Studies of bioactive heterocycles: Amino Claisen rearrangement of 4-N-(4-aryloxybut-2-ynyl),N-methylaminocoumarins

Article abstract of DOI:10.1016/S0040-4039(01)00656-6

Thermalamino-Claisen rearrangement of 4-N-(aryloxybut-2-ynyl),N-methyl-aminocoumarins (8a-e) in refluxing o-dichlorobenzene gave 4-aryloxymethylene-1-methyl-1,2,3-trihydropyrido[3,2-c][1]benzopyran-5-ones (9a-e) in 56-72% isolated yields. Substrates (8a-f) were prepared from 4-chlorocoumarin (6a,b) and N-(4-ary-loxybutynyl),N-methylamine (7a-f) in 68-77% yields.

Full text of DOI:10.1016/S0040-4039(01)00656-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4231–4233
Studies of bioactive heterocycles: amino Claisen rearrangement
of 4-N-(4-aryloxybut-2-ynyl),N-methylaminocoumarins
K. C. Majumdar* and T. Bhattacharyya
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Received 9 November 2000; revised 12 January 2001; accepted 19 April 2001
Abstract—Thermal amino-Claisen rearrangement of 4-N-(aryloxybut-2-ynyl),N-methyl-aminocoumarins (8a–e) in refluxing o-
dichlorobenzene gave 4-aryloxymethylene-1-methyl-1,2,3-trihydropyrido[3,2-c][1]benzopyran-5-ones (9a–e) in 56–72% isolated
yields. Substrates (8a–f) were prepared from 4-chlorocoumarin (6a,b) and N-(4-ary-loxybutynyl),N-methylamine (7a–f) in 68–77%
yields. © 2001 Elsevier Science Ltd. All rights reserved.
Coumarin and coumarin derivatives are reported to
possess various physiological activities.1 3-Alkyl and
4-alkylcoumarins are well known2 for their
anthelmintic, hypnotic, insecticidal, antifungal activities
and anti-coagulant effect on blood and diuretic proper-
ties. Extensive work has been carried on the synthesis3
of these compounds. Pyrano[3,2-c][1]benzopyran-
5(2H)-one derivatives 1 and furo[3,2-c][1]benzopyran-4-
one derivatives 2 have been constructed by Claisen
rearrangements.4–6 Similarly, pyrano[2,3-c][1]benzo-
pyran-5(3H)-one derivatives 3 and furo[2,3-c][1]benzo-
pyran-4-one derivatives 4 have also been synthesised by
the application of Claisen rearrangements.4,7,8 Although
the oxygen Claisen rearrangement of coumarins has
been studied in detail, the amino-Claisen rearrangement
has not been studied so far. This prompted us to
undertake a study of the amino-Claisen rearrangement
of 4-N-(4-aryloxybut-2-ynyl),N-methylaminocoumarins
(8a–f).
POCl3 at 135–140°C for 4 h (Scheme 1). These were
characterised from their elemental analyses and spectro-
scopic data.
The starting materials 4-N-(4-aryloxybut-2-ynyl),N-
methylaminocoumarins 8a–f were prepared9 in 68–77%
yields by refluxing 4-chlorocoumarins (6a,b) and the
corresponding N-4-(aryloxybut-2-ynyl),N-methylamine
7a–f in ethanol for 10–14 h (Scheme 2).
Compounds 8a–f were characterised from their elemen-
tal analyses and spectroscopic data. The IR spectrum of
8a showed wmax at 1710 cm−1 due to the presence of a
1
carbonyl group. The H NMR spectrum of 8a revealed
a three proton singlet at l 2.99 due to the NCH3 and
two sets of two-proton singlets at l 4.09 and 4.76 due
to the NCH2 and OCH2, respectively. A one proton
singlet appeared at l 5.74 due to the C3-H of the
coumarin moiety. The mass spectrum of 8a showed a
molecular ion peak at m/z 319.
4-Chlorocoumarin (6a) and 8-methyl-4-chlorocoumarin
(6b) were prepared in 80 and 76% isolated yields by
heating the corresponding 4-hydroxycoumarins with
The substrates 8a–f possess two potential sites for
Claisen rearrangement. The aryloxypropargyl ether
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00656-6

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K. C. Majumdar, T. Bhattacharyya / Tetrahedron Letters 42 (2001) 4231–4233
a one proton singlet at l 8.23 due to CHꢀOAr. The
mass spectrum of 9a showed a molecular ion peak at
m/z 319.
To test the generality of the reaction, the thermal
rearrangements of five other aryloxybutynylamines 8b–f
were studied. In the cases of 8b–e the products 9b–e
were obtained in 56–64% yields. However, substrate 9f
remained unchanged even after 20 h of heating.
Scheme 1.
The formation of products 9 from 8 may be explained
by an initial [3,3] sigmatropic rearrangement of the
propargylamine moiety of the substrate 8 to give the
allene intermediate 10, followed by imine–enamine tau-
tomerism, [1,5]H shift and electrocyclic ring closure to
give the unstable endocyclic intermediate 13 (not iso-
lated). A [1,3] prototropic shift in 13 may give the final
product 9 (‘pathway a’). This ‘pathway a’ derives sup-
port from our recent observation13 that in the case of
the thermal rearrangement of 4-[N-(4-aryloxybut-2-
ynyl],N-methylamino-6-methyl-2-pyrone both endo-
cyclic and exocyclic products are formed and the
endocyclic products are converted to exocyclic products
under the same reaction conditions. However, in the
present study, despite strenuous efforts, we could not
isolate product of the type 13 at all. One more pathway
may be considered. Another [1,5]H shift or tau-
tomerism may convert 12 to butadienyl derivative 14,
which may then undergo a ‘6-endo’cyclization to give 9
(‘pathway b’) (Scheme 4).
moiety may undergo an oxy-Claisen rearrangement,
while the vinylpropargyl-N-methylamine fragment may
undergo an amino-Claisen rearrangement. Hence these
substrates provide scope for studying the competition
between oxygen Claisen and amino-Claisen rearrange-
ments. It is well known that the amino-Claisen
rearrangement10 requires higher activation energies
than the oxygen Claisen rearrangement. However, the
activation energy required for the arylpropargyl ether
rearrangement11 is much higher than that of propar-
gylvinyl ether rearrangement.12
The substrate 8a was refluxed in o-dichlorobenzene for
19 h at 180°C to give 4-aryloxymethylene-1-methyl-
1,2,3-trihydropyrido[3,2-c][1]benzopyran-5-one 9a, mp
88°C, in 72% yield (Scheme 3).
Compound 9a was characterised from its elemental
analysis and spectroscopic data. The IR spectrum of 9a
showed wmax at 2910 cm−1 due to aromatic CH stretch-
ing and at 1680 cm−1 due to the carbonyl group. The
1H NMR spectrum revealed a two-proton triplet at l
2.82 (J=5.4 Hz) due to CH2-CH2-N, another two-pro-
ton triplet at l 3.34 (J=5.4 Hz) due to N-CH2-CH2 and
The occurrence of a [3,3] sigmatropic rearrangement at
the propargyl vinyl amine moiety in preference to the
arylpropargyl ether moiety in all the substrates (4a–e)
studied so far is noteworthy. In the present examples
Scheme 2.
Scheme 3.

K. C. Majumdar, T. Bhattacharyya / Tetrahedron Letters 42 (2001) 4231–4233
4233
Scheme 4.
the amino-Claisen rearrangement leads to the exclusive
formation of unusual products containing exocyclic
double bonds (9a–e), instead of the normal products
containing a endocyclic double bond (13). It is interest-
ing to note that the occurrence of an oxygen Claisen
rearrangement at an aryloxy propargyl ether moiety has
recently been reported in preference to rearrangement
of the vinyl propargylamine moiety of 5-N-(4-aryloxy-
but-2ynyl),N-methyl-1,3-dimethylpyrimidine-2,4-dione
during a thermal rearrangement.14
3. (a) Staunton, J. In Comprehensive Organic Chemistry;
Sammes, P. G., Ed.; Pergamon Press: Oxford, 1979; Vol.
4; (b) Hepworth, J. D. In Comprehensive Heterocyclic
Chemistry; Boulton, A. J.; Mckillop, A., Eds.; Pergamon
Press: Oxford, 1984; Vol. 3, p. 799.
4. Majumdar, K. C.; Khan, A. T.; De, R. N. Synth. Com-
mun. 1988, 18, 1589.
5. Majumdar, K. C.; Das, D. P.; Khan, A. T. Synth.
Commun. 1988, 18, 2027.
6. Dholakia, V. N.; Trivedi, K. N. J. Indian Chem. Soc.
1971, 48, 344.
7. (a) Majumdar, K. C.; De, R. N.; Khan, A. T.; Chatto-
padhyay, S. K.; Dey, K.; Patra, A. J. Chem. Soc., Chem.
Commun. 1988, 777; (b) Majumdar, K. C.; De, R. N. J.
Chem. Soc., Perkin Trans. 1 1989, 1901.
8. (a) Majumdar, K. C.; Khan, A. T.; Das, D. P. Synth.
Commun. 1989, 19, 917; (b) Ahluwalia, V. K.; Gupta, M.
C.; Mehta, S. Indian J. Chem. 1979, 17B, 395.
9. Kawahara, N.; Nakajima, T.; Itoh, T.; Ogura, H. Chem.
Pharm. Bull. 1985, 33, 4740.
Acknowledgements
We are thankful to CSIR (New Delhi) for financial
assistance.
References
10. Marcinkiewcz, S.; Green, J.; Mamalis, P. Tetrahedron
1961, 14, 208.
11. (a) Zsindely, J.; Schmidt, H. Helv. Chim. Acta 1968, 51,
1510; (b) Majumdar, K. C.; Thyagarajan, B. S.; Bala-
subramanian, K. K. J. Heterocycl. Chem. 1973, 10, 159.
12. Claisen, L. Berichte 1912, 45, 3157.
13. Majumdar, K. C.; Ghosh, S. Tetrahedron 2001, 57, 1589.
14. Majumdar, K. C.; Jana, N. K. Synth. Commun. 2000, 30,
4183.
1. (a) Feur, G. In Progress in Medicinal Chemistry; Ellis, G.
P.; West, G. B., Eds.; North-Holland Publishing Com-
pany: New York, 1974; (b) Lauger, V. P.; Martin, H.;
Muller, P. Helv. Chim. Acta 1994, 27, 892; (c) Soine, T. J.
Pharm. Sci. 1964, 53, 231.
2. (a) Deana, A. A. J. Med. Chem. 1983, 26, 580; (b)
Gordon, M.; Grover, S. H.; Strothers, J. B. Can. J.
Chem. 1973, 51, 2092; (c) Wenkert, E.; Buckwalter, B. L.
J. Am. Chem. Soc. 1972, 94, 4367.
.