Stereoselective synthesis of tricyclic pyranoxepin derivatives by ruthenium-catalyzed enyne metathesis/Diels-Alder reaction

Article abstract of DOI:10.1055/s-2006-926238

Synthesis of tricyclic oxepin-annulated pyrone derivatives has been achieved by the ring-closing enyne metathesis using the first-generation Grubbs' catalyst under a nitrogen atmosphere. The Diels-Alder reaction of these cyclized products with the dienoph

Full text of DOI:10.1055/s-2006-926238

466
LETTER
Stereoselective Synthesis of Tricyclic Pyranoxepin Derivatives by Ruthenium-
Catalyzed Enyne Metathesis/Diels–Alder Reaction
Stereoselective
Sy
.
nthesis of Tr
C
icyclic Pyranoxe
p
.
in
D
erivativ
M
es ajumdar,* H. Rahaman, S. Muhuri, B. Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 26 August 2005
We planned the synthesis of oxepin derivatives from
Abstract: Synthesis of tricyclic oxepin-annulated pyrone deriva-
tives has been achieved by the ring-closing enyne metathesis using
the first-generation Grubbs’ catalyst under a nitrogen atmosphere.
The Diels–Alder reaction of these cyclized products with the dieno-
dienes connected to a pyrone moiety. To test this premise,
dichloromethane solutions of derivatives 1a,b and ruthe-
nium carbene complex A (10 mol%)5 were stirred at room
phile proceeded smoothly to afford the tricyclic compounds in temperature for six hours, leading to the formation of cy-
excellent yield.
clized products 2a,b in 80% and 78% yield, respectively
(Scheme 1).
Key words: pyrone, oxepin, heterocycles, ruthenium, ring-closing
metathesis, enyne metathesis, Diels–Alder reactions
PCy3
Ru
O
O
Cl
Cl
The importance of pyran-2-ones as synthons in the field of
synthetic and medicinal chemistry was recognized due to
their unique structural features and diverse pharmacolog-
ical properties.1 Compounds of this ring system are wide-
ly present in naturally occurring physiologically active
substances in the form of isolated or fused ring systems.
This has encouraged research with regard to the develop-
ment of procedures for the synthesis of this class of com-
pounds. On the other hand, very little information is
known about medium ring oxacycle fused pyrones, which
may, in part, be due to the lack of general methods for the
synthesis of such ring systems. There are no general syn-
theses of pyranoxepin derivatives. Bravo et al. have
reported2 the preparation of seven-membered annulated
ring complexes by the treatment of suitably substituted
pyran derivatives with amberlite-15. In recent years ring-
closing metathesis (RCM) has been shown to be a highly
effective and practical method in organic synthesis. It has
emerged as an efficient strategy to prepare various func-
tionalized carbocycles and heterocycles from acyclic di-
ene precursors.3 This success is based on the development
of stable metal carbenes as olefin metathesis catalysts. An
intramolecular enyne metathesis is a particularly interest-
ing reaction, because the double bond of the enyne cleaves
and the alkylidene part of the olefin migrates to the alkyne
carbon to afford a cyclized product that has a diene
moiety.4 It appeared to us that a combination of the
Claisen rearrangement and a ring-closing enyne metathe-
sis (RCEM) process could be used to access various
hitherto unknown medium-sized heterocycle-annulated
heterocyclic systems of interest. In this communication,
we wish to report some successful applications of this
general approach towards the construction of the oxepin-
annulated pyrones.
Ph
PCy3
A
R
R
O
O
CH2Cl2, r.t., 6 h
O
O
1a R = H
b R = CH3
2a R = H
b R = CH3
Scheme 1
The reaction was further extended to the synthesis of var-
ious seven-membered ring compounds connected with the
pyrone ring by enyne bond reorganization. Compounds
3a,b were prepared according to the earlier published pro-
cedure.6 Straightforward alkylation of 3a,b with the prop-
argyl bromides in refluxing acetone in the presence of
anhydrous K2CO3 for five hours gave 4a,b in 72% and
70% yield, respectively. Similarly, the compounds 4c–e
were obtained from 3a,b with 1-aryloxy-4-chlorobut-2-
ynes in 75–80% yield (Table 1).
Table 1 Alkylation of Compounds 3
R1
R2
O
OH
R1
propargyl bromide or
1-aryloxy-4-chlorobut-2-yne
dry acetone, K2CO3,
reflux, 5 h
O
O
O
O
4
3a R1 = H
b R1 = CH3
Compd 4a
R1
H
R2
H
Yield (%)
a
b
c
72
70
75
80
75
CH3
H
H
CH2OAr
CH2OAr
CH2OAr
d
e
H
H
SYNLETT 2006, No. 3, pp 0466–0468
1
5.
0
2.
2
0
0
6
a Ar = 2,4-Me2C6H3- (4c); Ar = 4-ClC6H4- (4d); Ar = 2,4-Cl2C6H3-
(4e).
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926238; Art ID: D26005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of Tricyclic Pyranoxepin Derivatives
467
We have successfully prepared some oxepin-annulated ring-closing metathesis/[4+2] cycloaddition have also
pyrone derivatives 5a–e, possessing a diene unit, by using been used for the preparation of several carbocyclic and
Grubbs’ catalyst A and the enynes 4a–e. Ring-closing heterocyclic systems.9 This prompted us to explore the
enyne metathesis (RCEM) of 4a–e with Grubbs’ catalyst synthesis of tricyclic oxepin-annulated pyrones 6c–e from
A in dichloromethane when stirred at room temperature our cyclized products 5c–e by [p4s + p2s] cycloadditions.
for 5–8 hours delivered the desired products 5a–e in 80– When a solution of 5d and dimethyl fumarate (DMF) was
90% yield (Table 2). Better results were obtained with stirred in benzene at 60 °C no reaction occurred even after
substituted propargyl aryl ethers, i.e. in the case of 4c–e. 30 hours. When the compound 5d was treated with di-
Compounds 5c–e were crystalline solids. However, com- methyl fumarate (DMF) in toluene at 100 °C, a single
pounds 5a,b could not be solidified at room temperature. diastereoisomer 6d was obtained within four hours in 95%
All the compounds 5a–e were eluted by 25% ethyl ace- yield. Other substrates 5c and 5e were also similarly treat-
tate–petroleum ether and characterized from their elemen- ed with dimethyl fumarate to give single diastereoisomers
tal analyses and spectroscopic data.7
6c and 6e in 95% and 96% yield, respectively (Scheme 2).
The formation of Diels–Alder products 6c–e was con-
firmed by their elemental analyses and spectroscopic
data.10 The cis stereochemistry of the mentioned pair of
hydrogens was confirmed by NOESY experiments.
These diene derivatives 5a–e can be useful substrates for
subsequent Diels–Alder reactions. Several yne–ene cross-
metathesis/cycloaddition sequences have recently been
reported in the literature8 in a stepwise manner. Sequential
Table 2 Ring-Closing Enyne Metathesis of 4a–e with Grubbs’ Catalyst
Entry
Substrate
Product
Time (h)
Yield (%)
82
O
O
1
5
5a
O
O
O
O
O
O
CH3
O
5b
2
3
6
8
80
CH3
OAr
O
O
O
O
OAr
OAr
OAr
5c
5d
5e
87
O
O
O
O
O
O
O
OAr
O
O
4
8
90
O
O
O
OAr
O
O
5
7
88
O
O
O
Synlett 2006, No. 3, 466–468 © Thieme Stuttgart · New York

468
K. C. Majumdar et al.
LETTER
(5) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
R1
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(6) (a) Moreno-Manas, M.; Ribas, J.; Virgili, A. J. Org. Chem.
1988, 53, 5328. (b) Manger, M. C.; Ollis, W. D.; Sutherland,
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1317.
(7) Typical Procedure for the Enyne RCM.
To a solution of substrate 4d (68.9 mg, 0.2 mmol) in dry
degassed CH2Cl2 (8 mL) under N2 was added catalyst A (15
mg) and the reaction was stirred at r.t. for 8 h. After the
removal of the solvent, the residue was purified by flash
column chromatography on silica gel (PE–EtOAc, 4:1) to
give 5d in 90% yield.
R2
O
O
R2
R1
H
O
CO2Me
O
CO2Me
H
dimethyl fumarate
toluene,
O
O
O
100 °C, 4 h
O
5c–e
NOE
6c–e
c R1 = Me, R2 = Me
d R1 = H, R2 = Cl
e R1 = Cl, R2 = Cl
Compound 5a: yield 82%; sticky liquid. IR (neat): nmax
=
1704, 1665, 1568 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.13 (s, 3 H), 3.47 (d, J = 6.55 Hz, 2 H), 4.99 (s, 2 H),
5.09 (d, J = 10.8 Hz, 1 H), 5.25 (d, J = 17.5 Hz, 1 H), 5.60
(s, 1 H), 6.24 (t, J = 6.55 Hz, 1 H), 6.29 (dd, J = 17.5 Hz,
J = 10.8 Hz, 1 H). MS: m/z = 204 [M+]. Anal. Calcd for
C12H12O3: C, 70.59; H, 5.88. Found: C, 70.73; H, 5.72%.
Compound 5d: yield 90%; light-yellow solid, mp 112 °C.
IR (KBr): nmax = 1698, 1658, 1568, 1491 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.13 (s, 3 H), 3.51 (d, J = 6.64 Hz, 2 H),
4.66 (s, 2 H), 5.07 (s, 2 H), 5.38 (s, 1 H), 5.41 (s, 1 H), 5.60
(s, 1 H), 6.39 (t, J = 6.64 Hz, 1 H), 6.82 (d, J = 8.88 Hz, 1 H),
7.21 (d, J = 8.88 Hz, 2 H). MS: m/z = 344, 346 [M+]. Anal.
Calcd for C19H17O4Cl: C, 66.18; H, 4.93. Found: C, 65.98;
H, 5.17%.
Scheme 2
We have been able to show that oxepin-annulated pyrone
heterocycles having diene moieties can easily be synthe-
sized by using ruthenium-catalyzed ring-closing metathe-
sis of enynes. It was also demonstrated that the dienes are
suitable substrates to prepare tricyclic compounds 6c–e.
In summary tricyclic compounds 6c–e have been stereo-
selectively obtained by ‘RCEM’ in combination with a
Diels–Alder cycloaddition process in excellent yield
without any Lewis acidic promotion.
(8) (a) Schurer, S. C.; Blechert, S. Chem. Commun. 1999, 1203.
(b) Zheng, G.; Dougherty, T. J.; Pandey, R. K. Chem.
Commun. 1999, 2469. (c) Smulic, J. A.; Diver, S. T.
Tetrahedron Lett. 2001, 42, 171.
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(10) Procedure for the Diels–Alder Reactions.
A solution of 5d (17.2 mg, 0.05 mmol) and
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dimethylfumarate (14.4 mg, 0.1 mmol) in toluene was
heated at 100 °C for 4 h. After removal of the solvent the
residue was purified by flash column chromatography on
silica gel (PE–EtOAc, 3:1) to give 6d in 95% yield.
Compound 6d: yield 95%; white solid, mp 118–119 °C. IR
(KBr): nmax = 1736, 1703, 1655, 1580 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.15 (s, 3 H), 2.44–2.48 (m, 1 H), 2.58–
2.69 (m, 3 H), 2.95–3.05 (m, 3 H), 3.67 (s, 3 H), 3.76 (s, 3
H), 4.39 (d, J = 11.2 Hz, 1 H), 4.47 (d, J = 11.2 Hz, 1 H),
4.79 (d, J = 13.6 Hz, 1 H), 5.04 (d, J = 13.6 Hz, 1 H), 5.65
(s, 1 H), 6.79 (d, J = 8.8 Hz, 2 H), 7.22 (d, J = 8.8 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 19.93, 27.11, 31.09,
41.86, 42.76, 47.74, 52.57, 52.69, 67.37, 69.49, 101.93,
102.54, 116.32, 126.79, 129.90, 130.79, 133.98, 157.35,
159.99, 166.12, 168.50, 174.01, 175.07. MS: m/z = 488, 490
[M+]. Anal. Calcd for C25H25O8Cl: C, 61.41; H, 5.12. Found:
C, 61.68; H, 5.30%.
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Compound 6e: yield 96%; white solid, mp 125 °C. IR (KBr):
n
max = 1736, 1704, 1650, 1580 cm–1. 1H NMR (400 MHz,
CDCl3): d = 2.15 (s, 3 H), 2.41–2.47 (m, 1 H), 2.58–2.68 (m,
3 H), 2.93–3.02 (m, 3 H), 3.67 (s, 3 H), 3.76 (s, 3 H), 4.39 (d,
J = 11.5 Hz, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.79 (d,
J = 13.4 Hz, 1 H), 5.05 (d, J = 13.4 Hz, 1 H), 5.65 (s, 1 H),
6.78 (d, J = 8.6 Hz, 1 H), 7.21–7.25 (m, 2 H). MS: m/z = 522,
524, 526 [M+]. Anal. Calcd for C25H24O8Cl2: C, 57.36; H,
4.59. Found: C, 57.66; H, 4.44%.
Synlett 2006, No. 3, 466–468 © Thieme Stuttgart · New York