A different route to 3-aryl-4-hydroxycoumarins

Article abstract of DOI:10.1016/j.tetlet.2010.08.013

We herein report the simple and direct arylation of 4-hydroxycoumarins by photoinduced reaction with aryl halides (iodobenzene, iodonaphthalene, 4-iodoanisole, 2-iodoanisole). Good yields of 3,4-disubstituted coumarins were obtained in these reactions (>60%). Extension of the procedure to the reaction with o-dihalobenzenes leads to the synthesis of ring closure products which bear a tetracyclic aromatic-condensed ring system, although in lower overall yields (≈45%).

Full text of DOI:10.1016/j.tetlet.2010.08.013

Tetrahedron Letters 51 (2010) 5322–5324
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Tetrahedron Letters
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A different route to 3-aryl-4-hydroxycoumarins
⇑
Sergio A. Rodríguez, Maria T. Baumgartner
INFIQC—Dpto. Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba 5000, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report the simple and direct arylation of 4-hydroxycoumarins by photoinduced reaction with
aryl halides (iodobenzene, iodonaphthalene, 4-iodoanisole, 2-iodoanisole). Good yields of 3,4-disubsti-
tuted coumarins were obtained in these reactions (>60%). Extension of the procedure to the reaction with
o-dihalobenzenes leads to the synthesis of ring closure products which bear a tetracyclic aromatic-con-
densed ring system, although in lower overall yields (ꢀ45%).
Received 1 July 2010
Revised 23 July 2010
Accepted 2 August 2010
Available online 9 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
4-Hydroxucoumarin
Aryl halides
Radical nucleophilic substitution
C3-Arylation
4-Hydroxycoumarins constitute an important class of benzopy-
rones. Many of them display pharmacological effects1 and are key
intermediates for different products.2 To date numerous com-
pounds have been isolated from natural products3 and synthetic
analogues have been prepared.4
The simplest synthetic route to 3-aryl-4-hydroxycoumarins is
via direct arylation at C3 of the coumarin ring. Different reactants
are used, for example aryldiazonium chloride,5 arylbismuthv re-
agents,6 and arylleadv triacetates.7
Scheme 1.
In recent years, it has been informed that the palladium-cata-
lyzed coupling reaction obtained this type of compounds. How-
ever, most of these approaches are focused on 3,4-disubstituted
coumarins.8 Only limited reactions for the synthesis of 3-substit-
ued 4-hydroxycoumarins have been reported. For example, phe-
nyliodonium zwitterion reacts with aryl boronic acids to give
products with good yield.9 The main limitations of these method-
ologies lie in the difficulty found in the preparation of reactants
or the toxicity of these.
The radical nucleophilic substitution can be considered as an
alternative route for the formation of carbon–carbon bonds.10 This
type of reactions finds increasing application in the synthesis of
complex organic molecules,11,12 particularly, since such reactions
are generally carried out under mild conditions and the substrates
tolerate many functional groups. It is well known that in an SRN1
reaction, a nucleophile is combined with an aryl radical to provide
the corresponding coupling product (Scheme 1).10 These nucleo-
philic substitutions involve electron transfer steps (ET) and the
intermediacy of radical and radical anions. Traditionally, aryl
halide substrates give the aryl radical in the photoelectron transfer
reaction from the nucleophile (Eqs. 1 and 2). The radicals thus
formed can react with the nucleophile to give the radical anion
of the substitution product (Eq. 3), responsible for continuing the
propagation chain of the mechanism proposed (Eq. 4) (Scheme 1).
Continuous efforts toward the coumarin synthesis have been
reported due to the importance of these molecules. In this Letter
we propose a selective arylation approach, based on the radical
nucleophilic substitution mechanism, for the generation of 3-
aryl-4-hydroxycoumarins from commercially available reactants.
Finally, the methodology we report herein can be extended to
obtaining a tetracyclic aromatic ring structure by the reaction of
either anion with o-dihalobenzenes.
The results of the photoinitiated reactions of the anion of 4-
hydroxycoumarin (1) with different aryl halides (2) (Scheme 2)
are shown in Table 1.
The general procedure for the above-mentioned reactions is as
follows: to a solution of anion 1, obtained by deprotonation of
4-hydroxycoumarin with potassium tert-butoxide (KBuO-t) in
DMSO, was added the substrate.13 Following this approach, the
4-hydroxycumarin anion (1), as an electron donor, was unreactive
toward 2a under photostimulation and afforded only 32% yield of
⇑
Corresponding author. Tel.: +54 351 4334170/73; fax: +54 351 4333030.
E-mail address: tere@mail.fcq.unc.edu.ar (M.T. Baumgartner).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.013

S. A. Rodríguez, M. T. Baumgartner / Tetrahedron Letters 51 (2010) 5322–5324
5323
(17%) (Table 1, entries 6 and 7). High yields of C3-arylation were
also obtained by the reaction with iodobenzene (2c) (75%) (Table 1,
entry 8). 2-Iodoanisole (2d) reacts with anion of 1 to afford 3d and
anisole in 54% and 40% yields, respectively (Table 1, entry 9).
Unfortunately, 1-iodo-2-methoxynaphthalene (2e) failed to af-
ford the arylation of the nucleophile, the main reaction being its
reduction to 2-methoxynaphthalene (>80%) (Table 1, entries 10
and 11). A similar behavior was found when this substrate reacted
with other nucleophiles.12,15 These results show that the coupling
reaction of the anion of 1 is sensitive to the high steric hindrance of
the aryl radical.
The relative reactivity of the anion of 1 was determined in com-
petition experiments and estimated according to the approxima-
tion previously reported.17 We could determine that 4-
hydroxycumarin ion is 4 times less reactive than 2-naphthoxide
ion, the latter being a hydroxy anion more reactive in this
mechanism.10,15
Scheme 2.
Table 1
Photoinduced reactions of aryl halides with the anion of 4-hydroxycoumarin (1) in
DMSOa
On the basis of the promising results obtained with the aryl ha-
lides tested, the photoinduced methodology has been extended to
the reaction of 1 with dihalobenzenes. The 1-chloro-4-iodoben-
zene gives the substitution product with retention of chloride (6)
in 65% of yield (Table 2, entry 1). This product can then be modified
by different chemical reactions.
Exp.
1
Substrate
Base
Productsb (% yields)
M ꢁ 103
M ꢁ 103
M ꢁ 103
ArH
Substitution
1c
2
3
77
308
508
156
152
304
501
508
500
300
2000
508
77
2a, 27
2a, 52
2a, 50
2a, 52
2a, 54
2b, 58
2b, 50
2c, 52
2d, 49
2e, 53
2e, 200
5, 52
80
458
654
298
298
476
604
650
650
476
2600
650
80
11
44
21
—
3a, traces
3a, 27
3a, 64
—
4d,e
5e,f
6
—
—
35
17
nqg
40
80
96
nq
11
3b, 62
3b, 79
3c, 75
3d, 54
—
7
8
9
10
11
12
13c
ð5Þ
—
6, 75
3a, traces
2a, 27
We investigated the reaction of anion 1 with o-dihalobenzenes
as an alternative procedure to the synthesis of the tetracyclic ring
systems 8 by biaryl coupling followed by intramolecular hetero-
cyclization.11 o-Diiodobenzene 7a reacts with the anion of 1 to af-
ford the reduced-substituted product 3c and the substituted-
cyclized compound 8 in 60% and 39% yields, respectively (Table 2,
exp. 1). On the other hand, compounds 3c and 8 were obtained by
reaction of the anion of 1 with o-bromoiodobenzene 7b (40% and
28% yields, respectively, Table 1, exp. 2).
a
Photoinitiated reactions (unless indicated), carried out under nitrogen. Reaction
time (180 min). Xꢂ (%) >90% determined potentiometrically on the basis of ArX
concentration.
b
Determined by GLC and the internal standard method on the basis of ArX
concentration.
c
Reaction time = 300 min, Xꢂ (%) = 32%.
d
p-Dinitrobenzene (30 mmol %).
e
f
Xꢂ (%) <7%.
Reaction carried out in the dark.
nq = not quantified.
g
iodide ions, anisole (11%), and traces of the substitution product
(Table 1, entry 1). However, in the presence of an excess of
KBuO-t (KBuO-t/nucleophile/substrate ratio = 9:6:1) and under
irradiation (entrainment conditions)14 affording the product corre-
sponding to substitution at C3 of the coumarin cycle 3a (27%), and
anisole 4a (44%) after quenching with NH4NO3 (Table 1, entry 2).
The percentage of 3a increases to 64% with a nucleophile/sub-
strate ratio of 10 (Table 1, entry 3). This photoinduced reaction is
completely suppressed by the addition of a good electron-acceptor
such as p-dinitrobenzene (p-DNB) (Table 1, entry 4). This result, the
absence of reaction in the dark after 3 h (Table 1, entry 5) and the
presence of anisole, can be regarded as indicative of the SRN1 mech-
anism.10 In the initiation step a photoinduced ET from KOBu-t to 2
takes place (Eq. 1).10 The radical originated by dissociation of aryl
halide radical anion (Eq. 2) can couple with the nucleophile to form
the radical anion of the substitution product (Eq. 3) or can be re-
duced by hydrogen atom abstraction from the solvent to afford
compound 4.15 It is important to mention that the O-arylated prod-
uct of 116 or of KOBu-t10 is not formed in any of these reactions.
By employing this protocol, the reaction of the anion of 1 was
examined with the aryl halides (2b–e).
ð6Þ
However, o-chloroiodobenzene affords 3c and 8 (14% and 26%,
respectively). In this case we find the monosubstituted compound
with retention of halide, 4-hydroxy-3-(2-chlorophenyl)coumarin
(9). Further studies are in progress in order to replace the chlorine
atom of 6 and 9.
Table 2
Photoinduced reactions of o-dihalobenzene with the anion of 4-hydroxycoumarin (1)
in DMSOa
Exp.
1
7
Base
Productsb (% yields)
M ꢁ 103
635
630
508
M ꢁ 103
7a, 50
7b, 52
7c, 50
M ꢁ 103
810
820
743
ArH
3c
8
9
1
2
3
2
18
37
60
40
14
39
28
26
—
—
23
Similar results to those obtained in the reaction of 2a with 1
were observed when we used 1-iodonaphthalene (2b); the C3-ary-
lation compound (3b) was the main product formed (79% after 3 h
irradiation) accompanied by the reduction product naphthalene
a
Photoinitiated reactions (unless indicated), carried out under nitrogen. Reaction
time (180 min).
b
Determined by GLC and the internal standard method on the basis of ArX
concentration.

5324
S. A. Rodríguez, M. T. Baumgartner / Tetrahedron Letters 51 (2010) 5322–5324
8. Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423; Jia, C.; Piao, D.;
In summary, we have described an efficient and facile route for
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the synthesis of 3-aryl-4-substituted coumarins from commer-
cially available, easily handled, and inexpensive reactants via pho-
toinduced radical nucleophilic substitution under mild conditions
with good yields. The substrates tolerate many functional groups.
Moreover, the reaction provides an alternative access to the tetra-
cyclic system 8 in moderate yields.
9. Zhu, Q.; Wu, J.; Fathi, R.; Yang, Z. Org. Lett. 2002, 4, 3333–3336.
10. Rossi, R. A.; Peñéñory, A. B.; Pierini, A. B. In The Chemistry of Functional Groups,
Supplement D2; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons, 1994. Chapter
24; Rossi, R. A.; Peñéñory, A. B.; Pierini, A. B. Chem. Rev. 2003, 103, 71–168;
Pierini, A. B.; Peñéñory, A. B.; Baumgartner, M. T. In Electron Transfer Reactions
in Organic Synthesis; Vanelle, P., Ed.; 2002; pp 63–87. ISBN: 81-7736-086-8.
11. Tempesti, T.; Pierini, A. B.; Baumgartner, M. T. J. Org. Chem. 2005, 70, 6508–
6511; Rossi, R. A.; Baumgartner, M. T.. In Synthesis of Heterocycles by the SRN1.
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Acknowledgments
This work was supported by Agencia Córdoba Ciencia (ACC),
Consejo Nacional de Investigaciones Científicas y Técnicas (CONI-
CET), and Secretaría de Ciencia y Tecnología (SECyT), Universidad
Nacional de Córdoba (UNC), Argentina. S.A.R. thanks CONICET for
the award of a fellowship.
12. Baumgartner, M. T.; Tempesti, T. C.; Pierini, A. B. Arkivock 2003, part (X), 420–
433.
13. The reactions were carried out in a 50 mL three-neck round-bottomed flask
equipped with a nitrogen inlet and a magnetic stirrer. To 20 mL of dry and
degassed DMSO under nitrogen were added potassium tert-butoxide (1.456 g,
13 mmol) and then 4-hydroxycoumarin (1.620 g, 10 mmol). After 15 min 4-
iodoanisole (234 mg, 1.0 mmol) was added and the reaction mixture was
irradiated for 180 min. The reaction was quenched with an excess of
ammonium nitrate and water (30 mL). The mixture was extracted three
times with methylene chloride (20 mL); the organic extract was washed twice
with water, dried (MgSO4), the reduction products (ArH) were quantified by GC
in this extract and compared with authentic commercial samples; the
remaining aqueous phase was acidified with nitric acid 65% P/V to pH 3–4,
the precipitate was filtered with low pressure and redissolved with acetone.
Products were isolated by column or radial chromatography [hexane/ethyl
acetate (1:1 or 1.5:1)] and characterized by 1H NMR and 13C NNR and mass
spectrometry. All products are known and exhibited physical properties
identical to those reported in the literature.
Supplementary data
Supplementary data (general methods and materials. 1H NMR
and 13C NMR spectra and MS of compounds 3a, 3b, 3c, 3d, 6, 8
and 9) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.08.013.
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ꢂ
14. Entrainment is useful when Nu1 is rather unreactive at initiation (Eq. 1), but
ꢂ
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