Cu2O-catalyzed tandem ring-opening/coupling cyclization process for the synthesis of 2,3-dihydro-1,4-benzodioxins

Article abstract of DOI:10.1021/ol801444p

(Chemical Equation Presented) 2, 3-Dihydro-1, 4-benzodioxins can be prepared in a tandem one-pot procedure by reaction of o-iodophenols with epoxides catalyzed by Cu₂O/1, 10-phenanthroline/Cs₂CO ₃ system. The reaction is suggested to occur via a novel ring-opening/coupling mechanism, giving moderate to good yields. Moreover, both aryl and aliphatic epoxides are tolerated under these conditions.

Full text of DOI:10.1021/ol801444p

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3899-3902
Cu2O-Catalyzed Tandem Ring-Opening/
Coupling Cyclization Process for the
Synthesis of
2,3-Dihydro-1,4-benzodioxins
Weiliang Bao,* Yunyun Liu, Xin Lv, and Weixing Qian
Department of Chemistry, Zhejiang UniVersity, Xi Xi Campus, Hangzhou, Zhejiang
310028, P. R. of China
wlbao@css.zju.edu.cn
Received June 26, 2008
ABSTRACT
2, 3-Dihydro-1, 4-benzodioxins can be prepared in a tandem one-pot procedure by reaction of o-iodophenols with epoxides catalyzed by
Cu2O/1, 10-phenanthroline/Cs2CO3 system. The reaction is suggested to occur via a novel ring-opening/coupling mechanism, giving moderate
to good yields. Moreover, both aryl and aliphatic epoxides are tolerated under these conditions.
Compounds containing 1, 4-benzodioxane structures have
attracted considerable interest during the past few years due
to their interesting biological activities.1 For example,
fluparoxan (Figure 1, 1) is claimed to have potent antidepres-
sant properties,2 the mesylate salt of doxazosin (2) is an
effective antihypertension agent,3 piperoxan (3), an R-adr-
energic blocking agent with considerable stimulating activity,
has been used to diagnose pheochromocytoma and served
as an antihypertension agent,4 and WB 4104 (4) is recognized
as a selective R-adrenoceptor antagonist.5Moreover, they are
found in a variety of natural products, such as silybin,6
Figure 1
dioxanes.
. Structures of some biologically important 1,4-benzo-
isosilybin,7 haedoxan A,8 eusiderin,9 purpurenol,10 and so
(1) (a) Merlini, L.; Zanarotti, A.; Pelter, A.; Rochefort, M. P.; Haensel,
R. J. Chem. Soc., Chem. Commun. 1979, 695. (b) Bosseray, P.; Guillaumet,
G.; Coudert, G.; Wasserman, H. Tetrahedron Lett. 1989, 30, 1387. (c)
Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N Tetrahedron 1994, 50,
13583. (d) Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett
2004, 2449.
on.11 These compounds could also be used as intermediates
for further synthetic transformations.12
Several methods for the assembly of 1,4-benzodioxanes
have developed in recent years. One of the typical approaches
employs catechols as substrates, which can react with various
(2) Pinder, R. M.; Wieringa, J. H. Med. Res. ReV. 1993, 13, 2509.
(3) Fang, Q. K.; Grover, P.; Han, Z.; McConville, F. X.; Rossi, R. F.;
Olsson, D. J.; Kessler, D. W.; Wald, S. A.; Senanayake, C. H. Tetrahedron:
Asymmetry 2001, 12, 2169.
(4) Zhou, R.; Luo, G; Ewing, A. G. J. Neuroscience 1994, 14, 2402.
(5) Takano, Y.; Takano, M.; Yaksh, T. L. Eur. J. Pharmacol. 1992,
219, 465.
(8) (a) Taniguchi, E.; Oshima, Y. Agric. Biol. Chem. 1972, 36, 1013,
and references cited therein. (b) Ishibashi, F.; Taniguchi, E. Phytochemistry
1998, 49, 613.
(6) Hansel, R.; shulz, J.; Pelter, A. J. Chem. Soc., Chem. Commun. 1972,
195.
(9) Hobbs, J. J.; King, F. E. J. Chem. Soc. 1960, 4732.
(10) Debenedetti, S. L.; Nadinic, E. L.; Coussio, J. D.; De Kimpe, N.;
Dupont, J. F.; Declercp, J. P. Phytochemistry 1991, 30, 2757.
(7) Pelter, A.; Hansel, R. Chem. Ber. 1975, 108, 790.
10.1021/ol801444p CCC: $40.75
Published on Web 07/30/2008
2008 American Chemical Society

reagents, such as epoxides, R-haloalkene, 1,4-bis(methoxy-
carbonyloxy)but-2-ene or 3,4-bis (methoxycarbonyloxy)but-
1-ene, and so on.13 Another approach uses the cycloaddition
of a variety of o-quinones with dienophile, either directly or
via a two-step process involving a hetero-Diels-Alder
reaction followed by a [3,3] sigmatropic rearrangement.14
More recently, a method for the synthesis of 1,4-benzodiox-
ans from halo alcohols through a Pd-catalyzed intramolecular
etherification has been reported.15 However, these methods
have some limitations with respect to the availability of the
starting materials and the higher costs of Pd catalysts, as
well as tedious multistep sequence.
alkylbenzimidazoles in regioisomerically pure form starting
from o-haloanilines has been recently reported by Buchwald
and co-workers.20 The above reports developed a simple and
convenient method for synthesis of various heterocycles in
an efficient process. Here we would like to describe a new
general and practical methodology to synthesize 1,4-benzo-
dioxanes from o-iodophenols and epoxides catalyzed by a
Cu2O/1,10-phenanthroline system via cascade ring-opening/
coupling cyclization reactions.
In our initial screening experiment, the reaction of o-
iodophenol 5a with styrene oxide 6a mediated by cesium
carbonate was chosen as a model for exploring the suitable
reaction conditions (Table 1). It was found that the reaction
Thus, a general and practical method to prepare 1,
4-benzodioxanes is still required.
In the past few years, the formation of aryl C-X bonds
(X ) N, O, S, etc.) via copper-catalyzed Ullmann coupling
between aryl halides and heteroatom-centered nucleophiles
has drawn considerable attention.16 More recently, the
Ullmann coupling was successfully extended to the prepara-
tion of many heterocycles via copper-mediated cyclization.17
Li and co-workers reported a copper-catalyzed tandem
double-alkenyl C-N bond formation by the reaction of
(1Z,3Z)-1,4-diiodo 1,3-dienes with amides to form di- or
trisubstituted N-acylpyrroles.18 Ma and co-workers developed
a novel protocol for the elaboration of N-substituted 1,3-
dihydrobenzimidazol-2-ones from methyl o-haloarylcarbam-
ates via a CuI/amino acid catalyzed coupling with amines
and subsequent condensative cyclization.19 Copper-catalyzed
tandem C-N bond formation for the synthesis of N-
Table 1. Optimization of Experimental Conditions for 7aa
(11) (a) Woo, W. S.; Kang, S. S.; Wagner, H.; Chari, V. M. Tetrahedron
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Kim, J. Tetrahedron Lett. 2004, 45, 339.
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1981, 46, 3846. (c) Procopiou, P. A.; Brodie, A C.; Deal, M. J.; Hayman,
D. F. Tetrahedrom Lett. 1988, 29, 3671. (d) Massacret, M.; Lhoste, P.;
Lakhmiri, R.; Parella, T.; Sinou, D Eur. J. Org. Chem. 1999, 2665, and
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1969, 1692. (b) Ansell, M. F.; Leslie, V. J. J. Chem. Soc. C 1971, 1423.
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Tetrahedron Lett. 1986, 27, 3915. (d) Takada, M.; Oshima, R.; Yamauchi,
Y.; Kumanotani, J.; Seno, M. J. Org. Chem. 1988, 53, 3073. (e) Takuwa,
A. Chem. Lett. 1989, 5. (f) Nair, V.; Mathew, B.; Radhakrishnan, K. V.;
Rath, N. P. Tetrahedron 1999, 55, 11017. (g) Cameron, D. W.; Heisey,
R. M. Aust. J. Chem. 2000, 53, 109. (h) Xu, D. W.; Chiaroni, A.; Largeron,
M. Org. Lett. 2005, 7, 5723.
a Reaction conditions: CuX (15 mol %), Ligand (30 mol %), Cs2CO3
(2 mmol), solvent (2 mL), 48 h, ratio based on o-iodophenol. b Isolated
yield.
(15) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202, and references therein.
worked at 90 °C in toluene under the action of 15% CuI
and 30% 1,10-phenanthroline giving the corresponding
product 7a (entry 1). Raising the reaction temperature to 110
°C resulted in an improved yield (entry 2). When the
copper(I) source was switched to CuBr or Cu2O, the product
yield was enhanced (entries 4 and 5). From an economic
point of view, Cu2O was a better catalyst than CuBr. Several
solvents such as toluene, DMSO, NMP, butyronitrile, and
DMF were tested. DMF was superior to the other solvents
(entries 5-9). A brief study of the effect of the ligand was
also carried out; 1,10-phenanthroline L1 provided good
(16) For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
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Parisi, L. M. Org. Lett. 2003, 5, 3843. (b) Yang, T.; Lin, C.; Fu, H.; Jiang,
Y.; Zhao, Y. Org. Lett. 2005, 7, 4781. (c) Evinder, G.; Batey, R. A. J. Org.
Chem. 2006, 71, 1802. (d) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
(e) Martin, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007,
9, 3379. (f) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008,
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625.
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Chem. 2007, 72, 1510.
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(20) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749.
Org. Lett., Vol. 10, No. 17, 2008
3900

Table 2. Scope of the Sequential One-Pot Ring-Opening/Coupling Protocola
a Reaction conditions: o-iodophenol (1 mmol), epoxide (1.5 mmol), Cu2O (15 mol %), 1, 10-phenanthroline(30 mol %), Cs2CO3 (2 mmol), in DMF (2
mL) at 110 °C for 48 h. b Isolated yield. c The regioisomer ratios were based on NMR spectrum and GC.
catalytic activity in this transformation (entries 9-15). In
addition to the solvent and ligand, the ratio of o-iodophenol
to styrene oxide was found to have a dramatic influence on
the reaction outcome (compare entries 2 and 3 as well as
entries 7 and 10).
On the basis of the above results, the reaction scope was
explored with different epoxides and o-iodophenols. As
indicated in Table 2, both aryl and aliphatic epoxides could
react with o-iodophenols giving the corresponding products
in moderate to good yield. No spectacular electronic effects
were observed when cyclohexene oxide was submitted to
reaction with para-substituted o-iodophenols (entries 6 and
7). When styrene oxide 6a and 2-(phenoxymethyl)oxirane
6c were used as the substrates, the o-iodophenols with
electron-rich substituents were generally superior to electron-
deficient ones, as evidenced by giving better yields (compare
entries 8-10 and 16, as well as entries 11-13). This result
may be explained by the symmetry of the cyclohexene oxide.
Org. Lett., Vol. 10, No. 17, 2008
3901

2-(o-Tolyloxymethyl)oxirane 6d proved to be a significantly
less effective coupling partner due to its steric hindrance
(compare entries 3 and 4). Condensation of substituted
o-iodophenols with epoxides may afford a single regioisomer
or a mixture of two regioisomers. The configuration of the
isomers (7p and 8p) was determined by 1H NMR chemical
shifts of Ha and Hb on th naphthalene ring (entry 16). Takuwa
reported that Ha of 7p resonated at lower field than Hb of 8p
probably due to a deshielding effect of the phenyl group at
the position 2.14e The NMR signals of our products 7p and
8p were in very good agreement with the chemical shifts
provided by Takuwa, and 7p was the major regioisomer. The
phenate favored to attack the position of epoxide with less
steric hindrance under basic conditions.
Scheme 1. Plausible Mechanism
A plausible mechanism, which accounts for the formation
of the 1,4-benzodioxane compounds from the o-iodophenols
and epoxides, is shown in Scheme 1. First, in the presence
of base, the o-iodophenol (5) transformed into phenate
(5′)(step a), then it would attack onto electrophilic carbons
of the styrene oxide 6 (the assault onto the position A would
take priority) and the intermediates 8 would be formed (8A
was major) (step b). Coordination of the oxygen to copper
to give 9 (9A was major), followed by an oxidative addition
to 10 (10A was major), and then a reductive elimination to
release product 7 (7A was major) with concomitant regen-
eration of the catalyst/ligand (step e).
In conclusion, we have developed a novel, facile and
practical protocol for the synthesis of 1,4-benzodioxanes
through a Cu2O/1,10-phenanthroline-catalyzed tandem ring-
opening/coupling cyclization reaction. This method allows
the use of a wide range of o-iodophenols and epoxides to
assemble various products in moderate to good yields. The
readily accessible starting materials and relatively mild
conditions should provide a useful tool for intramolecular
C-O cyclization by copper catalysis in organic chemistry.
Acknowledgment. This work was financially supported
by the Natural Science Foundation of China (No. 20572095).
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801444P
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