A highly stereoselective synthesis of (Z)-N-Aryl(alkyl)-2-arylidine-2,3-dihydro-1,4-benzoxazines through palladium catalyzed reactions

Article abstract of DOI:10.1055/s-1998-1917

A highly efficient and stereoselective synthesis of (Z)-N-Aryl(alkyl)-2-arylidine-2,3-dihydro-1,4-benzoxazines is described where palladium-catalyzed reactions play a significant role.

Full text of DOI:10.1055/s-1998-1917

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A Highly Stereoselective Synthesis of (Z)-N-Aryl(alkyl)-2-arylidine-2,3-dihydro-1,4-
benzoxazines through Palladium Catalyzed Reactions
Gopeswar Chaudhuri, Chinmay Chowdhury, and Nitya G. Kundu*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta-700032, India.
Fax: (91) (33) 473 2805; e-mail: ocngk@iacs.ernet.in
Received 15 June 1998
Abstract: A highly efficient and stereoselective synthesis of (Z)-N-
Aryl(alkyl)-2-arylidine-2,3-dihydro-1,4-benzoxazines is described
where palladium-catalyzed reactions play a significant role.
The palladium catalyzed reactions were tolerant of various functional
groups (e.g. chloro, nitro, methoxy, thienyl etc.) in the aryl iodide
moiety. The yields were mostly in the range 72-95%. In the case of
entry 8, the bis-substituted product was obtained in 55% yield.
The cyclization of the intermediates (A) did not take place under the
palladium-catalyzed conditions. However, it could be accomplished by
refluxing the acyclic compounds (A) with excess of potassium
Benzo-1,4-oxazine structure has been found in many compounds of
natural occurrence and pharmalogical significance.1 Blepharin, a 1,4-
benzoxazine glycoside, has been isolated from rye, corn and seeds of
Blepharis edulis pers.2 Actinomycin-D, an anticancer drug isolated
from streptomyces, has the benzoxazine structural moiety in the
chromophoric part of the molecule.3 The antiemetic,4 anti-
inflammatory5 and antibacterial6 properties of benzoxazine derivatives
have been reported. Although several classical methods1,7 for the
synthesis of 1,4-benzoxazine structure are available, the palladium-
catalyzed reactions8 which have been so successfully utilized for
carboannulation9 and heteroannulation10 processes, have not yet been
used for building the 1,4-benzoxazine structure. In continuation of our
studies11 on palladium-catalyzed heteroannulation processes, we
became interested in the development of the 1,4-benzoxazine structure
through palladium-catalyzed reactions.
hydroxide in ethanol-water where
a completely stereoselective
cyclization to the (Z)-2-arylidene benzoxazines (11-17, 19-22) took
place11e,f. The presence of a N-benzyl or N-alkyl group was found to be
essential for the cyclization process. Thus, 2-(N-prop-2-ynyl)amino
phenol (23) underwent the palladium-catalyzed arylation to 24 which
did not cyclize to the corresponding 1,4-benzoxazine derivative with
potassium hydroxide in ethanol-water. However, 24 could be cyclized
to 2-arylidene-1,4-benzoxazine (25) with palladium acetate (5 mol%),
LiCl (0.5 equiv.), potassium carbonate (2.5 equiv.) in
dimethylformamide by heating at 100oC for 16h12, in poor yield (10-
20%) only (Scheme 2).
This procedure for the synthesis of 2-arylidene-1,4-benzoxazines was
found to be quite expeditious where both aromatic and heteroaromatic
iodides could be used with excellent overall yields (59-85%).When
there was a nitro substituent (entry 11), the cyclization of the
intermediate acylic product went in poor yield giving a 36% overall
yield of the 1,4-benzoxazine. The method is also equally adaptable to
the synthesis of the bis-benzoxazinylated compound 18 in modest yield
(34%) with complete stereoselectivity. The structures of the products
were established from their spectroscopic data. The assignment of the Z-
configuration was based on the chemical shift positions of the vinylic
protons13 and the 3JCH values14 of the vinylic proton and the methylenic
carbon of the heterocyclic rings.
In this communication, we report that when 2-[N-benzyl(or alkyl)-N-
prop-2-ynyl]aminophenyl tosylate 1 was treated with aryl iodide 2-10,
in the presence of bis(triphenylphosphine)palladium(II) chloride and
cuprous iodide in triethylamine, the di-substituted alkyne A could be
isolated, which on cyclization with potassium hydroxide in ethanol-
water yielded the (Z)-N-aryl(alkyl)-2-arylidine-2,3-dihydro-1,4-
benzoxazines (11-17, 19-22) in excellent overall yields (Scheme 1 and
Table 1).
The palladium catalyzed reactions were carried out in triethylamine
which acted both as a solvent and as a base. Use of DMF as a solvent
with triethylamine as a base led to the formation of colouring materials
which lowered the yields of the acyclic products (A). The reactions were
usually run under mild conditions, e.g. at room temperature. Use of
higher temperature did not improve the yield. We found that the
reactions were most effectively done on the N-benzyl or the N-alkyl
derivatives with the phenolic hydroxyl group being protected as a tosyl
derivative. Usually the N-benzyl derivatives yielded the best results.
Thus, we have described a highly efficient and stereoselective method
for the synthesis of (Z)-2-arylidene-1,4-benzoxazines starting from
easily available starting materials through palladium-catalyzed reaction
procedures. The 2-arylidene-1,4-benzoxazines could be easily
hydrogenated15 to 2- substituted-2,3-dihydro-1,4-benzoxazines which
are important structural moieties of many important naturally occurring
and medicinally important compounds.16
Scheme 1
Scheme 2

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Acknowledgement: Financial assistance under the project no.
01(1385)/95/EMR-II, from the Council of Scientific and Industrial
Research, Government of India, New Delhi, is gratefully acknowledged.
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Hippenmeyer, P.J.; Holwerda, B.C. Bioorg. Med. Chem. Letters,
1997, 7, 2105.
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