 mol % catalyst I
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