Microwave-assisted Claisen rearrangement. Application to the synthesis of Angelicin derivatives

Article abstract of DOI:10.1002/jhet.5570430336

4-(Hydroxy, chloro, amino, acetoxy and methoxy)-methyl- 4,5-dimethylangelicins were efficiently and rapidly synthesized via Claisen rearrangement of 4-methyl-7-[4-(hydroxy, chloro, amino, acetoxy and methoxy)-but-2-ynyloxy]-coumarins respectively under mi

Full text of DOI:10.1002/jhet.5570430336

May-Jun 2006
763
Microwave-assisted Claisen rearrangement. Application to the
Synthesis of Angelicin Derivatives
Hassan Valizadeh * a and Abbas Shockravi b
aDepartment of Chemistry, Faculty of Science, Azarbaydjan University of Tarbiat-Moallem, P. O. Box 53714-
161, Tabriz, Iran. b Faculty of Chemistry, Teacher Training University of Tehran, Tehran, Iran.
Received April 1, 2005
Me
X
Me
microwave irradiation
O
X
O
O
O
O
O
DEA
CH2
CH3
1
2
4'-(Hydroxy, chloro, amino, acetoxy and methoxy)-methyl- 4,5'–dimethylangelicins were efficiently and
rapidly synthesized via Claisen rearrangement of 4-methyl-7-[4-(hydroxy, chloro, amino, acetoxy and
methoxy)-but-2-ynyloxy]-coumarins respectively under microwave irradiation. Prominent among the
advantages of this new method are operational simplicity, good yields in short reaction times and easy
work-up procedures employed.
J. Heterocyclic Chem., 43, 763 (2006).
Furocoumarins, such as the angular angelicin and the
rearrangemant of the prop-2-ynyloxy benzen derivatives
[11]. Majumdar et al. have reported the regioselective
synthesis of pyrano[2,3-c]coumarins from aryloxybut-2-
ynyloxy coumarins [12]. Otter et al. studied the Claisen
linear psoralen (Figure 1), are natural products derived
from umbelliferone (7-hydroxycoumarin), which are
present in members of the Apiaceae, Leguminosae,
Rutaceae and Umbelliferae families [1]. Furocoumarins
are active photosensitizing drugs widly used in photo-
medicine [2]. Furocoumarin/ultraviolet therapy, known as
photopheresis, has recently been used for treatment of
cutaneous T cell lymphoma, Sezary syndrome and related
diseases [3,4]. Photochemotherapeutic effect of furo-
coumarins is based on intercalation of the furocoumarin
molecule between pyrimidine bases of the microorganism
DNA [5].
Given the interest in furocoumarins, it is no surprise
that numerous synthetic ways to these compounds have
been reported [6]. Most approaches can be seen as
belonging to one of two types: 1) fusion of a furan ring to
a coumarin derivative and 2) fusion of a pyrone ring to a
benzofuran derivative.
rearrangement of 5-(prop-2-ynyloxy)-uracil under
variety of conditions [13].
a
In this paper we wish to report the facile and
inexpensive route to preparation of 4'-(hydroxy, chloro,
amino, methoxy and acethoxy)methyl- 4,5'–dimethyl-
angelicins via Claisen rearrangement under microwave
irradiation.
The starting materials 4-methyl-7-[4-(hydroxy, chloro,
amino, acetoxy and methoxy)-but-2-ynyloxy)-coumarins
4(a-e) were prepared as mentioned in Figure 1.
Compounds 4(a-e) were placed in an house hold
microwave oven for (20-30) minutes, products were
purified by column chromatography and identified as
related angelicins 5(a-e) Figure 2. Negligible amounts of
psoralens were detected in this methodology. The reaction
was tested under thermal conditions also, but monitoring
of the reaction by TLC in different solvent systems
visualizing spots with UV lamp or iodine vapour show
that in no case the progress of reaction was noticeable.
Hydroxy and amino functional groups on the
angelicins, lead to increasing of the lipophilic character of
these compounds [7]. In many cases aminomethyl-
angelicins were synthesized by a three-step technique
involving initial chloromethylation, displacement of the
halide by potassium phthalimide, and subsequent
hydrazinolysis of phthalimidomethyl angelicin [8,9].
A survey of the literature revealed that the Claisen
rearrangement under microwave irradiation has received
little attention in the past [10]. There are several thermal
methods for the preparation of five-membered hetero-
cyclic ring in benzo[b]thiophenes and indoles via Claisen
EXPERIMENTAL
All of melting points were determined on an Electrothermal
9100 apparatus and are uncorrected. IR spectra were recorded on
a Perkin-Elmer model 843. 1H-NMR spectra were recorded on a
Bruker Avance 500 MHz or JEOL FX90 MHz instruments.
Mass spectrum was obtained on Shimadzu QP 1100EX
instrument. Analytical calculation was obtained on LECO

764
H. Valizadeh and A. Shockravi
Vol 43
OBz
Me
O
Me
O
K2CO3
+
TsOCH2
CH2OBz
HO
O
acetone, reflux
96%
O
O
1
2
3
2CO3
K
methanol
reflux
98%
OH
O
Me
O
OAc
Me
CH3COCl, CH3CN
H2O, KOH, 91%
O
O
O
O
4a
pyridine
91%
SOCl2
Cl
4d
Me
O
O
O
1) potassium phthalimid
4b
2) hydrazine hydrate
75%
MeOH, reflux
71%
OMe
NH2
Me
O
Me
O
O
O
O
O
4e
4c
Figure 1
Me
X
Me
microwave irradiation
DEA
O
X
O
O
O
O
O
CH2
CH3
(4a) X = OH
(4b) X = Cl
(5a) X = OH
(5b) X = Cl
(4c) X = NH2
(4d) X = OAc
(4e) X = OMe
(5c) X = NH2
(5d) X = OAc
(5e) X = OMe
Figure 2

May-Jun 2006
Microwave-assisted Claisen rearrangement
765
CHNO-932 Analyzer instrument. MIele Electronic M720 domestic
oven was used for microwave irradiation.
methylen), 6.31(s, 1H, olefinic CH), 7.1(d, J =7.7,1H, aromatic
proton), 7.3 (d, J =7.7, 1H, aromatic proton); 13C-NMR (CDCl3):
ꢀ 8.5, 20.7, 21.2, 49.7, 108.3, 111.4, 112.5, 114.6, 118.2, 122.1,
148.6, 150.4, 152.7, 152.8, 160.9, 170.3. IR (KBr disc), ꢁ, cm-1:
1725(C=O), 1620(C=C). EIMS (EI, 70ev) m/z: (M+ 286).
Anal. Calcd. for C16H14 O5: C, 67.13; H, 4.89. Found: C
67.15. H 4.9.
Preparation of Angelicins.
General Procedure.
Compounds 4(a-e) (0.008 mol) was dissolved in N,N-diethyl-
aniline (DEA, 5ml) in a sealed Teflon container (screw cap type, 25
ml). The mixture was subjected to microwave irradiation with
540W for 20-30 minutes. The progress of the reaction was moni-
tored by TLC. After the completion of the reaction, the intimate
mixture was taken up to cold water and the precipitated solid was
collected by filtration and washed with water. The crude was
directly subjected to column chromatography using chloroform/
ethylacetate (20/5) as eluent to obtain the related products.
Caution: Although we did not have any accident in this work,
it is highly recommended that the reaction should be performed
in an efficient hood.
4'-Methoxymethyl-4,5'-dimethylangelicin (5e).
1
Yield 62 %, m.p: 137-9 °C ; H-NMR (CDCl3, 90 MHz): ꢀ
2.41 (s, 3H, Me), 2.43 (s, 3H, Me), 3.48 (s, 3H, OMe), 4.3 (s,
2H, methylen), 6.31 (s, 1H, olefinic CH), 7.2(d, J =7.8, 1H,
aromatic proton), 7.3 (d, J =7.8, 1H, aromatic proton); 13C-NMR
(CDCl3): ꢀ 8.5, 21.2, 58.7, 58.9, 108.3, 111.4, 112.5, 114.6,
118.2, 122.1, 148.6, 150.4, 152.7, 152.8, 160.9. IR (KBr disc), ꢁ,
cm-1: 1725(C=O), 1610(C=C). EIMS (EI, 70ev) m/z: (M+ 258).
Anal. Calcd. for C15H14 O4: C, 69.76; H, 5.42. Found: C, 69.9;
H, 5.44.
Selected Data .
Acknowledgement.
4'-Hydroxymethyl-4,5'-dimethylangelicin (5a).
1
The office of the Research Vice Chancellor of Azarbaijan
University of Tarbiat Moallem supported this work.
Yield 56%, m.p: 201-202 °C; H-NMR (CDCl3, 500 MHz): ꢀ
2.467(s, 3H, Me), 2.476 (s, 3H, Me), 4.87 (s, 2H, methylen), 6.25 (s,
1H, olefinic CH), 7.31(d, J =7.8, 1H, aromatic proton), 7.42 (d, J
=7.8, 1H, aromatic proton); 13C-NMR (CDCl3): ꢀ 8.5, 21.2, 49.6,
108.3, 111.4, 112.5, 114.6, 118.2, 122.1, 148.6, 150.4, 152.7, 152.8,
160.9. IR (KBr disc), ꢁ, cm-1: 3220-3510 (O-H), 1700(C=O),
1610(C=C). EIMS (EI, 70ev) m/z: (M+ 244), 226, 198, 170.
Anal. Calcd. for C14H12O4: C, 68.8; H, 4.9. Found %: C, 67.7;
H, 5.2.
REFERENCES
*
Corresponding author. Fax: +98-412-4524991. e-mail:
h-valizadeh@azaruniv.edu
[1] D. Mal, M. Bandhyopadhyay, K. Datta, K. V. S. N. Murty,
Tetrahedron, 54, 7525 (1998) and references cited therein.
[2] J. A. Parrish, R. S. Stern, M. A. Pathak, T. B. Fitzpatrick, The
Science of Photomedicine, Plenum press: New York 595 (1982).
[3] R. L. J. Edelson, Photochem. Photobiol B: Biol., 10, 165
(1991).
4'-Chloromethyl-4,5'-dimethylangelicin (5b).
1
Yield 60%, m.p: 213-14 °C; H-NMR (CDCl3, 90 MHz): ꢀ
2.45 (s, 3H, Me), 2.42 (s, 3H, Me), 4.6 (s, 2H, methylen), 6.25
(s, 1H, olefinic CH), 7.30 (d, J =7.7, 1H, aromatic proton), 7.40
(d, J =7.7, 1H, aromatic proton); 13C-NMR (CDCl3): ꢀ 7.7, 21.2,
27.9, 108.3, 111.4, 112.5, 114.6, 118.2, 122.1, 148.6, 150.4,
152.7, 152.8, 160.9. IR (KBr disc), ꢁ, cm-1: 1710(C=O),
1620(C=C), EIMS (EI, 70ev) m/z: (M+ 262, M+2 264).
Anal. Calcd. for C14H11ClO3: C, 64.12; H, 4.2. Found: C,
64.15; H, 4.21.
[4] A. Guiotto, A. Chilin, P. Manzini, F. Dall’Aqua, F. P.
Bordin, Il Rodighiere, Farmaco 50, 479(1995).
[5] W. A. Saffran, F. P. Gasparro, In Psoralen DNA
Photobiology, Ed, CRC Press: INC. Boca Raton, Fl, Chapter 6, 73,
(1998).
[6] E. J. Bisagni, Photochem. Photobiol 14, 23 (1992).
[7] J. A. Parrish, T. B. Fitzpatrick, L. Tanenbaum, M. A. J.
Pathak, Invest. Dermatol, 68, 628 (1997).
4'-Aminomethyl-4,5'-dimethyl angelicin (5c).
[8a] K. D. U. S. Kaufman, Patent 4,294,822, (1981); Chem.
Abstr., 96, 35224k, (1982). [8b] S. T. Isaacs, C. J. Shen, J. E. Hearst, H.
Rapoport, Biochemistry, 16, 1058, (1977).
1
Yield 52%, m.p: 238-243 °C; H-NMR (CDCl3, 90 MHz): ꢀ
2.43(s,3H, Me), 2.40(s,3H, Me), 2.81(s,2H, NH2), 4.0(s,2H,
methylen), 6.31(s,1H, olefinic CH), 7.3(d, J =7.8,1H, aromatic
proton), 7.4(d, J =7.8, 1H, aromatic proton); 13C-NMR (CDCl3):
ꢀ 8.2, 21.2, 34.0, 108.3, 111.4, 112.5, 114.6, 118.2, 122.1, 148.6,
150.4, 152.7, 152.8, 160.9. IR (KBr disc), ꢁ, cm-1: 3300-3500
(NH2),1715(C=O), 1615(C=C). EIMS (EI, 70ev) m/z: (M+ 243).
Anal. Calcd. for C14H13 NO3: C, 69.13; H, 5.34. Found: C,
69.16; H, 5.36; N, 5.71.
[9] K. D. Kaufman, D. J. Erb, T. M. Blok, R. W. Carlson D. J.
Knoechel, L. McBride, T. J. J. Zeitlow, Heterocyclic Chem. 19, 1051,
(1982).
[10a] K. C. Majumdar, B. S. Thyagarajan, J. Chem. Soc., Chem.
Commun., 83 (1972); [b] J. B. Hillard, K. V. Reddy, K. C. Majumdar,
B. S. Thyagarajan, Tetrahedron Lett., 1999 (1974).
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93, (1972).
[12] J. B. Hillard, K. V. Reddy, K. C. Majumdar, B. S.
Thyagarajan, Tetrahedron Lett., 1999 (1974).
4'-Actoxymethyl-4,5'-dimethylangelicin (5d).
1
Yield 48%, m.p: 108-10 °C ; H-NMR (CDCl3, 90 MHz): ꢀ
2.40(s, 3H, Me), 2.43(s, 3H, Me), 2.48(s, 3H, OAc), 4.2(s, 2H,
[13] B. A. Otter, S. S. Saluja, J. J. J. Fox, J. Org. Chem., 37, 2858
(1972).