Palladium-catalyzed cyclization of enediynes to benzopyranones

Article abstract of DOI:10.1002/adsc.200700516

Treatment of methyl 2-[6-substituted-3(Z)-hexen-1,5-diynyl]benzoates (1) with five mol% of palladium chloride and three equivalents of cupric chloride in refluxing acetonitrile gave dibenzo[b,d]pyran-6-ones (2) in modest to good yields.

Full text of DOI:10.1002/adsc.200700516

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DOI: 10.1002/adsc.200700516
Palladium-Catalyzed Cyclization of Enediynes to Benzopyranones
Wei-Ren Chang,a Yu-Hsiang Lo,a Chia-Ying Lee,a and Ming-Jung Wua,*
a
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
Fax : (+886)-7-312-5339; e-mail: mijuwu@kmu.edu.tw
Received: October 30, 2007; Revised: April 1, 2008; Published online: May 16, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Treatment of methyl 2-[6-substituted-
3(Z)-hexen-1,5-diynyl]benzoates (1) with five mol%
of palladium chloride and three equivalents of
cupric chloride in refluxing acetonitrile gave
dibenzo
yields.
ACHTREUNG[b,d]pyran-6-ones (2) in modest to good
Keywords:
alkynes;
cyclization;
dibenzo-
ACHTREUNG[b,d]pyranones; enediynes; heterocycles; palladium
Many biologically active natural products and phar-
maceutically important compounds contain a dibenzo-
ACHTREUNG[b,d]pyran-6-one skeleton. Thus, the development of
syntheses of functionalized dibenzoACHTRE[UNG b,d]pyran-6-ones
has attracted much attention from organic chemists.[1]
Palladium-catalyzed cyclization reactions are very
powerful methods for the construction of heterocyclic
compounds.[2] Ma reported the use of a catalytic
Scheme 1. Preparation of 1a–f.
amount of PdCl2 and equivalents of CuCl2 for the car- of 4 with methanol in the presence of potassium car-
bonylation of propargyl alcohols and amines to give bonate to give 5 in 85% yield. Compound 5 was then
b-lactones[3] and b-lactams,[4] respectively. Similar re- coupled with various vinyl chlorides 6a–f under the
action conditions have been applied to the carbonyla- Sonogashira coupling reaction conditions to give the
tion of terminal alkynes[5] and the synthesis of 3-halo- desired products 1a–f in 59–89% yields, respectively.
benzo[b]furans by Li.[6] Recently, we found that treat- The synthesis of methyl 2-[6-aryl-3(Z)-hexen-1,5-di-
ment of 1,2-dialkynylbenzenes with five mol% of
PdCl2 and two equivalents of CuCl2 gave benzoful- pound 5 was coupled with vinyl chloride 6g using
venes in good chemical yields.[7] Our continued inter-
Pd(PPh3)4 as the catalyst to give enediyne 7 in 76%
ACHTREyUNG nyl]benzoates (1g–n) is outlined in Scheme 2. Com-
A
ACHTREUNG
est in the cyclization reactions of enediynes for the yield. Compound 7 was then treated with various aryl
synthesis of heterocycles[8] encouraged us to investi- iodides in the presence of a catalytic amount of Pd-
gate the cyclization reaction of methyl 2-[6-substitut-
ACHTREUNG
ed-3(Z)-hexen-1,5-diynyl]benzoates (1) in the pres-
ence of catalytic amount of PdCl2 and three equiva- PdCl2 and three equivalents of CuCl2 in various or-
lents of CuCl2 to give functionalized dibenzo- ganic solvents gave cyclization adduct 2a in 3–65%
A
yields. It was found that compound 2a could be ob-
The synthesis of methyl 2-[6-alkyl-3(Z)-hexen-1,5- tained in the highest yield (65%) in refluxing acetoni-
diynyl]benzoates (1a–f) starting from methyl 2-iodo- trile. The results are summarized in Table 1 and the
benzoate (3) is outlined in Scheme 1. A Sonogashira structure of compound 2a was unambiguously deter-
coupling reaction of 3 with trimethylsilylacetylene mined by X-ray crystallography[9] (Figure 1).
using Pd
A
Other methyl 2-[6-substituted-3(Z)-hexen-1,5-diyn-
91% yield. The silyl group was removed by treatment
AHCTREUNG
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Palladium-Catalyzed Cyclization of Enediynes to Benzopyranones
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Table 2. Synthesis of various dibenzoACHTRE[UNG b,d]pyran-6-ones.
Compounds
R
Products (Yield [%])
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
C
2a (65)
2b (63)
2c (40)
2d (11)
2e (47)
2f (76)
2g (65)
2h (47)
2i (50)
2j (32)
2k (39)
2l (35)
2m (42)
2n (28)
A
7c (8)
7d (15)
A
Scheme 2. Preparation of 1g–n.
7g (11)
7h (13)
Table 1. Solvent effects on the cyclization reactions.
7j (8)
7k (10)
7n (trace)
terminal alkynes have also been subjected to the cyc-
lization reaction under the optimal reaction condi-
tions. The results are summarized in Table 2. With the
exception of compound 1d, these reactions gave the
Solvent
Temp [oC]
Time [h]
Yield [%]
CH3CN
THF
Et2O
Toluene
DMF
Benzene
DMSO
CH2Cl2
CH3OH
reflux
reflux
reflux
80
80
reflux
80
1
1
65
45
30
24
23
22
9
dibenzo
ACHTREUNG
12
24
24
24
24
24
24
The low yield of dibenzoAHCTREUNG
by cyclization of 1d could be due to steric hinderance
caused by the tert-butyl group, which adversely affects
the cyclization reaction. It was also found that if a
bulky substituent, such as isobutyl, is present at the 6-
position a small amount (8%) of an undesired prod-
uct (7c) was obtained. The structure of 7c was unam-
biguously determined by X-ray crystallography[9]
(Figure 2). Similar results were observed in the reac-
tions of 1d, 1g and 1h. Compounds 2d, 2g and 2h
were obtained in 11%, 65% and 45% yields along
with 7d, 7g and 7h in 15%, 11% and 13% yields, re-
spectively. Reaction of 1i under the same reaction
conditions gave cyclization adduct 2i in 50% yield,
however no five-membered ring adduct of the type 7
was observed. Compounds 1g, 1h and 1i all have an
aryl group at the alkyne terminus, but only 1i bearing
an electron-withdrawing group at the para position of
the aryl ring did not give the five-membered ring
adduct 7. This observation led us to explore substitu-
ent effects upon this cyclization reaction. Accordingly,
compounds 1j–n were prepared and subjected to the
cyclization reaction conditions. The results show that
compounds bearing an electron-donating group on
the aryl ring, such as 1j and 1k, gave dibenzo-
reflux
reflux
9
3
AHCTREUNG
Figure 1. ORTEP plot of the X-ray crystal structure of 2a.
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Wei-Ren Chang et al.
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Scheme 3. Synthesis of compound 2o.
We have also carried out control experiments by
simply treating 1a with three equivalents of CuCl2 in
the absence of PdCl2 in refluxing CH3CN for 1 h. The
monocyclized product 10a was obtained in 64% yield
along with 10b in 32% yield [Eq. (2)]. However,
Figure 2. ORTEP plot of the X-ray crystal structure of 7c.
10% yields, respectively. Compound 1l bearing a tri-
fluoromethyl group at the 2-position of the phenyl
ring gave only the dibenzoACHTER[UNG b,d]pyran-6-one 2l albeit
in lower yield (35%). The low yield of this reaction
could be due to steric hinderance caused by the ortho
substituent. The electron-deficient pyridinyl ring has
also been employed in this cyclization reaction. Cycli-
zation of compound 1m gave compound 2m as the
only product. Compound 1n containing a more elec-
tron-rich thienyl group gave 2n in 28% yield and a
trace amount of the five-membered ring adduct 7
1
could be observed in the H NMR spectrum of the
crude reaction mixture.
treatment of 1a with one equivalent of PdCl2 under
Compound 1o has also been prepared by the palla- the same reaction conditions, gave compound 2a in
dium-catalyzed coupling reaction of 5 with 2-(1-hept- 61% yield as the only product. As a result of these
ACHTREUNG
AHCTREUNG
ACHTREUNG
63% yield. (Scheme 3) Finally, compound 2f was con- dium(II) coordinates with the triple bond of the sub-
verted to the seven-membered ring lactone 9f in 82% strate (1) to form complex 10. The carbonyl oxygen
yield by treatment with methanol in the presence of of the ester functionality then attacks C-2 of the
potassium carbonate [Eq. (1)].
alkyne to form oxonium ion 11. This vinyl palladium
intermediate may then undergo either 6-endo or 5-
exo cyclization to form intermediate 12 or 14, respec-
À
tively. In the presence of CuCl2, the C Pd bond
À
would be cleaved to form a C Cl bond to provide in-
termediate 13. Finally, the methyl group of 13 is then
removed by nucleophilic attack of chloride to give
À
compounds 2. On the other hand, cleavage of the C
Pd bond of intermediate 14 by CuCl2, followed by re-
moving the methyl group of 15 by nucleophilic attack
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Palladium-Catalyzed Cyclization of Enediynes to Benzopyranones
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solution and extracted with EtOAc (60 mL”3). The com-
bined organic extracts were washed with saturated Na2CO3
solution and dried over anhydrous MgSO4. After filtration
and removal of solvent, the residue was purified by column
chromatography (silica gel 400 mesh, 1:30 EtOAc:hexane as
eluent) to give the products.
Cyclization of Methyl 2-[6-Substituted-3(Z)-hexen-
1,5-diynyl]benzoate (Method B)
The reaction mixture of methyl 2-[6-substituted 3(Z)-hexen-
1,5-diynyl]benzoate (0.36 mmol), PdCl2 (3.16 mg, 5 mol%)
and CuCl2 (145 mg, 1.08 mmol) in CH3CN (5 mL) was
heated to reflux and stirred at this temperature for 1 h.
After cooling to room temperature, the reaction mixture
was quenched with saturated NH4Cl solution and extracted
with EtOAc (30 mL”2). The combined organic extracts
were dried over anhydrous MgSO4. After filtration and re-
moval of solvent, the residue was purified by column chro-
matography (silica gel 400 mesh, 1:30 EtOAc:hexane as
eluent) to give the products.
Acknowledgements
We thank the National Science Counci of the Republic of
Chinal for financial support.
Scheme 4. The proposed mechanism for the formation of
compounds 2 and 7.
References
of chloride would give fulvene 16. Compound 16 may
react with CuCl2 to give trichloro products 7. Basical-
ly, the second cyclization step favors the 6-endo path-
way to provide the aromatized product. However,
when the substituent on the terminal alkyne is a more
sterically hindered alkyl group or a more electron-
rich aryl ring, the 5-exo adducts are obtained as minor
products.
In conclusion, we have developed an efficient syn-
thetic method for the construction of the dibenzo-
ACHTREUNG[b,d]pyran-6-one ring system. This method involves a
one-step palladium-catalyzed tandem cyclization reac-
tion of enediynes. Yields are from modest to good.
We have also observed substituent effects on this cyc-
lization reaction. The application of this methodology
to the synthesis of natural products is currently under
investigation.
[1] a) J. M. Schmidt, G. B. Tremblay, M. Page, J. Mercure,
M. Feher, R. Dunn-Dufault, M. G. Peter, P. R. Redden,
J. Med. Chem. 2003, 46, 1289; b) X. Wang, K. F. Bastow,
C. M. Su, Y. L. Lin, H. J. Yu, M. D. Don, T. S. Wu, S. Na-
kamura, K. H. Lee, J. Med. Chem. 2004, 47, 5816; c) X.
Wang, K. Nakagawa-Goto, K. F. Bastow, M. D. Don,
T. S. Wu, K. H. Lee, J. Med. Chem. 2006, 49, 5631; d) T.
Kawasaki, Y. Yamamoto, J. Org. Chem. 2002, 67, 5138;
e) L. D. Via, E. Uriarte, E. Ouezada, A. Dolmella, M. G.
Ferlin, O. Gia, J. Med. Chem. 2003, 46, 3800; f) Q. J.
Zhou, K. Worm, R. E. Dolle, J. Org. Chem. 2004, 69,
5147; g) V. T. H. Nguyen, P. Langer, Tetrahedron Lett.
2005, 46, 1013; h) H. Abe, K. Nishioka, S. Takeda, M.
Arai, Y. Takeuchi, T. Harayama, Tetrahedron Lett. 2005,
46, 3197; i) R. Girotti, A. Marracchi, L. Minuti, O. Pier-
matti, F. Pizzo, L. Vaccaro, J. Org. Chem. 2006, 71, 70;
j) S. Madan, C. H. Cheng, J. Org. Chem. 2006, 71, 8312.
[2] a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic
Chemistry: A Guide for the Synthetic Chemist, Elsevier
Science Ltd., Oxford, 2000; b) J. Tsuji, Palladium Re-
agents and Catalyst: Innovations in Organic Synthesis,
John Wiley & Sons, New York, 1995; c) R. F. Heck, Pal-
ladium Reagentsin Organic Syntheiss , Academic Press,
New York, 1985.
Experimental Section
Coupling Reaction of Methyl 2-Ethynylbenzoate (5)
with Vinyl Chloride (6) (Method A)
[3] S. Ma, B. Wu, X. Jiang, S. Zhao, J. Org. Chem. 2005, 70,
2568.
To a stirred solution of vinyl chloride (7.5 mmol) in anhy-
drous ether (20 mL) in the presence of Pd
A
[4] S. Ma, B. Wu, X. Jiang, J. Org. Chem. 2005, 70, 2588.
[5] J. H. Li, S. Tang, Y. X. Xie, J. Org. Chem. 2005, 70, 477–
479.
[6] Y. Ling, S. Tang, X. D. Zhang, L. Q. Mao, Y. X. Xie,
J. H. Li, Org. Lett. 2006, 8, 3017.
was added a solution of methyl 2-ethynylbenzoate (1.2 g,
7.5 mmol) , CuI (5 mol%) and n-butylamine (0.5 mL) in an-
hydrous ether (20 mL). The resulting solution was stirred at
room temperature for 6 h, quenched with saturated NH4Cl
Adv. Synth. Catal. 2008, 350, 1248 – 1252
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Wei-Ren Chang et al.
COMMUNICATIONS
[7] C. Y. Lee, M. J. Wu, Eur. J. Org. Chem. 2007, 3463.
[8] a) M. J. Wu, C. F. Lin, S. H. Chen, Org. Lett. 1999, 1,
767; b) M. J. Wu, C. Y. Lee, C. F. Lin, Angew. Chem.
2002, 114, 4251; Angew. Chem. Int. Ed. 2002, 41, 4077;
c) M. J. Wu, C. F. Lin, W. D. Lu, J. Org. Chem. 2002, 67,
5907; d) C. Y. Lee, C. F. Lin, J. L. Lee, C. C. Chiu, W. D.
Lu, M. J. Wu, J. Org. Chem. 2004, 69, 2106; e) Z. Y.
Chen, M. J. Wu, Org. Lett. 2005, 7, 475.
tal data for 7c: C17H15Cl3O2, unit cell parameters: a=
7.21130 (10), b=9.01260 (10), c=14.2796 (3), a=
105.4050 (10), b=90.5200 (10), g=112.8580 (10), space
group P-1. CCDC 683257 (2a) and CCDC 683176 (7c)
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or CCDC, 12
Union Road, Cambridge CB2 1ED, UK[fax: +44-
(1223)-336-033; e-mail deposit@ccdc.cam.ac.uk.
[9] Crystal data for 2a: C18H17ClO2, unit cell parameters:
a=10.790 (3), b=12.210 (4), c=13.502 (4), a=71.731
(5), b=67.179 (5), g=68.035 (5), space group P-1. Crys-
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