An easy palladium-catalyzed access to substituted 3-methylene-3,4-dihydro-2H-1,5-benzodioxepines

Article abstract of DOI:10.1055/s-2001-16092

Palladium-catalyzed condensation of substituted benzene-1,2-diols with the biscarbonate of 2-(hydroxymethyl)allyl alcohol gave the corresponding 3-methylene-3,4-dihydro-2H-1, 5-benzodioxepines in good yields.

Full text of DOI:10.1055/s-2001-16092

1456
SHORT PAPER
An Easy Palladium-Catalyzed Access to Substituted 3-Methylene-3,4-dihydro-
2H-1,5-benzodioxepines
P
alladiu
m
-Cataly
e
zedAccess
l
to 3-M
i
ethyle
n
ne-3,4-dihyd
e
ro-
2
H
-1,5-benzod
D
ioxepines amez, Jean-Robert Labrosse, Paul Lhoste, Denis Sinou*
Laboratoire de Synthèse Asymétrique, UMR CNRS 5622, CPE Lyon, Université Claude Bernard Lyon 1, 43, boulevard du 11 Novembre
1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72448160; E-mail: sinou@univ-lyon1.fr
Received 12 March 2001; revised 23 April 2001
OH
OCO2CH3
Abstract: Palladium-catalyzed condensation of substituted ben-
zene-1,2-diols with the biscarbonate of 2-(hydroxymethyl)allyl al-
cohol gave the corresponding 3-methylene-3,4-dihydro-2H-1,5-
benzodioxepines in good yields.
a
+
R2
OH
OCO2CH3
R1
Key words: catalysis, palladium, cyclization, phenols, allyl com-
plexes
2
1 a-h
O
O
O
O
b
O
2H-1,5-Benzodioxepin-3(4H)-one (4a) is a key interme-
diate in the synthesis of analogs of 3,4-dihydro-2H-1,5-
benzodioxepine, which possess interesting biological
properties. For example, members of this series constitute
a unique class of -adrenergic stimulants and have also in-
teresting bronchial dilator activity.1 The antifungal strobi-
lurins I and K are also derivatives of 3,4-dihydro-2H-1,5-
benzodioxepine.2 These compounds have been obtained
in very low yields by condensation of benzene-1,2-diol
(1a) and 1,3-dichloro-2-hydroxypropane followed by ox-
R2
R1
4a
3 a-g
a R1 = R2 = H; b R1 = CH3, R2 = H; c R1 = H, R2 = CH3;
d R1 = OCH3, R2 = H; e R1 = H, R2 = OCH3; f R1 = H, R2 = CHO;
g R1 = CHO, R2 = H; h R1 = NO2, R2 = H
Scheme 1 Reaction conditions: a) Pd2(dba)3, dppb, THF, 25°C, 24
h; b) cat. OsO4, NaIO4, EtOH–acetone–H2O, 4 h, then H2O, 86%
3
idation with KMnO4 or by an allylation-epoxidation-cy-
clization-oxidation sequence.2 An alternative synthesis
started with the condensation of benzene-1,2-diol (1a)
with ethyl bromoacetate. Dieckmann cyclization of the
obtained diester with sodium tert-butoxide yielded 2H-
1,5-benzodioxepin-3(4H)-one (4a).4 In another case, 6-
methoxy-3-oxo-2H-[1,5]-benzodioxepine was obtained
by Thorpe cyclization of 1,2-bis(cyanomethoxy)benzene,
affording an enaminonitrile which was easily hydrolyzed
to the ketone 4a.1
1,5-benzodioxepin-3(4H)-ones 4 by a simple oxidative
cleavage (Scheme 1).
The condensation of substituted benzene-1,2-diols 1 with
the allylic biscarbonate 2 was performed at room temper-
ature in THF in the presence of a catalytic amount of pal-
ladium acetate and 1,4-bis(diphenylphosphino)butane
(dppb). The mechanism of this cyclization is shown in
Scheme 2. Reaction of the biscarbonate 2 with palladi-
um(0) gave the corresponding -allylpalladium complex.
The attack of the phenolate obtained by exchange between
benzene-1,2-diol and methylate anion afforded the inter-
mediate A. Subsequent formation of a new -allylpalladi-
um complex, followed by the intramolecular attack of the
phenolate, gave the substituted 3-methylene-3,4-dihydro-
2H-1,5-benzodioxepines. The results obtained, using var-
ious substituted benzene-1,2-diols, are summarized in the
Table.
We have shown that benzene-1,2-diol (1a) can act as a
bisnucleophile in -allylpalladium chemistry. The palla-
dium-catalyzed condensation of substituted benzene-1,2-
diols with 1,4-bis(methoxycarbonyloxy)but-2-ene gave
the corresponding 2,3-dihydro-2-vinylbenzo-1,4-dioxines
in good yields,5 whereas the same condensation per-
formed with substituted 2-aminophenols or substituted
1,2-diaminobenzenes gave the corresponding 2-vinyl-3,4-
dihydro-2H-1,4-benzoxazines6 or 2-vinyl-1,2,3,4-tetrahy-
droquinoxalines,7 respectively. We expected that this
methodology would be suitable for the synthesis of substi-
tuted 3-methylene-3,4-dihydro-2H-1,5-benzodioxepines
3, which are valuable precursors of the corresponding 2H-
Condensation of carbonate 2 and benzene-1,2-diol (1a)
gave the corresponding cyclic compound 3a in 88% yield
after column chromatography (Table, entry 1). 3-/4-Meth-
yl-substituted benzene-1,2-diols 1b and 1c afforded 6-me-
thyl-3-methylene-3,4-dihydro-2H-1,5-benzodioxepine
(3b) and 7-methyl-3-methylene-3,4-dihydro-2H-1,5-
benzodioxepine (3c) in 99% and 97% yield, respectively
(Table, entries 2 and 3). 3-/4-Methoxybenzene-1,2-diols
1d and 1e gave also the corresponding benzodioxepine
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
1437-210X,E;2001,0,10,1456,1458,ftx,en;T02101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
Palladium-Catalyzed Access to 3-Methylene-3,4-dihydro-2H-1,5-benzodioxepines
1457
OH
+
PdLn
O
CH3O-
OH
OCO2CH3
OCO2CH3
Pd°Ln
R
OCO2CH3
OH
OCO2CH3
R
A
Pd°Ln
+
+
PdLn
PdLn
O
O
O
O
CH3O-
O-
OH
(- CH3OH)
R
R
R
Scheme 2
derivatives 3d and 3e in very good yields (99% and 94%, substituted 3-methylene-3,4-dihydro-2H-1,5-benzodiox-
respectively) (Table, entries 4 and 5). The presence of an epines, particularly when the substituent is an electron-do-
electron-withdrawing group on benzene-1,2-diol seems nating group. These compounds are easily transformed
detrimental for the cyclization. For example, 3-formyl- into the corresponding 2H-1,5-benzodioxepin-3(4H)ones
benzene-1,2-diol (1f) gave the cyclized product 3f in 79% as exemplified for 4a.
yield (Table, entry 6), whereas 4-formylbenzene-1,2-diol
(1g) gave the cyclized compound 3g in only 22% yield,
Reactions involving palladium catalysis were performed in Schlenk
whatever conditions we used (Table, entry 7). More note-
worthy, 4-nitrobenzene-1,2-diol (1h) underwent no reac-
tion at all, even at higher temperature, the carbonate 2 was
recovered. Such a behavior was previously noticed in the
palladium-catalyzed alkylation of nitrophenols with vari-
ous allylic carbonates.8 This could be due to the fact that
the nitrophenoxy group itself in intermediate A is a better
leaving group than the carbonate, or that the phenoxy an-
ion with an electron-withdrawing group is such a poor nu-
cleophile that it does not react with the -allylpalladium
intermediate.
tubes under N2. THF was purified by distillation in the presence of
sodium and benzophenone. TLC was performed on precoated
sheets 60F254, and silica gel chromatography was done using Merck
silica gel (Gerudan SI 60, 0.040–0.063 mm). Melting points are un-
1
corrected. H NMR spectra were recorded at 200 MHz, and 13C
NMR spectra at 75 MHz; NMR chemical shifts are reported in ppm
downfield from TMS, and J values are given in Hertz. Pd2(dba)3,
bis-1,4-(diphenylphosphino)butane (dppb), starting benzene-1,2-
diols 1a–d,f,g and 2-(hydroxymethyl)allyl alcohol were purchased
from a commercial source. 4-Methoxybenzene-1,2-diol (1e) was
prepared according to the literature.9 Petroleum ether used refers to
the fraction boiling at 40–65°C.
Oxidation of compound 3a in a one-pot reaction by addi-
tion of OsO4 and NaIO4 afforded after column chromatog-
raphy the corresponding 2H-1,5-benzodioxepin-3(4H)-
one (4a) in 86% yield.
2-{[(Methoxycarbonyl)oxy]methyl}allyl Methyl Carbonate (2)
Methyl chloroformate (3.9 mL, 45.4 mmol) was added at 0°C to a
solution of 2-(hydroxymethyl)allyl alcohol (1 g, 11.4 mmol),
DMAP (0.56 mg, 4.6 mmol), and pyridine (3.9 mL, 45.4 mmol) in
CH2Cl2 (40 mL). After stirring for 24 h at r.t., the mixture was hy-
drolyzed with sat. aq solution of CuSO4 (20 mL) and extracted with
Et2O (3 50 mL). Evaporation of the solvent followed by flash-
In conclusion, we have shown that the palladium-cata-
lyzed condensation of various substituted benzene-1,2-di-
ols with the biscarbonate derived from 2- chromatography on silica gel using a 5:1 mixture of petroleum
ether–EtOAc as the eluent afforded 2.19 g of the biscarbonate 2
(94%); Rf 0.38 (petroleum ether–EtOAc, 5:1).
(hydroxymethyl)allyl alcohol allows an easy access to
1H NMR (CDCl3): = 3.70 (s, 6 H, CH3), 4.60 (s, 4 H, OCH2), 5.25
(s, 2 H, =CH2). 13C NMR (CDCl3): = 54.8, 67.6, 117.9, 137.7,
Table Palladium-Catalyzed Cyclization of 1a–h with 2
155.4.
Entry
Benzene-1,2-diol
Product
3a
Yield (%)
These analytical data are in agreement with the literature.10
1
2
3
4
5
6
7
8
1a (R1 = R2 = H)
88
99
97
99
94
79
22
0
3-Methylene-3,4-dihydro-2H-1,5-benzodioxepines 3a–h;
General Procedure
1b (R1 = CH3, R2 = H)
1c (R1 = H, R2 = CH3)
1d (R1 = OCH3, R2 = H)
1e (R1 = H, R2 = OCH3)
1f (R1 = CHO, R2 = H)
1g (R1 = H, R2 = CHO)
1h (R1 = H, R2 = NO2)
3b
The palladium catalyst was prepared by stirring a solution of
Pd2(dba)3 (20.8 mg, 0.023 mmol) and dppb (41.4 mg, 0.09 mmol)
in THF (7 mL) under argon for 0.5 h. This solution was added under
argon at r.t. to a solution of benzene-1,2-diol 1 (0.91 mmol) and bis-
carbonate 2 (222.6 mg, 1.1 mmol) in THF (7 mL). After stirring for
24 h, the solvent was evaporated and the residue was purified by
flash-chromatography on silica gel to afford the cyclized product 3.
3c
3d
3e
3f
3g
3-Methylene-3,4-dihydro-2H-1,5-benzodioxepine (3a)
Oil; Rf 0.60 (petroleum ether–EtOAc, 20:1).
3h
Synthesis 2001, No. 10, 1456–1458 ISSN 0039-7881 © Thieme Stuttgart · New York

1458
C. Damez et al.
SHORT PAPER
1H NMR (CDCl3): = 4.83 (s, 4 H, OCH2), 5.08 (s, 2 H, =CH2),
6.87–7.00 (m, 4 Harom).
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.29; H,
5.31.
13C NMR (CDCl3): = 73.9, 112.1, 121.1, 123.2, 144.1, 149.7.
These analytical data are in agreement with the literature.11
3-Methylene-3,4-dihydro-2H-1,5-benzodioxepine-7-
carbaldehyde (3g)
Oil; Rf 0.25 (petroleum ether–EtOAc, 50:1).
1H NMR (CDCl3): = 4.75 (s, 2 H, OCH2), 4.82 (s, 2 H, OCH2),
5.05 (br s, 1 H, =CH2), 5.09 (br s, 1 H, =CH2), 7.25–7.45 (m, 3
6-Methyl-3-methylene-3,4-dihydro-2H-1,5-benzodioxepine (3b)
Oil; Rf 0.31 (petroleum ether–EtOAc, 50:1).
1H NMR (CDCl3): = 2.25 (s, 3 H, CH3), 4.77 (s, 2 H, OCH2), 4.79
(s, 2 H, OCH2), 5.09 (br s, 2 H, =CH2), 6.80 (br s, 3 Harom).
13C NMR (CDCl3): = 16.3, 73.7, 73.9, 111.9, 118.8, 122.4, 124.7,
130.3, 144.4, 148.2, 149.8.
Harom), 9.81 (s, 1 H, CHO).
13C NMR (CDCl3): = 73.5, 74.3, 112.8, 121.9, 122.9, 125.6, 131.8,
139.8, 143.5, 149.5, 190.4.
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.47; H,
5.30.
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 74.50; H,
6.83.
2H-1,5-Benzodioxepin-3(4H)-one (4a)
7-Methyl-3-methylene-3,4-dihydro-2H-1,5-benzodioxepine (3c)
Oil; Rf 0.38 (petroleum ether–EtOAc, 50:1).
1H NMR (CDCl3): = 2.25 (s, 3 H, CH3), 4.73 (s, 2 H, OCH2), 4.75
(s, 2 H, OCH2), 5.08 (br s, 2 H, =CH2), 6.69–6.88 (m, 3 Harom).
13C NMR (CDCl3): = 20.6, 73.8, 74.1, 112.2, 120.8, 121.4, 123.6,
133.0, 144.2, 147.4, 149.3.
A 2.5% ethanolic solution of OsO4 (0.12 mL, 0.01 mg, 0.01 mmol),
followed by NaIO4 (330 mg, 1.5 mmol) was added to a solution of
3a (82.3 mg, 0.5 mmol) in a 3:1 mixture of acetone–H2O (6 mL)
cooled to 0°C. After stirring for 4 h at r.t., the mixture was diluted
with H2O (40 mL) and extracted with EtOAc (3 20 mL). Evapo-
ration of the solvent followed by flash-chromatography on silica gel
using a 5:1 mixture of petroleum ether–EtOAc as the eluent afford-
ed 70.8 mg of 4a as a white solid (86% yield).
Rf 0.51 (petroleum ether–EtOAc, 5:1); mp 33–35°C (Lit.3 mp 40–
42°C).
1H NMR (CDCl3): = 4.68 (s, 4 H, OCH2), 6.94–7.05 (m, 4 Harom).
13C NMR (CDCl3): = 75.7, 121.0, 133.9, 148.4, 204.6.
These analytical data are in agreement with the literature.3
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 75.18; H,
7.04.
6-Methoxy-3-methylene-3,4-hihydro-2H-1,5-benzodioxepine
(3d)
Oil; Rf 0.10 (petroleum ether–EtOAc, 50:1).
1H NMR (CDCl3): = 3.81 (s, 3 H, CH3), 4.75 (s, 2 H, OCH2), 4.82
(s, 2 H, OCH2), 5.05 (br s, 2 H, =CH2), 6.55 (d, 1 Harom, J = 8.3 Hz),
6.59 (d, 1 Harom, J = 8.3 Hz), 6.84 (t, 1 Harom, J = 8.3 Hz).
References
13C NMR (CDCl3): = 56.3, 73.9, 74.4, 106.1, 112.2, 113.5, 122.1,
139.5, 143.9, 150.6, 151.6.
(1) Rooney, C. S.; Stuart, R. S.; Wasson, B. K.; Williams, H. W.
R. Can. J. Chem. 1975, 53, 2279.
(2) Hellwig, V.; Dasenbrock, J.; Klostermeyer, D.; Kroib, S.;
Sindlinger, T.; Spiteller, P.; Steffan, B.; Steglich, W.;
Engler-Lohr, M.; Semar, S.; Anke, T. Tetrahedron 1999, 55,
10101.
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 69.14; H,
6.35.
7-Methoxy-3-methylene 3,4-dihydro-2H-1,5-benzodioxepine
(3e)
(3) Rosnati, V.; DeMarchi, F. Tetrahedron 1962, 18, 289.
(4) Tyman, J. H. P.; Grundy, J.; Brown, G. R. J. Chem. Soc.,
Perkin Trans. 1 1981, 336.
(5) (a) Massacret, M.; Lhoste, P.; Lakhmiri, R.; Parella, T.;
Sinou, D. Eur. J. Org. Chem. 1999, 2665. (b) Massacret,
M.; Lakhmiri, R.; Lhoste, P.; Nguefack, C.; Ben
Abdelouahab, F. B.; Fadel, R.; Sinou, D. Tetrahedron:
Asymmetry 2000, 11, 3561.
Oil; Rf 0.12 (petroleum ether–EtOAc, 50:1).
1H NMR (CDCl3): = 3.71 (s, 3 H, CH3), 4.68 (s, 2 H, OCH2), 4.75
(s, 2 H, OCH2), 5.05 (br s, 1 H, =CH2), 5.10 (br s, 1 H, =CH2), 6.45
(dd, 1 Harom, J = 8.8, 2.9 Hz), 6.49 (d, 1 Harom, J = 2.9 Hz), 6.87 (d, 1
Harom, J = 8.8 Hz).
13C NMR (CDCl3): = 55.7, 73.7, 74.5, 106.0, 108.5, 112.8, 121.6,
143.5, 144.1, 150.3, 155.7.
(6) Lhoste, P.; Massacret, M.; Sinou, D. Bull. Soc. Chim. Fr.
1997, 134 , 343.
(7) Massacret, M.; Lhoste, P.; Sinou, D. Eur. J. Org. Chem.
1999, 129.
(8) Goux, C.; Massacret, M.; Lhoste, P.; Sinou, D.
Organometallics 1995, 14, 4585.
(9) Aihara, K.; Urano, Y.; Higuchi, T.; Hirobe, M. J. Chem.
Soc., Perkin Trans. 2 1993, 2165.
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 69.07; H,
6.24.
3-Methylene-3,4-dihydro-2H-1,5-benzodioxepine-6-
carbaldehyde (3f)
Oil; Rf 0.32 (petroleum ether–EtOAc, 20:1).
1H NMR (CDCl3): = 4.78 (s, 2 H, OCH2), 4.90 (s, 2 H, OCH2),
5.10 (br s, 1 H, =CH2), 5.14 (br s, 1 H, =CH2), 6.93 (t, 1 Harom, J = 7.8
Hz), 7.15 (dd, 1 Harom, J = 7.8, 1.6 Hz), 7.47 (dd, 1 Harom, J = 7.8, 1.6
Hz), 10.4 (s, 1 H, CHO).
13C NMR (CDCl3): = 74.1, 74.3, 113.2, 122.2, 122.7, 127.4, 128.2,
142.8, 150.0, 152.7, 189.7.
(10) Buono, F.; Tenaglia, A. Synlett 1998, 1153.
(11) Schirmann, J. P.; Isard, A.; Weiss, F. Tetrahedron 1968, 24,
6475.
Synthesis 2001, No. 10, 1456–1458 ISSN 0039-7881 © Thieme Stuttgart · New York