One step of palladium catalyzed benzodioxane ring C-O bond formation, synthesis of isoamericanol A and isoamericanin A

Article abstract of DOI:10.1081/SCC-120030759

A number of benzodioxane compounds were synthesized using the palladium-catalyzed etherification of aryl halides by employing triphenylphosphane ligands. This method was used as key step in the synthesis of two natural products isoamericanol A and isoamericanin A.

Full text of DOI:10.1081/SCC-120030759

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One Step of Palladium Catalyzed Benzodioxane Ring
C–O Bond Formation, Synthesis of Isoamericanol A
and Isoamericanin A
Xiaobi Jing a , Yaocheng Shi a , Yonghong Liu a , Ying Han a , Chaoguo Yan a & Li Wang a
a College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou,
225002, China
Version of record first published: 16 Aug 2006.
To cite this article: Xiaobi Jing, Yaocheng Shi, Yonghong Liu, Ying Han, Chaoguo Yan & Li Wang (2004): One Step of
Palladium Catalyzed Benzodioxane Ring C–O Bond Formation, Synthesis of Isoamericanol A and Isoamericanin A, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:9, 1723-1727
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1723–1727, 2004
One Step of Palladium Catalyzed
Benzodioxane Ring C–O Bond Formation,
Synthesis of Isoamericanol A and
Isoamericanin A
*
Xiaobi Jing, Yaocheng Shi, Yonghong Liu, Ying Han,
Chaoguo Yan, and Li Wang
College of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou, China
ABSTRACT
A number of benzodioxane compounds were synthesized using the
palladium-catalyzed etherification of aryl halides by employing triphenyl-
phosphane ligands. This method was used as key step in the synthesis of
two natural products isoamericanol A and isoamericanin A.
Key Words: Benzodioxane; Isoamericanol A; Isoamericanin A; Palla-
dium.
*
Correspondence: Xiaobi Jing, College of Chemistry and Chemical Engineering,
Yangzhou University, Yangzhou 225002, China; E-mail: jingxiaobi@yahoo.com.cn.
1723
DOI: 10.1081/SCC-120030759
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Jing et al.
INTRODUCTION
Aryl ethers and oxygen heterocycles are common structures in many
pharmaceutically and agriculturally important compounds.[1,2] Traditional
methods for the preparation of these compounds include the Williamson
ether synthesis (for a review see Ref.[3]), direct nucleophilic substitution
reactions (for a review see Ref.[4]), and Ullman-type couplings of alkoxides
with aryl halides (for a review see Ref.[5]). Each of these reactions, however,
usually requires either highly reactive aryl halides, an excess of the alkoxide,
or harsh conditions.
Recently, Buchwald has reported to extend the scope and utility of the
intramolecular C–O bond forming reaction.[2] From their work, we developed
a convenient method to couple benzodioxane ring from o-dibromoaryl and
dialcohol by one step.
We found in our lab that 1,2-ethanediol and o-dibromobenzene are
difficult to be coupled to get benzodioxane at the presence of Cs2CO3 and
catalyzed amount of PdCl2 (yield ,10%). But once triphenylphosphane is
added, the yield of benzodioxane will be improved to about 65%. Toluene
is the best solution to the reaction, as show in Table 1. We are now giving
further research about the mechanism of the reaction.
As shown in Table 2, different benzodioxane rings can be formed by using
this method. Both aryl chlorides and bromides can be cyclized using this
catalyst system. Primary as well as secondary alcohol substrates are efficiently
cyclized.
Table 1. Yield of benzodioxane.
PdCl2
(mol%)
Ph3P
(mol%)
Yield
(%) (3)
Entry
1 : 2
T (8C), t (hr)
Solution
1
2
3
4
5
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
2
2
2
2
2
0
50, 24
50, 24
r.t., 50
Toluene
Toluene
Acetone
Ether
8
65
44
20
56
2.5
2.5
2.5
2.5
r.t., 30
Reflux, 24
CH3CN

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Synthesis of Isoamericanol A and Isoamericanin A
1725
Table 2. Formation of benzodioxane ring.
Entry
R
X
R0
Yield (%)
1
2
3
4
5
H
Br
Cl
Br
Br
Br
H
65
63
60
61
60
H
CN
H
H
COOCH3
H
H
Me
Application of this method for the formation of benzodioxane natural
products is important because those structures are widely found in nature
and biologically active compound. Isoamericanol A[6] 9 and isoamericanin
A[7] 10 are two benzodioxane natural products. They are reported to have
CHAT activity. Herein, we report a novel and short route for the synthesis
of isoamericanol A and isoamericanin A.
As shown in Sch. 1, compound 6 is easily synthesized from caffeic alde-
hyde 4 under the conditions reported. Under the above palladium catalyzed
Scheme 1. Reagents and conditions: i. Ac2O, Py, .99%; ii. H2O2, 94%; iii. Cs2CO3,
Ph3P, PdCl2, 63%; iv. LAH, 88%; v. MnO2/SiO2, 81%.

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Jing et al.
condition, compound 6 and compound 7 are coupled to obtain compound 8.
Then compound 9 and compound 10 are easily obtained by reduction and
oxidation. From the melting point and the spectrum of the compounds 9
and 10, isoamericanol A[8] and isoamericanin A,[8] we inferred compound 9
is isoamericanol A and compound 10 is isoamericanin A. We are now giving
further research about the mechanism of the regioselectivity.
EXPERIMENTAL
Melting points were measured on a Kofler apparatus and were uncor-
rected. MS were performed on ZAB-HS spectrometer. 1H-NMR spectra
were recorded on a Bruker AM-500 and AM-400 instruments. Chemical shifts
are referred to TMS on the “d” scale. Standard flash chromatography were
employed to purify the crude reaction mixture using 200–300 mesh silica
gel under positive nitrogen pressure.
Compounds 5 and 6 were synthesized by the reported procedure.[8]
Compound 8. To a solution of 115 mg 7 and 110 mg 6 in 100 mL dry
toluene, catalytic amount of PdCl2 and Ph3P were added. After stirred for
20 min at r.t., the solution was added to 192 mg Cs2CO3. At 508C, the mixture
stirred for 24 hr more. The mixture was filtered, evaporated, and purified by
flash-chromatography (ethyl acetate : petroleum ether ¼ 1 : 1) to obtain
1
white powder 102 mg, 63% yield; m.p.: 127–1298C. H-NMR (400 MHz,
DMSO-d6, ppm) d 9.72 (d, 1H, 7.6 Hz, –CHO), 6.62. (d, 1H, 16 Hz, H-70),
6.70–7.30 (m, 5H, Ar-H), 6.25 (dd, 1H, 16 Hz, 8 Hz, H-80), 5.70 (d, 1H,
8 Hz, H-7), 5.44 (m, 1H, H-8), 4.20 (dd, 2H, 12.3 Hz, 5 Hz, H-9). HRFABMS
(m/z) 412.3952 (Mþ C22H20O8) requires 412.3949.
Isoamericanol A 9. Isoamericanol A were synthesized by the reported
1
procedure.[8] Isoamericanol A: white powder, m.p.: 155–1578C, H-NMR
(500 MHz, DMSO-d6, ppm) d 6.96 (d, 1H, 2 Hz, H-20), 6.93 (dd, 1H, 8 Hz,
2 Hz, H-60), 6.87 (d, 1H, 8 Hz, H-70), 6.70 (dd, 1H, 8 Hz, 2 Hz, H-6), 6.42
(d, 1H, 16 Hz, H-7), 6.20 (dt, 1H, 16 Hz, 5 Hz, H-80), 4.81 (d, 1H, Hz), 4.07
(t, 1H, H-90), 4.03 (m, 1H, H-8), 3.51 and 3.32 (dd, 2H, 12.3 Hz, 5 Hz,
H-9). HRFABMS (m/z) 330.1143 (Mþ C18H18O6) requires 330.1111, EIMS
(m/z) 330, 166, 148, 123.
All the spectra data are in good agreement with those of literature report.[8]
Isoamericanin A 10. Isoamericanin A were synthesized by the reported
procedure. Isoamericanin A: yellow powder, m.p.: 173–1768C; HRMS (m/z)
328.0931 (Mþ C18H16O6) requires 328.0933, 1H-NMR (400 MHz, DMSO-d6,
ppm) d 9.53 (d, 1H, 7.6 Hz, –CHO), 7.52 (d, 1H, 16 Hz, H-70), 6.70–7.30
(m, 5H, Ar-H), 6.67 (dd, 1H, 16 Hz, 8 Hz, H-80), 4.85 (d, 1H, 8 Hz, H-7),
4.14 (m, 1H, H-8), 3.35 and 3.57 (dd, 2H, 12.3 Hz, 5 Hz, H-9).

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Synthesis of Isoamericanol A and Isoamericanin A
1727
All the spectra data are in good agreement with those of literature
report.[8]
REFERENCES
1. Gu, W.X.; Jing, X.B.; Pan, X.F.; Chan, A.C.S.; Yang, T.K. First asym-
metric synthesis of chiral 1,4-benzodioxane lignans. Tetrahedron Lett.
2000, 41, 6079.
2. Kuwabe, S.; Torraca, K.E.; Buchwald, S.L. Palladium-catalyzed intra-
molecular C22O bond formation. J. Am. Chem. Soc. 2001, 123, 12202.
3. Feuer, H.; Hooz, J. Williamson ether synthesis. In Chemistry of the Ether
Linkage; Patai, S., Ed.; Wiley Interscience: New York, 1967; chapter III,
445.
4. Paradisi, C. Nucleophilic substitution reactions. In Comprehensive Org-
anic Synthesis; Trost, B.M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, chapter II, 423.
5. Lindley, J. Copper assisted nucleophilic substitution of aryl halogen.
Tetrahedron 1984, 40, 1433.
6. Fukuyama, Y.; Hasegawa, T.; Toda, M.; Kodama, M.; Okazaki, H. Struc-
tures of americanol A and isoamericanol A having a neurotrophic property
from the seeds of Phytolacca americana. Chem. Pharm. Bull. 1992, 40 (1),
252.
7. Hasegawa, T.; Fukuyama, Y.; Asakawa, Y. Neolignans from the leaves of
Phytolacca americana. Chem. Lett. 1987, 182 (2), 329.
8. She, X.; Gu, W.; Wu, T.; Pan, X. A convenient stereoselective synthesis of
isoamericanol and isoamericanin A. Synthetic Commun. 1999, 29 (15),
2625–2628.
Received in Japan October 6, 2003

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