Preparation of tricyclic and tetracyclic benzoxepin derivatives by one-pot enyne metathesis/Diels-Alder reaction

Article abstract of DOI:10.1055/s-2001-18077

Tricyclic and tetracyclic benzoxepin derivatives were prepared by one-pot enyne metathesis/Diels - Alder reactions starting from differently substituted 2-allyl-1-propargyloxybenzenes (endo stereoselectivity).

Full text of DOI:10.1055/s-2001-18077

1784
LETTER
Preparation of Tricyclic and Tetracyclic Benzoxepin Derivatives by One-Pot
Enyne Metathesis/Diels-Alder Reaction
Preparationof
T
ricycli
a
c
and
T
etra
r
cyclic
B
c
i
erivat
a
ives l Moreno-Mañas, Roser Pleixats,* Antoni Santamaria
Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola, 08193-Barcelona, Spain
Fax +34(93)5811265; E-mail: Roser.Pleixats@uab.es
Received 14 June 2001
of 2-vinylbutenolide prepared by enyne metathesis gives
Abstract: Tricyclic and tetracyclic benzoxepin derivatives were
prepared by one-pot enyne metathesis/Diels–Alder reactions start-
ing from differently substituted 2-allyl-1-propargyloxybenzenes
(endo stereoselectivity).
the perhydroisobenzofuranone rac-differolide.9 One-pot
ring-closing enyne metathesis/Diels–Alder reaction with-
out isolation of diene intermediate has been reported in
the preparation10 of tetrahydropyran and dihydrofuran de-
rivatives, for the construction of heterocyclic boronic es-
ter derivatives,11 and in the synthesis12 of perhydroindenes
and perhydroisoindoles. In the last case the cycloaddition
was carried out under Lewis acidic conditions. Prompted
by these very recent reports we want to present here our
work concerning the preparation of tricyclic and tetracy-
clic benzoxepin derivatives by one-pot enyne metathesis
and Diels–Alder reaction from 2-allyl-1-propargyloxy-
benzenes.
Key words: ruthenium, catalysis, enyne metathesis, Diels-Alder
reactions, tandem reactions
The ring-closing metathesis1 (RCM) reaction of olefins
promoted by metal carbenes has become in the last years
an efficient and selective method for C=C bond cleavage
and formation leading to carbo and heterocyclic com-
pounds of different size, from five-membered rings to
macrocyclic structures. Ring closing enyne metathesis has
also been explored in recent years,2–4 providing 1-vinylcy-
cloalkene derivatives5,6 from acyclic enynes in an atom
economical process. These diene derivatives can be useful
substrates for subsequent Diels–Alder reaction. Several
yne-ene cross-metathesis/cycloaddition sequences have
been recently reported in the literature in a stepwise man-
ner.7 Sequential ring-closing metathesis/[4+2] cycloaddi-
tion have also been used in the last years for the
preparation of several carbocyclic and heterocyclic sys-
tems.8 Spontaneous dimerization by Diels–Alder reaction
There are no general syntheses of benzoxepin derivatives.
Snieckus et al had reported13 the preparation of benzannu-
lated oxygen heterocycles of different ring size by con-
necting directed ortho metalation and olefin metathesis
strategies. In this way they obtained the natural products
radulanin A and racemic helianane containing 2,5-dihy-
drobenzoxepin and benzoxepane moieties.
Our work is summarized in the Scheme. Treatment of
phenolic derivatives 1a–d with propargyl bromide and
potassium carbonate in refluxing acetone gave 2-allyl-1-
EtO2C
CO2Et
N
N
iii
ii
i
OH
O
O
O
Y
Y
Y
Y
2a-d
3a-d
Y = H,
4
iv
v
Y = H,
1a
= Me, 1b
= OMe, 1c
= NO2, 1d
O
O
EtO2C
X
CO2Et
O
H
H
O
H
H
O
O
Y = H, X = O,
Y = H, X = NH, 7
Y = Me, X = NH, 8
6
Y
O
11
Y = H,
5
Y
Y = OMe, X = NH, 9
Y = NO2, X = NH, 10
Scheme i: Propargyl bromide, K2CO3, acetone, reflux; ii: RuCl2(PCy3)2=CHPh (2–6% molar), CH2Cl2, r.t., 5 h; iii: EtO2C-N=N-CO2Et,
CH2Cl2, reflux, 4 days; iv: benzoquinone, CH2Cl2, reflux, 4 days; v: maleimide or maleic anhydride, CH2Cl2, reflux, 4 days.
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
propargyloxybenzenes 2a–d (72–98%). Compound 1d
1437-2096,E;2001,0,11,1784,1786,ftx,en;D14701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Preparation of Tricyclic and Tetracyclic Benzoxepin Derivatives
1785
was prepared14 from o-nitrophenol by standard allylation In summary, tricyclic and tetracyclic compounds 4–10
and subsequent Claisen rearrangement.
have been stereoselectively obtained by one-pot ring-
closing enyne metathesis and Diels–Alder cycloaddition
from 2a–d in good overall yields, without removal of the
ruthenium catalyst or isolation of the intermediate dienes
3a–d. No Lewis acidic conditions are required for the
[4+2] cycloaddition and most of the cycloadducts can be
isolated and purified without chromatography of the crude
mixtures.
Enyne metathesis on 2a–d with Grubbs’ catalyst15 (2-6%
molar) in dichloromethane (0.024-0.048 M) at room tem-
perature for 5 h afforded 3-vinyl-2,5-dihydrobenzo[b]ox-
epins 3a–d. Only diene 3a was isolated once.16 In all cases
the corresponding dienophile was added to the dichlo-
romethane solution containing the enyne and the mixture
was refluxed for 4 days to give cycloadducts 4–10. Over-
all yields and representative analytical data of the com-
pounds are collected in the Table.
Acknowledgement
Financial support from DGESIC (project PB98-0902 and predocto-
ral scholarship to A.S.) and CIRIT-Generalitat de Catalunya (pro-
jects SGR98-0056 and SGR2000-0062) is gratefully
acknowledged.
Table Results from One-Pot Enyne Metathesis and Diels–Alder
Reactions.
Comp. Overall
Yield (%)
Mp (ºC) (solvent)
oil
EA or HRMS (Calcd.)
(Found)
References
4
5
6
7
82
50
53
51
346.1528
346.1543
(1) For some reviews and highlights see: (a) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(b) Schmalz, H.-G. Angew. Chem. Int. Ed. Engl. 1995, 34,
1833. (c) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed.
Engl. 1997, 36, 2037. (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (e) Armstrong, S. K. J. Chem.
Soc., Perkin Trans 1 1998, 371. (f) Randall, M. L.; Snapper,
M. L. J. Mol. Catal. A 1998, 133, 29. (g) Ivin, K. J. J. Mol.
Catal. A 1998, 133, 1. (h) Maier, M. E. Angew. Chem. Int.
Ed. 2000, 39, 2073. (i) Fürstner, A. Angew. Chem. Int. Ed.
2000, 39, 3012. (j) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18.
129–130
(cyclohexane)
280.1099
280.1106
184–186
(isopropanol)
270.0892
270.0892
177–179
(CH2Cl2 /Et2O)
71.36%C, 5.61%H,
5.20%N
71.10%C, 5.59%H,
5.19%N
8
9
50
61
62
8
87–90
(Et2O)
283.1208
283.1214
(2) For a review on enyne metathesis see: Mori, M. Top.
Organomet. Chem. 1998, 1, 133.
(3) For some recent articles on intramolecular enyne metathesis
with ruthenium alkylidenes see: (a) Clark, J. S.; Trevitt, G.
P.; Boyall, D.; Stammen, B. Chem. Commun. 1998, 2629.
(b) Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem.
Commun. 1998, 2249. (c) Barrett, A. G. M.; Baugh, S. P. D.;
Braddock, D. C.; Flack, K.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A.; White, A. J. P.; Williams,
D. J. J. Org. Chem. 1998, 63, 7893. (d) Leeuwenburgh, M.
A.; Kulker, C.; Duynstee, H. I.; Overkleeft, H. S.; Van der
Marel, G. A.; Van Boom, J. H. Tetrahedron 1999, 55, 8253.
(e) Leeuwenburgh, M. A.; Appeldoorn, C. C. M.; van Hooft,
P. A. V.; Overkleeft, H. S.; van der Marel, G. A.; van Boom,
J. H. Eur. J. Org. Chem. 2000, 873. (f) Mori, M.; Kitamura,
T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2, 543.
(g) Undheim, K.; Efskind, J. Tetrahedron 2000, 56, 4847.
(h) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654.
(i) Marco-Contelles, J.; Arroyo, N.; Ruiz-Caro, J. Synlett
2001, 652. (j) Clark, J. S.; Townsend, R. J.; Blake, A. J.;
Teat, S. J.; Johns, A. Tetrahedron Lett. 2001, 42, 3235.
(4) For some recent articles on enyne metathesis catalyzed by
PtCl2 see: (a) Fürstner, A.; Szillat, H.; Gabor, B.; Mynott, R.
J. Am. Chem. Soc. 1998, 120, 8305. (b) Fürstner, A.; Szillat,
H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785.
(c) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000,
122, 3801.
224–225
(CH2Cl2 /Et2O)
299.1157
299.1158
10
11
209–211
(CH2Cl2)
314.0903
314.0909
oil
314.1154
314.1158
Cycloaddition of 3a with 1,2-diphenyldiazene failed in re-
fluxing dichloromethane and in toluene at 100 °C. Diethyl
acetylenedicarboxylate reacted also sluggishly and the
corresponding cycloadduct 11 could be isolated in only
8% overall yield (chromatography on SiO2, hexane–dieth-
yl ether 9:1) after treatment of 2a with Grubbs’ catalyst in
toluene at room temperature for 5 h and then five days
with the dienophile in refluxing toluene. Compounds 4
and 717 were isolated by flash chromatography of the
crude mixture on silica gel. In the case of compound 7
only one diastereoisomer was eluted, corresponding to the
endo stereochemistry, the exo diastereoisomer being not
detected. In the other cases the cycloadducts crystallized
from the dark oily crude mixtures by addition of diethyl
ether. Once again, only the endo diastereoisomer was iso-
lated.18
(5) For some earlier reports on the formation of 1-vinylcyclo-
alkenes by enyne metathesis with chromium and tungsten
Synlett 2001, No. 11, 1784–1786 ISSN 0936-5214 © Thieme Stuttgart · New York

1786
M. Moreno-Mañas et al.
LETTER
carbenes, [RuCl2(CO)3]2 or palladacyclopentadiene
derivatives see: (a) Katz, T. J.; Sivavec, T. M. J. Am. Chem.
Soc. 1985, 107, 737. (b) Sivavec, T. M.; Katz, T. J.; Chiang,
M. Y.; Yang, G. X.-Q. Organometallics 1989, 8, 1620.
(c) Mori, M.; Watanuki, S. J. Chem. Soc., Chem. Commun.
1992, 1082. (d) Chatani, N.; Morimoto, T.; Muto, T.; Murai,
S. J. Am. Chem. Soc. 1994, 116, 6049. (e) Trost, B. M.;
Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636.
(f) Trost, B. M.; Trost, M. K. Tetrahedron Lett. 1991, 32,
3647. (g) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991,
113, 1850.
resulting solution extracted with hexane. The aqueous phase
was acidified with 6 M HCl and extracted with CH2Cl2. The
organic layer was washed with water, it was dried with
anhydrous Na2SO4 and the solvent was evaporated to give
1d (664 mg, 66% yield) as an oil; 1H NMR (CDCl3, 250
MHz) = 8.02 (dd, J = 8.5, 1.6 Hz, 1 H), 7.50 (dd, J = 7.3,
1.6 Hz, 1 H), 6.94 (dd, J = 8.5, 7.3 Hz, 1 H), 6.09–5.93 (m,
1 H), 5.18–5.09 (m, 2 H), 3.50 (d, J = 6.5 Hz, 2 H); 13C NMR
(CDCl3, 62.5 MHz) = 153.0, 137.2, 134.8, 133.4, 131.1,
122.8, 119.2, 116.5, 33.3; IR (film) 3215, 1610, 1540, 1451,
1334, 1249 cm-1; MS (EI) m/z (%) = 179 (M+, 53), 162 (100),
132 (88), 131 (68), 104 (22), 103 (58), 77 (64).
(6) For some earlier reports on ring closing enyne metathesis
with Grubbs ruthenium alkylidenes see: (a) Kinoshita, A.;
Mori, M. Synlett 1994, 1020. (b) Kim, S.-H.; Bowden, N.;
Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801.
(c) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356.
(7) (a) Schürer, S. C.; Blechert, S. Chem. Commun. 1999, 1203.
(b) Zheng, G.; Dougherty, T. J.; Pandey, R. K. Chem.
Commun. 1999, 2469. (c) Schürer, S. C.; Blechert, S. Synlett
1999, 1879. (d) Schürer, S. C.; Blechert, S. Tetrahedron
Lett. 1999, 40, 1877. (e) Kotha, S.; Halder, S.;
Brahmachary, E.; Ganesh, T. Synlett 2000, 853. (f) Smulik,
J. A.; Diver, S. T. Tetrahedron Lett. 2001, 42, 171.
(8) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem.
1998, 63, 6082. (b) Heerding, D. A.; Takata, D. T.; Kwon,
C.; Huffman, W. F.; Samanen, J. Tetrahedron Lett. 1998, 39,
6815. (c) Kotha, S.; Sreenivasachary, N.; Brahmachary, E.
Tetrahedron Lett. 1998, 39, 2805. (d) Kotha, S.;
Sreenivasachary, N. Chem. Commun. 2000, 503. (e) Lane,
C.; Snieckus, V. Synlett 2000, 1294. (f) Kotha, S.;
Sreenivasachary, N.; Brahmachary, E. Eur. J. Org. Chem.
2001, 787. (g) Duboc, R.; Hénaut, C.; Savignac, M.; Genet,
J. P.; Bhatnagar, N. Tetrahedron Lett. 2001, 42, 2461.
(h) Sémeril, D.; Le Nôtre, J.; Bruneau, C.; Dixneuf, P. H.;
Kolomiets, A. F.; Osipov, S. N. New. J. Chem. 2001, 25, 16.
(9) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1,
277.
(15) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem. Int. Ed. Engl. 1995, 34, 2039.
(16) After evaporation of CH2Cl2 and flash chromatography on
SiO2 (cyclohexane–CH2Cl2, 5:1) diene 3a was obtained in
41% yield as an oil; 1H NMR (CDCl3, 250 MHz) = 7.28–-
7.02 (m, 4 H), 6.24 (dd, J = 17.7, 11.2 Hz, 1 H), 5.97 (td, J =
5.6, 0.6 Hz, 1 H), 4.93 (d, J = 11.3 Hz, 1 H), 4.91 (d, J = 17.7
Hz, 1 H), 4.81 (d, J = 1.8 Hz, 2 H), 3.59 (d, J = 5.6 Hz, 1 H);
MS (EI) m/z (%) = 173 (13), 172 (M+, 100), 171 (32), 157
(48), 145 (28), 144 (28).
(17) Preparation of 2,3,3a,4,6,12,12a,12b-octahydro-1H-
benzo[6,7]-oxepino[4,3-e]isoindole-1,3-dione, 7: A solution
of 2a (0.510 g, 2.9 mmol) and Grubbs’ catalyst (85 mg,
0.11 mmol) in degassed CH2Cl2 (60 mL) was stirred under
nitrogen at r.t. for 5 h. Then, a solution of maleimide
(0.320 g, 3.3 mmol) in CH2Cl2 (10 mL) was added and the
mixture refluxed for 4 days. The solvent was evaporated and
the crude oily residue was flash chromatographed on SiO2.
Elution with hexane–EtOAc 9:1 afforded 7 as a white solid
(0.410 g, 51%); 1H NMR (400 MHz, CDCl3): = 7.79 (br s,
1 H), 7.09 (br t, J = 8.2 Hz, 2 H), 7.03 (d, J = 7.6 Hz, 1 H),
6.81 (br t, J = 7.3 Hz, 1 H), 6.77 (d, J = 7.9 Hz, 1 H), 6.06–
6.04 (m, 1 H), 5.09 (d, J = 13.2 Hz, 1 H), 4.31 (d, J = 12.6
Hz, 1 H), 4.16 (apparent t, J ca 13.7 Hz, 1 H), 3.29–3.20 (m,
2 H), 2.91 (br d, J ca 13 Hz, 1 H), 2.81 (dd, J = 15.8, 2.9 Hz,
1 H), 2.76 (dd, J = 15.5, 7.1 Hz, 1 H), 2.23 (br d, J ca 15.5
Hz, 1 H); 13C NMR (62.5 MHz, CDCl3): = 180.1, 178.4,
156.8, 140.7, 132.7, 128.5, 126.7, 125.4, 121.4, 119.4, 70.3,
46.0, 41.9, 38.9, 34.5, 24.6; IR (KBr) 3244, 1781, 1720,
1694 cm-1; MS (EI) m/z (%) = 270 (8), 269 (M+, 45), 172
(23), 171 (68), 107 (100), 91 (50), 77 (21).
(18) The structural assignments were based on the data obtained
from 1H and 13C NMR on compound 7: COSY, DEPT and
HMBC experiments were used to assign the proton and
carbon signals of the spectra. NOE experiments showed a
relative cis configuration between all three methinic protons
(H12a, H12b, and H3a). Coupling constants are in agreement
with this assignment. The methinic proton H12a (2.91 ppm, br
d, J ca 13.7 Hz) shows a large J value with one of the protons
at C-12 (at 4.16 ppm), and two other small J values due to
the coupling with the other proton at C-12 (at 2.81 ppm) and
with the H12b (in a relative cis position).
(10) Ackermann, L.; Bruneau, C.; Dixneuf, P. H. Synlett 2001,
397.
(11) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem. Int. Ed.
2000, 39, 3101.
(12) Bentz, D.; Laschat, S. Synthesis 2000, 1766.
(13) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808.
(14) o-Nitrophenol (2.1 g, 15.1 mmol) was added to a suspension
of K2CO3 (3.14 g, 23.1 mmol) in acetone (40 mL) and the
mixture was refluxed for 30 min. Then, allyl bromide (1.7
mL, 2.4 g, 19.6 mmol) was added and the mixture was
maintained under reflux for 16 h. After addition of H2O (30
mL), the solution was extracted with CH2Cl2. The organic
phase was dried with anhydrous Na2SO4 and the solvent was
evaporated to give 1-allyloxy-2-nitrobenzene (2.36 g, 87%
yield) as an oil. This compound (1.00 g, 5.6 mmol) was
heated at 170 °C for 45 h (GC monitoring). A 5 M aqueous
solution of NaOH was added to the crude mixture and the
Synlett 2001, No. 11, 1784–1786 ISSN 0936-5214 © Thieme Stuttgart · New York