The Michael reaction of N-cinnamoylazoles with phenols. A simple synthesis of 4-arylchroman-2-ones and 1-arylbenzo[f]chroman-3-ones

Article abstract of DOI:10.1055/s-2000-6233

4-Arylchroman-2-ones 3 and 1-arylbenzo[f]chroman-3-ones 6 have been prepared in moderate to good yields by reaction of dihydric or trihydric phenols with p-substituted N-cinnamoylazoles in dichloromethane under reflux in the presence of DBU.

Full text of DOI:10.1055/s-2000-6233

PAPER
123
The Michael Reaction of N-Cinnamoylazoles with Phenols. A Simple Synthesis
of 4-Arylchroman-2-ones and 1-Arylbenzo[f]chroman-3-ones
Giovanna Speranza,* Carlo F. Morelli, Paolo Manitto
Dipartimento di Chimica Organica e Industriale, Università di Milano and Centro di Studio per le Sostanze Organiche Naturali, CNR,
via Venezian 21, I-20133 Milano, Italy
Fax: +39(2)2364369; E-mail: giovanna.speranza@unimi.it
Received 3 August 1999
We have recently shown that 4-arylchroman-2-ones 3 and
Abstract: 4-Arylchroman-2-ones 3 and 1-arylbenzo[f]chroman-3-
1-arylbenzo[f]chroman-3-ones 6 can be easily obtained
ones 6 have been prepared in moderate to good yields by reaction of
dihydric or trihydric phenols with p-substituted N-cinnamoylazoles
by the one-pot two-component [3+3] coupling reaction4
depicted in the Scheme (Y = OMe; reaction conditions :
o-xylene under reflux without any catalyst added).3 This
reaction provides especially high yields in lactones when
the cinnamate educt bears an electron-releasing group in
the para position. Thus, in accordance with this tendency,
no reaction was observed with methyl p-nitrocinnamate.
in dichloromethane under reflux in the presence of DBU.
Key words: Michael reaction, N-cinnamoylazoles, 4-arylchroman-
2-ones, 1-arylbenzo[f]chroman-3-ones, phenols
The hydroxy- and/or methoxy-substituted 4-arylchroman-
2-one system is of relevant interest in that it is present in
a number of natural molecules, e.g. neoflavonoids.1 In ad-
dition it represents a valuable intermediate in the prepara-
tion of 4-arylcoumarins.2
We report here a novel mild procedure, which can be re-
garded as complementary to that mentioned above. In
fact, it appears to be particularly convenient for preparing
compounds such as 3 and 6 wherein X is an electron-with-
drawing group. This method (Scheme, Y = N-azolyl
group) is based on the conjugated additions5 of di- and tri-
hydric phenols to N-(E)-cinnamoylazoles (“azolides”)6 in
which the masked carboxy group promotes the attack of
both a soft nucleophile on the β-carbon (C-C bond forma-
tion) and of a hard nucleophile on the carbonyl group (O-
C bond formation).
The simplest synthetic approach to 4-arylchroman-2-ones
consists in the condensation of phenols with cinnamic ac-
ids (or methyl cinnamates) as well as in the cyclization of
phenyl cinnamates. Strong acidic media and different
Lewis acids have been widely explored to construct the
heterocyclic ring, but complex mixtures of reaction prod-
ucts were observed in all cases.3
HO
O
O
HO
O
O
O
Y
3
1
1'
HO
OH
4
+
+
- HY
4'
1'
OH
OH
OH
1
X
X
X
3a,b
4a,b
2a,b
X
X
1'
4'
O
1'
1
3
O
OH
- HY
10
2a-i
+
O
O
+
4a
3
OH
5
1
7
OH
OH
6a-g
7a, c-e
X = OMe, Me, H, F, Cl, Br, NO2
N
N
;
N
Y =
N
N
Scheme
See Table 1 for substituents on specific compounds
Synthesis 2000, No. 1, 123–126 ISSN 0039-7881 © Thieme Stuttgart · New York

124
G. Speranza et al.
PAPER
Table 1 Condensation of Di- and Trihydric Phenols with N-Cinnamoylazoles in the Presence of DBU
Entry
Reagents
X
Ya
Solvent
under reflux
Reaction time
(h)
Productb/Yield (%)c
L/Ed
1
2
1/2a
1/2b
5/2c
5/2d
5/2a
5/2e
5/2f
5/2g
5/2b
5/2h
5/2i
H
Im
Im
Im
Im
Im
Im
Im
Im
Im
Taz
Taz
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
2.0
1.5
2.0
2.0
1.5
2.5
1.5
1.5
1.0
2.0
2.0
3a/38 ; 4a/17
3b/55 ; 4b/5
6c/31 ; 7c/30
6d/37 ; 7d/15
6a/50 ; 7a/12
6e/62 ; 7e/9
6f/75
2.2
11.0
1.0
NO2
OMe
Me
H
3
4
2.5
5
4.1
6
F
6.8
7
Cl
8
Br
6g/72
9
NO2
OMe
H
6b/80
10
11
6c/51 ; 7c/21
6a/67 ; 7a/13
2.4
5.2
THF
a Im = N-imidazolyl, Taz = 1,2,4-triazol-1-yl.
b All compounds gave satisfactory elemental analyses: C 0.35, H 0.29.
c Isolated yields from cinnamic acids.
d Lactone/ester ratio.
The general procedure described below was used for pre- the corresponding chromanones 3 and 6, respectively, un-
paring the 4-arylchroman-2-ones 3a,b and the 1-arylben- der the reaction conditions.
zo[f]chroman-3-ones 6a-g listed in Table 1. The structure
It can be noticed that the yields in chromanones from ex-
periments 3-6 (Table 1), and also the corresponding ra-
tios between the 1,4- and 1,2-adducts (L/E), roughly
of each product was confirmed by the spectral data report-
ed in Table 2.
The solvent of general applicability for the condensation correlate with the Hammet constants10 of the substituents
of imidazolides with phenols appears to be dichlo- on the N-cinnamoylimidazole.
romethane under reflux. Other polar solvents, e.g. hydro-
Azolides, usually imidazolides, are well recognised reac-
gen-bond acceptors such as THF and DMSO, afforded,
tive forms of carboxylic acids for preparing esters, amides
even at different temperatures, lower yields in lactones
and other derivatives.6 However, to our knowledge, the
(and higher in esters). An approximate. 1:1 molar ratio be-
1,4-addition of phenols to N-cinnamoylazoles is an un-
precedented example of the use of α,β-unsaturated
azolides as conjugate acceptors in a base-promoted
tween the phenolic educt and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) was found to be optimal. We have also
examined a few other azolides as conjugate acceptors us-
Michael reaction.5
ing naphthoresorcinol (5) as reference donor and varying
the azolyl group [4(5)-nitroimidazol-1-yl,7 1,2,4-triazol-
1-yl,8 1,2,3-triazol-1(2)-yl9], the para-substituent on the
Mps (Büchi apparatus) are uncorrected. Microanalyses were ob-
1
tained with a Perkin-Elmer 240 Elemental Analyzer. H- and 13C
benzene ring, and the solvent. Satisfactory yields in chro-
NMR spectra were recorded on a Bruker AC 300 or on a Bruker AC
manones were obtained with only two 1,2,4-triazolides
200 spectrometer in DMSO-d6, using the solvent signal as internal
(entries 10 and 11, Table 1), the solvent being THF in both
standard (δH 2.50, δC 39.50). Silica gel (Merck, 40-63 µm) was
used for flash chromatography. Analytical TLC was performed on
cases.
Si gel 60 F254 aluminum sheets (0.2 mm thickness, Merck) using the
following eluents: A (CHCl3:EtOAc, 3:5), B (CHCl3:EtOAc, 5:1).
noted that monohydric phenols and naphthols (as well as
As concerns the reactivity of phenolic educts, it must be
All reagents were of commercial quality or purified prior to use by
standard methods. Cinnamic acid, p-methoxy-, and p-nitrocinnamic
acids were commercially available. The other cinnamic acids were
synthesized by condensation of the corresponding aldehydes with
malonic acid in pyridine soln in the presence of piperidine.11
resorcinol) did not give rise to the corresponding chro-
manones even when the counterpart was the highly reac-
tive N-(p-nitrocinnamoyl)imidazole.
From a mechanistic point of view, it is reasonable to as-
sume an initial conjugate addition5 followed by lactone
formation.6 An alternative path, wherein these two bond-
forming steps are reversed, is to be ruled out by the obser-
vation that aryl cinnamates 4 and 7 are not converted into
Compounds 3 and 6; General Procedure
To a soln of cinnamoyl chloride (prepared from 1.2 mmol of cin-
namic acid by the standard procedure using oxalyl chloride) in an-
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The Michael Reaction of N-Cinnamoylazoles with Phenols
125
Table 2 Chromanones (3a,b, 6a–g) Prepared
Product Rf (eluent)a Mp (°C)
1H NMR (DMSO-d6)
d, J (Hz)
13C NMR (DMSO-d6)
d
3a
3b
6a
6b
0.52 (A)
0.49 (A)
0.59 (B)
0.56 (B)
209–210
2.86 (br d, 1 H, J = 15.6, H-3a), 3.21 (dd, 1 H, J = 15.6, 6.8, 33.88, 37.11, 94.88, 98.98, 103.81,
H-3b), 4.49 (br d, 1 H, J = 6.8, H-4), 6.07 (d, 1 H, J = 2.1) 126.66, 128.58, 142.56, 153.06,
and 6.22 (d, 1 H, J = 2.1) (H-6, H-8), 7.09–7.13 (m, 2 H) and 155.43, 158.02, 167.73
7.21–7.30 (m, 3 H) (Ar-H), 9.48 (s, 1 H) and 9.65 (s, 1 H)
(Lit16 210–211)
(5-OH, 7-OH)
210–212
222–223
182–184
2.87 (br d, 1 H, J = 15.7, H-3a), 3.28 (dd, 1 H, J = 15.7, 6.5, 33.90, 36.49. 94.99, 98.92, 101.92,
H-3b), 4.56 (br d, 1 H, J = 6.5, H-4), 6.03 (br s, 1 H) and
123.98, 128.14, 146.55, 150.43,
6.17 (br s, 1 H) (H-6, H-8), 7.34 (d, 2 H, J = 8.5, H-2’, H- 153.08, 155.57, 158.46, 167.41
6’), 8.14 (d, 2 H, J = 8.5, H-3’, H-5’), 9.56 (s, 1 H) and 9.78
(s, 1 H) (5-OH, 7-OH)
2.92 (dd, 1 H, J = 15.9, 1.0, H-2a), 3.45 (dd, 1 H, J = 15.9, 36.00, 37.54, 99.10, 108.35,
7.2, H-2b), 4.99 (dd, 1 H, J = 7.2, 1.0, H-1), 6.72 (s, 1H, H- 122.67, 123.11, 123.82, 126.77,
5), 7.01–7.31 (m, 5 H) and 7.34–7.52 (m, 2 H) (Ar-H), 7.75 127.00, 127.68, 128.88, 131.44,
(d, 1 H, J = 8.2, H-10), 8.16 (d, 1 H, J = 8.5, H-7), 10.68 (s, 142.19, 149.76, 154.40, 167.42
1 H, 6-OH)
2.99 (br d, 1 H, J = 16.0, H-2a), 3.55 (dd, 1 H, J = 16.0, 7.1, 35.78, 36.99, 99.20, 107.27,
H-2b), 5.21 (br d, 1 H, J = 7.1, H-1), 6.75 (s, 1 H, H-5), 7.41 122.89, 123.00, 124.11, 124.21,
(d, 2 H, J = 8.6, H-2’, H-6’), 7.38–7.53 (m, 2 H, H-8, H-9), 128.02, 128.42, 128.72, 131.37,
7.74 (d, 1 H, J = 8.1, H-10), 8.15 (d, 2 H, J = 8.6, H-3’, H- 131.65, 146.74, 149.98, 154.88,
5’), 8.18 (d, 1 H, J = 8.3, H-7), 10.76 (s, 1 H, 6-OH)
167.07
6c
0.55 (B)
0.62 (B)
176–178
see Ref. 15
see Ref. 15
(Lit15 176–178)
6d
174–177
2.22 (s, 3 H, CH3), 2.90 (br d, 1 H, J = 16.5, H-2a), 3.42 (dd, 20.38, 35.57, 37.53, 99.00, 108.42,
1H, J = 16.5, 6.9, H-2b), 4.95 (br d, 1H, J = 6.9, H-1), 6.74 122.55, 123.02, 123.66, 126.54,
(s, 1 H, H-5), 7.01 (d, 2 H, J = 8.6) and 7.10 (d, 2 H, J = 8.6) 127.50, 128.64, 129.32, 131.34,
(H-2’, H-3’, H-5’, H-6’), 7.35–7.57 (m, 2 H, H-8, H-9), 7.75 136.07, 139.04, 149.59, 154.22,
(d, 1 H, J = 8.4, H-10), 8.14 (d, 1 H, J = 8.4, H-7), 10.67 (s, 167.34
1 H, 6-OH)
6e
0.61 (B)
215–217
2.96 (br d, 1 H, J = 15.8, H-2a), 3.45 (dd, 1 H, J = 15.8, 7.0, 35.12, 37.44, 99.03, 107.97, 115.51
H-2b), 5.04 (br d, 1 H, J = 7.0, H-1), 6.75 (s, 1 H, H-5),
(2JC,F = 21 Hz), 122.61, 122.91,
7.08–7.24 (m, 4 H, H-2’, H-3’, H-5’, H-6’), 7.42 (approx. t, 12§.74, 127.63, 128.63 (3JC,F = 5
1 H, J = 7.5) and 7.51 (app t, 1 H, J = 7.5) (H-8, H-9), 7.76 Hz), 131.21, 137.78, 149.38,
(d, 1 H, J = 8.3, H-10), 8.19 (d, 1 H, J = 8.2, H-7), 10.66 (s, 154.46, 160.86 (1JC,F = 246 Hz),
1 H, 6-OH)
167.00
6f
0.57 (B)
0.57 (B)
210–211
230–232
2.93 (br d, 1 H, J = 15.6, H-2a), 3.47 (dd, 1 H, J = 15.6, 7.0, 35.23, 37.22, 99.02, 107.80,
H-2b), 5.02 (br d, 1 H, J = 7.0, H-1), 6.71 (s, 1 H, H-5), 7.13 122.62, 122.89, 123.78, 127.66,
(d, 2 H, J = 8.7, H-2’, H-6’), 7.32 (d, 2 H, J = 8.7, H-3’, H- 128.64, 128.74, 131.24, 131.63,
5’), 7.35–7.58 (m, 2 H, H-8, H-9), 7.75 (d, 1 H, J = 8.1, H- 141.00, 149.72, 154.47, 167.11
10), 8.17 (d, 1 H, J = 8.2, H-7), 10.66 (s, 1 H, 6-OH)
6g
2.93 (br d, 1 H, J = 15.2, H-2a), 3.46 (dd, 1 H, J = 15.2, 7.2, 35.28, 37.14, 99.00, 107.73,
H-2b), 5.02 (br d, 1 H, J = 7.2, H-1), 6.64 (s, 1 H, H-5), 7.08 120.08, 122.60, 122.90, 123.78,
(d, 2 H, J = 7.9, H-2’, H-6’), 7.49 (d, 2 H, J = 7.9, H-3’, H- 127.67, 129.00, 131.24, 131.68,
5’), 7.35–7.58 (m, 2 H, H-8, H-9), 7.73 (d, 1 H, J = 8.0, H- 141.46, 149.71, 154.45, 167.10
10), 8.18 (d, 1 H, J = 8.0, H-7), 10.65 (s, 1 H, 6-OH)
a See experimental section for eluents.
hyd CH2Cl2 (5 mL) was added dropwise a soln of imidazole (2.4
mmol) in anhyd CH2Cl2 (10 mL) at 0 °C. After stirring for 1 h at r.t.,
the precipitated imidazolium chloride was filtered off and the fil-
trate was evaporated under reduced pressure. The resulting N-cin-
namoylimidazole (87% yield), mp 131-133 °C (Lit.12 mp 133-
134 °C), was used in the next step without further purification. The
other N-acylazoles were prepared in a similar manner6 in ≥ 80%
yield using dry CH2Cl2 or THF as solvent.
To a suspension of the phenol and of the N-acylazole, as obtained
above, (1:1 molar ratio) in dry CH2Cl2 (or THF) (10 mL) under N2
was added DBU (1.5 mL) in anhyd CH2Cl2 (or THF) (5 mL). The
reaction mixture was refluxed with stirring until TLC (eluent A or
B) showed complete disappearance of the phenol, and then acidified
with 0.2 N HCl. The organic layer was separated and the aqueous
phase was extracted with EtOAc. The combined organic extracts
were dried (Na2SO4), filtered, concentrated under reduced pressure
and the residue chromatographed on silica gel using a CHCl3/
Synthesis 2000, No. 1, 123–126 ISSN 0039-7881 © Thieme Stuttgart · New York

126
G. Speranza et al.
PAPER
EtOAc gradient for elution. Each isolated product was recrystal-
lized from proper solvent and its purity checked by TLC and ele-
mental analysis.
4a: Rf = 0.62 (eluent A); mp 198-200 °C (Lit.13 mp 200-202 °C),
see reference 14 for NMR data.
References
(1) Donnelly, D. M. X.; Boland, G. In The Flavonoids. Advances
in Research since 1986; Harborne, J. B., Ed.; Chapman &
Hall: London, 1993; p 239.
(2) Panetta, J. A.; Rapoport, H. J. Org. Chem. 1982, 47, 946.
(3) Speranza, G.; Di Meo, A.; Zanzola, S.; Fontana, G.; Manitto,
P. Synthesis 1997, 931, and refs. cited therein.
(4) Posner, G. H. Chem. Rev. 1986, 86, 831.
(5) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
(6) Staab, H. A. Angew. Chem. Int. Ed. Engl. 1962, 1, 351.
(7) Fife, T. H.; Natarajan, R.; Werner, M. H. J. Org. Chem. 1987,
52, 740.
(8) Temple, C. The Chemistry of Heterocyclic Compounds.
Triazoles 1,2,4; Wiley: New York, 1992, p 121.
Potts, K. T.; Crawford, T. H. J. Org. Chem. 1962, 27, 2631.
(9) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles.
Structure, Reactions, Syntheses and Applications; Thieme:
Stuttgart, 1995; p 200.
4b: Rf = 0.54 (eluent A); mp 231-233 °C.
1H NMR (300 MHz, DMSO-d6): δ = 6.09 (br s, 2H) and 6.18 (d, 1H,
J = 2.0 Hz) (H-2, H-4, H-6), 7.02 (d, 1H, J = 16.0 Hz, H-2′), 7.94
(d, 1H, J = 16.0 Hz, H-3′), 8.10 (d, 2H, J = 8.5 Hz, H-5′, H-9′), 8.29
(d, 2H, J = 8.5 Hz, H-6′, H-8′), 9.52 (s, 2H, 3-OH, 5-OH).
7a: Rf = 0.68 (eluent B); mp 144-146 °C.
1H NMR (200 MHz, DMSO-d6): δ = 6.71 (d, 1H, J = 2.0 Hz) and
7.19 (d, 1H, J = 2.0 Hz) (H-2, H-4), 6.92 (d, 1H, J = 16.0 Hz, H-2′),
7.40-7.56 (m, 5H) and 7.69-7.85 (m, 3H) (Ar-H), 7.90 (d, 1H,
J = 16.0 Hz, H-3′), 8.13 (d, 1H, J = 8.2 Hz, Ar-H), 10.52 (s, 1H, 1-
OH).
7c: Rf = 0.66 (eluent B); mp 167-169 °C, see reference 15 for NMR
data.
(10) March, J. Advanced Organic Chemistry, 4th ed., Wiley: New
York, 1992; p 280.
7d: Rf = 0.67 (eluent B); mp 131-134 °C.
(11) Copinga, S.; Tepper, P. G.; Grol, C. J.; Horn, A. S.;
Dubocovich, M. L. J. Med. Chem. 1993, 36, 2891.
(12) Staab, H. A.; Lüking, M.; Dürr, F. H. Chem. Ber. 1962, 95,
1275.
(13) Krajniak, E. R.; Ritchie, E.; Taylor, W. C. Aust. J. Chem.
1973, 26, 899.
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(15) Speranza, G.; Di Meo, A.; Manitto, P.; Monti, D.; Fontana, G.
J. Agric. Food Chem. 1996, 44, 274.
1H NMR (200 MHz, DMSO-d6): δ = 2.33 (s, 3H, CH3), 6.72 (brs,
1H, Ar-H), 6.87 (d, 1H, J = 16.0 Hz, H-2′), 7.03-7.86 (m, 9H, Ar-
H and H-3′), 8.13 (d, 1H, J = 8.0 Hz, Ar-H), 10.51 (s, 1H, 1-OH).
7e: Rf = 0.68 (eluent B); mp 135-137 °C.
1H NMR (200 MHz, DMSO-d6): δ = 7.00-7.17 (m, 3H), 7.31-7.49
(m, 4H), 7.73-7.80 (m, 2H), 7.94-8.03 (m, 3H), 9.56 (s, 1H, 1-
OH).
(16) Nair, V. Synth. Commun. 1987, 17, 723.
Acknowledgement
We thank MURST (Italy) for financial support.
Article Identifier:
1437-210X,E;2000,0,01,0123,0126,ftx,en;P04699SS.pdf
Synthesis 2000, No. 1, 123–126 ISSN 0039-7881 © Thieme Stuttgart · New York