A mild and convenient one-pot photochemical synthesis of chroman-4-one derivatives. the photo-Fries rearrangement of (hetero)aryl 3-methyl-2-butenoate esters under basic catalysis

Article abstract of DOI:10.1016/j.tetlet.2010.06.063

The biphasic base catalysis-mediated photo-Fries rearrangement reaction of aryl 3-methy-2-butenoate esters in room temperature cyclohexane - 10% KOH system was investigated. This mild photochemical reaction leads to the formation of chroman-4-one derivatives in good to high yield and in short reaction times (30-120 min) in a one-pot photochemical reaction. Also, the photochemical reaction, as a convenient, versatile, and general method, applies efficiently to polycyclic and heterocyclic 3-methy-2-butenaote esters.

Full text of DOI:10.1016/j.tetlet.2010.06.063

Tetrahedron Letters 51 (2010) 4387–4390
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Tetrahedron Letters
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A mild and convenient one-pot photochemical synthesis of chroman-4-one
derivatives. The photo-Fries rearrangement of (hetero)aryl
3-methyl-2-butenoate esters under basic catalysis
*
Cecilia Samaniego López, Rosa Erra-Balsells, Sergio M. Bonesi
CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, 3er Piso,
Ciudad Universitaria,1428, Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 March 2010
Revised 4 June 2010
Accepted 12 June 2010
Available online 17 June 2010
The biphasic base catalysis-mediated photo-Fries rearrangement reaction of aryl 3-methy-2-butenoate
esters in room temperature cyclohexane—10% KOH system was investigated. This mild photochemical
reaction leads to the formation of chroman-4-one derivatives in good to high yield and in short reaction
times (30–120 min) in a one-pot photochemical reaction. Also, the photochemical reaction, as a conve-
nient, versatile, and general method, applies efficiently to polycyclic and heterocyclic 3-methy-2-buten-
aote esters.
Ó 2010 Elsevier Ltd. All rights reserved.
The synthesis, chemistry, occurrence in nature, and biological
activity of chromanones have been the subject of several compre-
hensive reviews.1 Chroman-4-ones are also important synthetic
intermediates for chromans, chromenes, and chromanols which
themselves posses diverse pharmacological properties such as
b-blockade, anticonvulsant, antiestrogen, and antimicrobial.1c Pre-
cocenes are modern pesticides with potent insect antijuvenile hor-
mone agents2 and cromakalim and related analogues, which are
discovered potassium channel openers,3 contain the benzopyrane
moiety. Also, mollugin, dihydrolapachenole, lapachenole, and their
6-methoxyderivatives contain the 2,2-dimethylnaphtho[1,2-b]pyr-
an moiety in their structures and show biological activity.4,5
Because of their widespread occurrence and valuable proper-
ties, numerous syntheses have been developed for the construction
of chroman-4-ones.6 The reported methods for the synthesis of
chroman-4-ones and benzochroman-4-ones are well documented
and involve: (i) condensation of phenols with 3,3-dimethylacrylic
acids or its derivatives (Friedel–Craft reaction together with
thermal Fries rearrangement);7 (ii) Claisen rearrangement of
propargyl ethers of phenols;8 and (iii) Knoevenagel condensation
of o-hydroxyacetophenones with aliphatic aldehydes and ketones
(Kabbe reaction).9 Perhaps the most convenient and practical
method is the base-catalyzed Knoevenagel condensation between
a 2-hydroxyacetophenone and an aldehyde. In turn, the requisite
acetophenones are usually readily available via a thermal Fries
rearrangement of the adduct obtained from an appropriate acid
(or derivative thereof) and a substituted phenol.10
An alternative methodology scarcely considered is the photo-
Fries rearrangement reaction as a key step in the synthesis of
chroman-4-ones depicted in Scheme 1a. Thus, o-hydroxy ketone
derivative II is an adequate key intermediate that can be easily
achieved after a photo-Fries rearrangement reaction of phenyl
3-methyl-2-butenoate ester III. Cyclization reaction of synthon II
could be carried out using different methodologies such as a base
(K2CO3, NaOH, PhONa, Et3N, piperidine, and morpholine) in reflux-
(a) Retrosynthetic approach.
OH
O
O
O
O
O
(III)
(II)
(I)
(b) Substrates studied.
O
O
O
O
O
O
1
2
3
O
O
O
O
O
N
O
4
5
* Corresponding author. Tel./fax: +54 11 4 576 3346.
E-mail address: smbonesi@qo.fcen.uba.ar (S.M. Bonesi).
Scheme 1. Aryl 3-methyl-2-butenoate esters studied and retrosynthetic analysis of
2,2-dimethyl-chroman-4-one.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.063

4388
C. S. López et al. / Tetrahedron Letters 51 (2010) 4387–4390
ing ethanol11 or K2CO3 in acetone12 at room temperature, where
the target molecule I is obtained in good chemical yield. Our pro-
posed alternative synthetic approach can be accomplished in a
one-pot base-mediated irradiation of compound III to afford di-
rectly the target molecule I without isolation of synthon II. Accord-
ing to our knowledge, Miranda et al. have only synthesized the
6-methoxy-2,2-dimethylchroman-4-one and 6-methoxy-2-meth-
ylchroman-4-one using the biphasic base-mediated photochemical
reaction successfully.13 Since the discovery of the photo-Fries rear-
rangement reaction in 196014, mechanistic elucidation of the
reaction rather than its use in synthesis has been devoted.15–18
Since the photo-Fries rearrangement of aryl 3-methyl-2-butenoate
esters 1–5 (see Scheme 1b) has not been investigated under base
catalysis conditions19 and, due to our interest on the photo-Fries
reaction,20 herein we report the photochemical studies of esters
1–5 in a biphasic base catalysis system to afford directly chro-
man-4-ones in good to high yield.
(see Table 1, entries 5 and 6, respectively). We also carried out
the photochemical reaction of 1 in the presence of perchloric acid
(homogeneous system) and again compound 1c was formed in
quantitative yield through a photo solvolysis process. Besides, irra-
diation of 1 with our standard condition but under oxygen atmo-
sphere affords compound 1c in 89% yield and some brownish
tarry residue is also formed (Table 1, entry 8). Therefore, the pho-
tochemical reactions were carried out under Argon atmosphere
(bubbling the biphasic system during 20 min before irradiation).
In order to analyze the effect of the excitation wavelength on
the biphasic base catalysis—mediated photochemical reaction
additional experiments were carried out. Thus, the photochemical
reaction of 2 under basic catalysis was performed at two different
wavelengths, 254 and 313 nm, and 2,2-dimethylnaphtho[1,2-
b]pyran-4-one (2a) was obtained in 93% and 95% yield, respec-
tively (compare entries 1 and 2 in Table 2). Similar results were
obtained when ester 3 was irradiated at two different excitation
wavelengths (compare entries 4 and 5 in Table 2) and chroman-
4-one (3a) was formed in high yield. Also, irradiation of ester 2
using benzene instead of cyclohexane, as the organic solvent of
the reaction system, affords chroman-4-one 2a in nearly quantita-
To begin we simply subjected ester 1 to our photochemical con-
ditions. Gratifyingly, these conditions afforded quantitatively 2,2-
dimethyl-chroman-4-one (1a) within 60 min (Table 1, entry 3).
To build from this result, the photoreaction of ester 1 was screened
against different base sources, acid sources, solvents, and different
excitation wavelength.
tive yield (see entry 3 in Table 2). These results mean that the low-
*
p,p excited
est singlet excited state, which is most likely to be
In the absence of base no chroman-4-one 1a formation was
seen after 120 min of irradiation. Instead, the expected photo-Fries
products were formed in fairly good yield (see Table 1, entry 1).
Then, changing the base source a noticeable drop of the yield of
1a was observed together with significant amounts of compounds
1b and 1c (see Table 1, entries 2 and 4). Thus, the use of the bipha-
sic system cyclohexane—KOH 10% aq is the optimized condition for
the photochemical reaction of ester 1 giving 2,2-dimethyl-chro-
man-4-one (1a) in quantitative yield (see Table 1, entry 3).
The use of benzene instead of cyclohexane in the biphasic sys-
tem for the photochemical reaction of 1 affords quantitatively
compound 1a. Besides, irradiation of 1 in acetonitrile in the pres-
ence of triethylamine (homogeneous system) gives phenol (1c) in
95% yield due to a photo solvolysis process induced by the amine
state,21 is the photo reactive excited state of esters 2 and 3. Photo-
sensitization experiment of 2 with benzophenone (kexc: 366 nm),
which is a triplet—energy donor,21 does not afford the chroman-4-
one 2a. In this regard, the lowest triplet excited state of ester 2, if
it is populated efficiently, does not give any photoproducts and
deactivates through a radiationless process.20b–d,21 Thus, our opti-
mal conditions were determined to be the first condition examined,
namely, 0.010 M of esters, hm (254 or 313 nm) in a biphasic system
(cyclohexane (2.5 mL) and KOH 10% aq (0.5 mL)) under Argon atmo-
sphere at room temperature. To the best of our knowledge, this is the
first example of a one-pot photochemical reaction of esters of the
type 1–5 for the synthesis of 2,2-dimethyl chroman-4-one deriva-
tives. Also, the procedure is much simpler, milder, regioselective
than other thermal reactions that need the use of Lewis acids and
harsh conditions (i.e. high reaction temperature).7,8,5
Extension of the methodology to heteroaryl esters 4 and 5 affor-
ded the chroman-4-one derivatives in high yields. It is interesting
Table 1
Photo-Fries rearrangement reaction of phenyl 3-methyl-2-butenoate ester (1)a
hν
OH
O
O
OH
O
O
(254 nm)
+
+
Table 2
O
Photo-Fries rearrangement reaction of (hetero)aryl 3-methyl-2-butenoate esters
Solvent
r.t., Ar
(2–5) in cyclohexane under basic catalysis (KOH 10% aq; biphasic system)a
1
1a
1b
1c
Entry
Esters
D
t (min)
Conv. (%)
Yield (%)
95d
93d
Entry
Conditions [Irradiation time (min)]
Conv. (%)
Yield (%)
1
2
3
2
10
100
100
100
O
10b
1a
1b
1c
10c
95d
O
1
2
Cyclohexane [120]
Cyclohexane
K2CO3 10% aq [60]
Cyclohexane
KOH 10% aq [60]
Cyclohexane
Et3N 0.10 M [60]
Benzene
KOH 10% aq [100]
MeCN
Et3N 0.10 M [75]
MeCN
90
69
—
22
41b
47
21
—
2a
O
4
5
3
30
100
100
89
95
30b
O
3
4
5
6
7
8
70
93
100
26
100
—
—
25
—
5
—
3a
30
—
O
O
O
6
7
4
5
30
40
90
100
100
95
O
4a
100
100
70
95
100
—
O
N
—
—
—
100
O
HClO4 0.10 M [75]
Cyclohexane
5a
Reaction conditions: 0.010 M of ester, excitation wavelength: 310 nm, quartz
89
KOH 10% aqc [60]
a
a
vessel, degassed solvent (2.5 mL), under Ar, room temperature. The yields are based
on the conversion of the starting material.
Reaction conditions: 0.010 M of 1, excitation wavelength: 254 nm, quartz ves-
sel, degassed solvent (2.5 mL), under Ar, room temperature. The yields are based on
the conversion of the starting material.
b
Standard conditions, excitation wavelength: 254 nm.
Standard conditions, organic solvent: benzene, excitation wavelength: 310 nm.
c
b
The para-isomer (1d) was also formed in 22% yield.
Standard condition, non-Argon degassed solution.
d
c
2-(1-Hydroxynaphthyl) isobutenyl ketone (2b) was formed in 5–6% yield.

C. S. López et al. / Tetrahedron Letters 51 (2010) 4387–4390
4389
to note that the 3,4-(methylenedioxy)phenyl 3-methyl-2-buteno-
ate (4) gave only one chroman-4-one derivative, the compound
4a, in our standard condition in quantitative yield (30 min of irra-
diation) with a noticeable regioselectivity (see entry 6 in Table 2).
The stereo-electronic repulsion between the n electrons of the car-
bonyl oxygen and the oxygen of the 3,4-methylenedioxy moiety
accounts for the regioselectivity observed. Likewise, 8-quinolyl
3-methyl-2-butenoate (5) is easily photocyclized to the corre-
sponding chroman-4-one derivative 5a in quantitative yields and
in 40 min according to our standard conditions (see Table 2, entry
7). The results shown in Table 2 prove that the biphasic base catal-
ysis-mediated photo-Fries rearrangement reaction of esters 2–5 is
a mild and general method for the synthesis of chroman-4-one
derivatives in high yields and with a noticeable regiochemistry.
With regard to mechanism, the findings herein and from other
studies13 led us to surmise that these biphasic photoreactions ad-
vance via 2-hydroxyphenone intermediates which are formed dur-
ing the photolysis of esters 1–5 and do not need to be isolated. To
rationalize the reaction mechanism we proposed that the whole
photochemical reaction of esters 1–5 takes place really in two con-
secutive steps: (i) the formation of the rearrangement product
(ortho-hydroxy ketone) photochemically and (ii) the thermal intra-
molecular cyclization of the ortho-isomer to the corresponding
chroman-4-one through an intramolecular oxa-Micheal addition
reaction. A simplified mechanism for this reaction is shown in
Scheme 2, where kd means all the deactivation processes (fluores-
cence emission and internal conversion) that compete with the
photochemical reaction kr. The success of the thermal reaction
can be ascribed to the polarization of the double bond, due to con-
jugation with the ketone group that determines the occurrence of
the nucleophilic attack exclusively at C(3) of the double bond, in
late as an actinometer.22 The ur values range between 0.25 and
0.40 indicating that the photoreaction is efficient and competes
with the deactivation processes of the photo reactive singlet ex-
cited state, namely, fluorescence emission and internal conversion.
In summary, biphasic base catalysis-mediated photo-Fries rear-
rangement reactions of esters 1–5, rapidly and mildly afford chro-
man-4-one, benzochroman-4-one, and heteroarylchroman-4-one
derivatives in good to high yields at room temperature. The whole
reaction is initiated through a photo-Fries rearrangement at differ-
ent excitation wavelength followed by a base catalysis cyclization,
namely, an intramolecular oxa-Michael addition reaction, of the 20-
hydroxyphenone intermediate. Also, this synthon does not need to
be isolated from the photolyzed system. This method exhibits
predictable regioselectivity, applies efficiently to polycyclic and
heterocyclic aryl 3-methyl-2-butanoate esters, takes place in a
one-pot fashion reaction, and can be considered as a general and
wide useful methodology. Finally, the method is inexpensive, with
simple work-up and does not need the use of Lewis acid agents and
harsh thermal conditions.
Acknowledgments
The authors thank Universidad de Buenos Aires (X072 and
X408), CONICET (PIP5443 and PIP0155), and ANPCYT (PICT06-
615) for financial support. R. Erra-Balsells and S. M. Bonesi are re-
search members of CONICET.
Supplementary data
Supplementary data (general method and spectroscopic charac-
terization of starting materials and photoproducts) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.063.
agreement with the usual reactivity of a,b-ethylenic carbonyl com-
pounds.11d,e Furthermore, the success of the intramolecular oxa-
Michael addition is improved in our experimental conditions due
to the formation of the phenoxide ion of the 2-hydroxyphenone
intermediate under basic catalysis. In this regard, the phenoxide
ion becomes a better nucleophile than the hydroxy group promot-
ing the nucleophilic attack at C(3) of the double bond efficiently to
afford chroman-4-one derivatives in high yields.
References and notes
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