Synthesis of E- and Z-substituted methylene-3,4-dihydro-2H-1-benzopyrans by regio- and stereocontrolled palladium-catalyzed intramolecular cyclization

Article abstract of DOI:10.1016/S0040-4039(01)00241-6

A stereocontrolled synthetic approach to E- and Z-substituted methylene-3,4-dihydro-2H-1-benzopyrans 5 is described from acyclic derivatives using as a key step the palladium-catalyzed intramolecular cyclic carbopalladation of iodoalkynes 4 followed by a

Full text of DOI:10.1016/S0040-4039(01)00241-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2657–2659
Synthesis of E- and Z-substituted
methylene-3,4-dihydro-2H-1-benzopyrans by regio- and
stereocontrolled palladium-catalyzed intramolecular cyclization
Olivier Barberan, Mou aˆ d Alami* and Jean-Daniel Brion
Laboratoire de Chimie Th e´ rapeutique associ e´ au CNRS (ESA 8076, BIOCIS), Facult e´ de Pharmacie, rue J.B. Cl e´ ment,
92296 Ch aˆ tenay Malabry Cedex, France
Received 9 January 2001; accepted 9 February 2001
Abstract—A stereocontrolled synthetic approach to E- and Z-substituted methylene-3,4-dihydro-2H-1-benzopyrans 5 is described
from acyclic derivatives using as a key step the palladium-catalyzed intramolecular cyclic carbopalladation of iodoalkynes 4
followed by a carbonylation or a hydride ion capture process. © 2001 Elsevier Science Ltd. All rights reserved.
3
4
The preparation of heterocyclic steroid derivatives has
been an area of great interest due to their biological
activities. Besides their well-known hormonal activity,
progesterone acetate, U42129 …). In order to increase
these therapeutic activities, we were interested in the
synthesis and evaluation of 6-oxasteroids for biological
activity.
1
some of them are already described as antineo-
plasic agents (for instance, 2-methoxyestradiol and
analogs which display cytotoxicity and inhibition of
4-Substituted methylene-3,4-dihydro-2H-1-benzopyrans
5 have been shown to be suitable key intermediates for
2
tubulin …) and/or antiangiogenic agents (medroxy-
O
OH
COOMe
R1
R2
O
O
O
1
2
3
R = H
R1
Pd/CO-MeOH
R
R
I
O
O
5
R = CH OH
4
2
Pd/HCOOH
1
a
R = H
a
b
c
R = H
R = COOMe
1
b
R = CH OH
LiAlH4
R = CH2OH
R = H
R = H
2
1
R = CH OH
2
Scheme 1.
Keywords: carbopalladation; cyclization; iodoalkynes; methylene-3,4-dihydro-2H-1-benzopyrans.
*
0
Corresponding author. Fax: +33(1) 46835828; e-mail: mouad.alami@cep.u-psud.fr
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00241-6

2
658
O. Barberan et al. / Tetrahedron Letters 42 (2001) 2657–2659
OH
I
I
I
HO
1/ LDA, THF, -40°C
2
/ (CH O) , -40°C
PPh , DEAD
THF, 20°C
2
n
OH
3
O
O
78%
4
a
4b
68%
Scheme 2.
the synthesis of 6-oxasteroid derivatives. Several
approaches to 5 from substituted chroman-4-ones 1
have been disclosed in the literature by using a Peter-
tion and completed the carbopalladation–carbonylation
sequence within 10 h at 100°C. Under these condi-
14
15
tions, the desired cyclic compound 5a was obtained
selectively in a 79% isolated yield and less than 2% of
acyclic methyl benzoate 2 was formed (5a/2 >98/2).
Further reduction of 5a using lithium aluminium
hydride in THF afforded stereoselectively the Z-alcohol
5c.
5
6
7
8
son, a Wittig, a Reformatsky or a Torgov type
reaction. Except in the last case, these methods display
little stereoselectivity and give a mixture of isomers.
Palladium-catalyzed bond forming processes, which
have evolved as powerful tools for the construction of
complex natural compounds, should in principle open
an attractive stereoselective alternative route to both Z-
and E-isomers. To our knowledge, approaches to 5
based on transition metal-catalyzed cyclization of
We next turned our attention to the stereoselective
synthesis of the E-alcohol 5b from iodoalkyne 4b by the
palladium catalyzed tandem cyclization-anion capture
9,10
16
acyclic compounds have scarcely been reported.
The
reported by Grigg. Thus, when using the catalyst
16
latter offer potent possibilities to obtain various deriva-
tives 5, since acyclic compounds are easily accessible. In
this communication, we wish to report a simple and
stereoselective approach to Z and E compounds 5 using
as a key step the palladium-catalyzed intramolecular
cyclic carbopalladation of iodoalkynes 4a–b. The result-
ing vinyl–palladium(II) intermediates may undergo
either carbonylation reaction in the presence of MeOH
to give (from 4a) the ester 5a precursor of the Z-alco-
hol 5c or hydride ion capture to afford the E-alcohol 5b
system Pd(OAc) (10%), PPh (20%), piperidine (4
2 3
equiv.), HCOOH (3 equiv.) in acetonitrile at 80°C, the
iodoalkyne 4b cyclized regio- and stereoselectively via a
6-exo-dig process to 5b over 18 h in 51% yield. Under
these conditions, a minor quantity (6%) of compound 3
was formed arising from direct anion capture by the
initial aryl–palladium species (5b/3: 90/10). Interest-
ingly, the use of sodium formate (2 equiv.) in DMF
instead of formic acid and piperidine in acetonitrile
resulted in better yield of 5b (64% instead of 51%) but
in similar selectivity (5b/3: 90/10). Finally, the addition
(
from 4b) (Scheme 1).
of Bu NCl (2 equiv.) selectively suppresses the forma-
4
The required alkyne 4a was readily prepared in 68%
yield by a Mitsunobu coupling reaction between ortho-
iodophenol and but-3-yn-1-ol. Subsequent deprotona-
tion of alkyne 4a with LDA followed by reaction with
paraformaldehyde led to aromatic alkyne 4b (Scheme
tion of 3 via direct anion capture process and provides
17
only the desired cyclic compounds 5b in a 79% iso-
lated yield.
In summary, we have succeeded in developing an
efficient and flexible synthetic route to E- and Z-substi-
tuted methylene-3,4-dihydro-2H-1-benzopyran com-
pounds starting from readily accessible acyclic
derivatives. The use of these latter as intermediates for
the synthesis of novel highly functionalized 6-oxas-
teroids is currently in progress and will be reported in
due course.
2).
Initial attempts to perform the cyclic carbopalladation–
carbonylation cascade of iodoalkyne 4a with
1
1
PdCl (PPh ) (5%), CO (1 atm) and Et N (4 equiv.) in
2
3 2
3
12
MeOH at 100°C following the procedure of Negishi
were encouraging. The desired cyclic product 5a was
formed (49%) together with the acyclic derivative 2
(
12%), due to a competitive carbonylation before car-
bopalladation, in a 80:20 ratio. Changing the solvent to
DMF–MeOH (1/1: v/v) resulted in better selectivity
Acknowledgements
(
5a/2: 90/10). This one was enhanced (5a/2: 97/3) by
12
adding water to the reaction mixture (DMF/MeOH/
ADIR (Servier Group) is gratefully thanked for a doc-
toral fellowship to O.B. Thanks are also due to the
CNRS for support of this research, and to J. Mahuteau
for the NMR analysis.
H O: 1/1/0.2, v/v/v). Under these conditions, 5a was
2
isolated in a 59% yield within 24 h. Palladium sources
including Pd(OAc) , Pd(dba) and Pd(PPh3)4 were
2
2
examined either with or without added triphenylphos-
phine ligand. The effect of the addition of various
1
3
additives (Et NCl, Tl CO , TlOAc and AgOAc) on
4
2
3
selectivity were also studied. Suitable conditions were
found which employed Pd(PPh ) (10%), CO (1 atm),
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3
sisting of 1:1:0.2 MeOH–DMF–H O at 100°C. The
2
presence of AgOAc accelerated the rate of the reac-

O. Barberan et al. / Tetrahedron Letters 42 (2001) 2657–2659
2659
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8
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7.3 and 1.5 Hz), 6.86 (1H, ddd, J=8.0, 7.3 and 1.4 Hz),
6.81 (1H, dd, J=8.5 and 1.4 Hz), 5.70 (1H, t, J=1.2 Hz),
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13
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mmol), sodium formate (170 mg, 2.49 mmol) and tetra-
butylammonium chloride (460 mg, 1.66 mmol) in anhy-
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added Pd(OAc) (19 mg, 0.083 mmol) and PPh (44 mg,
3
313–3328; (g) Ramadas, S. R.; Chaudhuri, A. P.
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9
. For the mercury trifluoroacetate-mediated cyclization of
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1. Performing the cyclization reaction under high pressures
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1
2
3
0.166 mmol). After stirring at 80°C for 12 h, the mixture
was hydrolyzed with a saturated aqueous solution of
ammonium chloride and extracted with diethyl ether. The
organic extract was dried over MgSO4 and the solvent
was removed in vacuo. Purification through silica gel
(eluent: petroleum ether/ether 80/20) gave 116 mg (79%)
1
1
of pure alcohol 5b as a colorless oil H NMR (400 MHz):
7.40 (1H, dd, J=8.2 and 1.2 Hz), 7.10 (1H, t, J=7.9 Hz),
1
6.79 (2H, m), 5.75 (1H, t, J=8.1 Hz), 4.51 2H, d, J=8.1
13
Hz), 4.11 (2H, t, J=5.9 Hz), 2.50 (2H, t, J=5.9 Hz);
C
5
1
931; (b) Cop e´ ret, C.; Negishi, E. Org. Lett. 1999, 1,
65–167.
NMR (100 MHz): 149.1, 141.2, 128.3, 126.4, 120.4, 119.4,
118.3, 114.6, 69.8, 59.7, 37.6.
.
.