Ph3P/I2-Mediated Synthesis of 3-Aryl-Substituted and 3,4-Disubstituted Coumarins

Article abstract of DOI:10.1055/s-0036-1588941

Ph₃P/I₂-Et₃N-mediated one-pot two-step esterification-cyclization toward 3-aryl coumarins and 3-aryl-4-methylcoumarins is reported. The reaction of a variety of aryl acetic acids containing steric or reactive group with 2-

Full text of DOI:10.1055/s-0036-1588941

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
W. Phakhodee et al.
Letter
Synlett
Ph3P/I2-Mediated Synthesis of 3-Aryl-Substituted and 3,4-Disub-
stituted Coumarins
Wong Phakhodee*
R
O
O
Chuthamat Duangkamol
Dolnapa Yamano
Z
Ar
O
Z
Ph3P, I2
R
+
Ar
HO
Et3N, CH2Cl2
25 °C
Mookda Pattarawarapan
O
OH
R = H, Me
Z = H, NO2, Cl, Br, OMe
(22 examples, up to 98%)
Department of Chemistry, Faculty of Science,
Chiang Mai University, Chiang Mai 50200,
Thailand
wongp2577@gmail.com
Received: 15.12.2016
Accepted after revision: 30.12.2016
Published online: 02.02.2017
such as 1,4-diazabicyclo[2.2.2]octane (DABCO),10 cyanuric
chloride,11 dicyclohexylcarbodiimide (DCC),12 SOCl2,13 N,N-
dimethyl(dichlorophosphoryloxymethylene)ammonium
chloride,14 POCl3,15 PhOP(O)Cl2,16 as well as the Mukaiyama
reagent.17 Nevertheless, many of these methods suffer from
the use of highly toxic reagents, strong bases, harsh condi-
tions, and limited substrate scope. Although a number of
transition-metal-catalyzed reactions have recently been
developed,18 these procedures generally require expensive
metals, long reaction times at elevated temperature, as well
as extra-dry and inert conditions. Thus, a new mild and
economic method that allows a convenient access to this
class of compounds from a wider range of substrates is still
of great demand.
DOI: 10.1055/s-0036-1588941; Art ID: st-2016-d0845-l
Abstract Ph3P/I2–Et3N-mediated one-pot two-step esterification–cy-
clization toward 3-aryl coumarins and 3-aryl-4-methylcoumarins is re-
ported. The reaction of a variety of aryl acetic acids containing steric or
reactive group with 2-hydroxybenzaldehydes or 2′-hydroxyacetophe-
none proceeded smoothly at room temperature to afford the corre-
sponding products in good to excellent yields using inexpensive and
readily available reactants and reagents.
Key words carboxylic acids, chemoselectivity, phosphorous, cycliza-
tion
Coumarins are an important class of heterocyclic com-
pounds that are prevalent in nature.1 Both synthetic and
naturally occurring coumarins are found to exhibit wide-
spread biological and pharmacological activities such as an-
tioxidant, anticancer, anti-inflammatory, antiviral, antico-
agulant, antihypertensive, and antimicrobial.1 Especially,
several 3-aryl coumarin derivatives have recently been
found to possess additional benefits such as antidepres-
sant,2 anti-proliferative,3 and inhibitors of monoamine oxi-
dase (MAO) involving neurodegenerative diseases.4 Brain
permeability and myelin-binding properties of some 3-
phenylcoumarin dyes are also potentially useful for nerve
mapping in surgical operations or as radiotracers for imag-
ing of myelination.5
Due to the valuable properties of substituted couma-
rins, special attention has been paid to the development of
an efficient synthetic method toward these compounds.
The classical approach for the synthesis of coumarin
scaffolds included Knoevenagel condensation,6 Wittig,7
Pechmann,8 and Perkin reactions.9 Other useful alternatives
involved condensation between 2-hydroxy benzaldehydes
and phenyl acetic acid derivatives using activating reagents
Triphenylphosphine (Ph3P) has been used as a versatile
reagent in a number of functional-group transformations
due to its inexpensiveness, ready availability, and reactivi-
ty.19 Especially, the combinations of Ph3P or its polymer-
bound analogues with halogenated additives are highly
useful for an activation of carboxylic acids toward nucleo-
philic acyl displacement.20 Although several phosphine-
mediated reactions have been developed for the prepara-
tion of important carboxylic acid derivatives such as am-
ides, esters, and thioesters, to the best our knowledge, these
types of methodologies have never been applied for the
synthesis of coumarins.
As part of our ongoing research involving phosphorous-
mediated reactions,21 herein, we wish to report another ap-
plication of the Ph3P/I2 system for a one-pot synthesis of 3-
aryl substituted and 3,4-disubstituted coumarins. It was
envisaged that acylation of substituted 2-hydroxy carbonyl
compounds with in situ activated aryl acetic acids, followed
by Dickmann-type cyclization of the generated aryl acetoxy
esters would led to the formation of the desired coumarin
products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
W. Phakhodee et al.
Letter
Synlett
We started our investigation by optimization of the re-
action conditions using salicylaldehyde and 4-methoxy
phenylacetic acid as the model substrates. Different sets of
conditions including types of solvents and bases, as well as
the molar ratios of the reagents were examined. For the
ease of comparison, all reactions were carried out at room
temperature for two hours before isolation of the product.
According to Table 1, using three equivalents of triethyl-
amine in dichloromethane led to an exclusive formation of
the corresponding ester without detectable amount of the
desired coumarin (Table 1, entry 1). The yield of the ester
decreased considerably when changing the solvent to tolu-
ene, DMF, or acetonitrile (Table 1, entries 2–4). To facilitate
the cyclization reaction, various bases were screened at in-
creasing concentration. Using five equivalents of triethyl-
amine enabled the formation of the coumarin product in
excellent yield (Table 1, entry 5). Other organic bases in-
cluding those applied in the Ph3P/I2-mediated esterification
conditions20e,f were ineffective giving lower yields of the cy-
clized product along with the unreacted ester (Table 1, en-
tries 6–9).
dehydes and aryl acetic acids are viable substrates in the re-
action which provide 3-aryl substituted coumarins in mod-
erate to high yields.22 The more electron-deficient 2-hy-
droxybenzaldehydes
containing
nitro
or
chloro
substituents were found to react in a much faster rate in
comparison to the bromo- or methoxy-substituted reac-
tants (Table 2, entries 1–5). Steric effect on the aryl acetic
acid component could be well tolerated as the reaction with
aryl acetic acids bearing OMe, NO2 or Cl at the ortho posi-
tion or those using 1-naphthyl acetic acid proceeded
smoothly to afford the corresponding coumarins in reason-
able yields (Table 2, entries 6–12). The reaction is also high-
ly chemoselective since 4-hydroxyphenylacetic acid could
be directly incorporate without protecting groups (Table 2,
entries 13–15).
Table 2 Ph3P/I2-Mediated Synthesis of Substituted Coumarinsa
R
O
O
Z
Ar
O
Z
Ph3P, I2
R
Ar
+
Et3N
CH2Cl2
HO
O
OH
Table 1 Optimization of Reaction Conditionsa
R = H, Me
OMe
, Ph3P, I2
Entry
1
Product
Time
Yield (%)
75
O
HO2C
OMe
H
O2N
OH
10 min
base, solvent
O
O
OMe
OMe
OMe
OMe
CHO
O
Cl
Br
2
3
4
5
6
10 min
91
80
98
90
71
O
O
O
O
O
Entry
Base (equiv)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
Et3N (3)
CH2Cl2
toluene
DMF
0 (98)
0 (76)
1 h
Et3N (3)
O
O
Et3N (3)
0 (39)
OMe
Et3N (3)
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 (trace)
98 (0)
Et3N (5)
2 h
DMAP (5)
imidazole (5)
DABCO (5)
NMM (5)
39 (47)
42 (45)
52 (36)
0 (84)
O
O
OMe
MeO
O2N
16 h
a Reaction conditions: 4-methoxy phenyl acetic acid (0.41 mmol), salicylal-
dehyde (0.45 mmol), Ph3P (0.62 mmol), I2 (0.62 mmol), solvent (4 mL),
base, 0–25 °C, 2 h.
O
O
b The yield of the ester is given in parenthesis.
O2N
10 min
With the established optimal conditions (Table 1, entry
5), the scope and generality of the reaction were further
evaluated. According to Table 2, various 2-hydroxybenzal-
O
O
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
W. Phakhodee et al.
Letter
Yield (%)
92
Synlett
Table 2 (continued)
Entry
17
Product
Time
8 h
Entry
7
Product
Time
10 min
Yield (%)
88
OMe
MeO
Cl
O
O
O
O
O
O
O
O
F
8
9
10 min
10 min
2.5 h
67
84
74
O2N
18
8 h
88
Cl
Br
O
Cl
Cl
O2N
19
20
16 h
72
83
O
O
O
O
O
10
10 min
NO2
Br
O
O
21
16 h
78
11
12
16 h
16 h
87
41
MeO
O
O
O
O
O
OH
O
Cl
22
16 h
52
MeO
Cl
a Reaction conditions: carboxylic acid (0.41 mmol), 2-hydroxyphenyl carbon-
yl compound (0.45 mmol), Ph3P (0.62 mmol), I2 (0.62 mmol), Et3N (2.05
mmol), CH2Cl2 (5 mL), 25 °C.
O
O
OH
13
14
16 h
16 h
61
62
The method is also applicable for the less reactive 2′-hy-
droxyacetophenone. The condensation reaction with a vari-
ety of aryl acetic acids including those having free hydroxyl
group proceeded without difficulty at room temperature to
provide 3,4-disubstituted coumarins in good to excellent
yields (Table 2, entries 16–22). Remarkably, 4-methyl-3-(2-
nitrophenyl)-2H-chromen-2-one (Table 2, entry 20) was
obtained in high yield within short reaction times suggest-
ing that the reaction proceeded via highly activated inter-
mediate(s).
It is important to note that although similar 3-aryl cou-
marins could be prepared using acetic anhydride (Ac2O)
and triethylamine in the Perkin-type reaction,23 highly cor-
rosive Ac2O is used as solvent at refluxing temperature
which is not applicable with acid-labile substrates or those
containing reactive groups. The conditions are also ineffec-
tive with ketone substrates. Moreover, due to the misuse of
Ac2O in narcotics synthesis, its use is severely restricted in
O
O
OH
Br
O
O
OH
MeO
15
16
16 h
67
89
O
O
8 h
O
O
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
W. Phakhodee et al.
Letter
Synlett
several countries. Our conditions are proven to be milder,
and the reagents are readily available which can be applied
with a wider range of substrates.
R
O
I
I
I
It should be noted also that low yields of 3,4-disubsti-
tuted coumarins are often encountered using other report-
ed procedures. For example, 45% of 4-methyl-3-phenylcou-
marin was obtained using the Mukaiyama protocol under
refluxing in acetonitrile.17 Only 37% of the product was ob-
tained via the rhodium-catalyzed annulation of 2′-hydroxy-
acetophenone with phenylacetylene.18b Rhodium-catalyzed
oxidative annulation of aryl thiocarbamates with internal
alkynes gave the product in 68% after 12 hours at 120 °C.18c
The palladium-catalyzed carbonylation annulation of 2′-hy-
droxyacetophenone with benzyl chloride also gave the cou-
marin in low yield (44%) after 16 hours at 100 °C.18d
Based on the above observation, the mechanism for the
formation of substituted coumarins was proposed as
shown in Scheme 1. An initial reaction between Ph3P and
iodine provides triphenylphosphonium iodide I along with
pentavalent triphenylphosphinediiodide II as the reactive
species. Nucleophilic displacement of these intermediates
by the carboxyl group of phenyl acetic acid or the phenolic
function of 2-hydroxy phenyl carbonyl compound could
produce an aryloxyphosphonium salt III along with an acyl-
oxyphosphonium salt V. It is highly likely that the pentava-
lent phosphorane IV is also generated in the equilibrium
which allows dual activation of both coupling partners to-
ward condensation.24 After an acyl transfer process through
the intermediates IV or V, the formed aryl acetoxy ester
then undergoes base-catalyzed cyclization yielding the cor-
responding coumarins. Also, the possible pathway through
the formation of ylides VI prior to cyclization should not be
excluded.25
I2
OH
Ph3P
Ph3P
Ph3P
I
O
Ar
I
II
OH
, Et3N
R
R
R
O
O
O
O
O
O
O
O
O
Ph3P
3
3
Ar
Ar
Ar
O
O
O
III
IV
V
O
R
O
R
Ar
Ar
Et3N
O
O
O
O
R
O
O
Ph3P
Ar
VI
Scheme 1 Proposed mechanism of the Ph3P/I2-mediated reaction be-
tween 2-hydroxy phenyl carbonyl compound and aryl acetic acid
Supporting Information
In summary, we have described a mild and efficient
metal-free method for the synthesis of substituted couma-
rins using Ph3P/I2 as a promoter. This one-pot two-steps
procedure enables a direct condensation of electron-rich as
well as electron-deficient 2-hydroxy phenyl carbonyl com-
pounds with a variety of aryl acetic acids containing steric
hindered group or free hydroxyl substituent. Several attrac-
tive features of this method include the use of low-cost and
easy-to-handle reagents, wide substrate scope, high yields,
and mild reaction conditions.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588941.
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p
p
ortiInfogrmoaitn
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References and Notes
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Acknowledgment
Financial support from The Thailand Research Fund through the Royal
Golden Jubilee PhD Program to C.D. (Grant No. PHD/0086/2557) and
the National Research University Project under Thailand’s Office of
the Higher Education Commission are gratefully acknowledged.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
W. Phakhodee et al.
Letter
Synlett
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added with aryl acetic acid (0.41 mmol) and hydroxybenzalde-
hyde (0.45 mmol) at 0 °C, followed by Et3N (2.05 mmol). After
that, the solution was allowed to warm up to r.t. and stirred
until the completion of reaction. The crude material was puri-
fied by column chromatography using EtOAc–hexanes as the
eluent to afford pure product.
3-(4-Methoxyphenyl)-2H-chromen-2-one (Table 2, Entry 4)
White solid (0.1013 g, 98% yield); mp 140–141 °C (lit.2 mp 140
°C); Rf = 0.38 (30% EtOAc–hexanes). 1H NMR (400 MHz, CDCl3):
δ = 7.75 (s, 1 H), 7.68 (d, J = 8.8 Hz, 2 H), 7.53–7.48 (m, 2 H), 7.34
(d, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2
H), 3.85 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 160.8, 160.2,
153.3, 138.5, 131.0, 129.9, 127.8, 127.1, 124.5, 119.9, 116.3,
113.9, 55.4.
6-Nitro-3-(2-nitrophenyl)-2H-chromen-2-one
(Table
2,
Entry 6)
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2012, 23, 611.
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40, 2284.
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170.
Yellow solid (0.0912 g, 71% yield); mp 217–218 °C; Rf = 0.41
(40% EtOAc–hexanes). 1H NMR (400 MHz, CDCl3 + TFA): δ = 8.55
(d, J = 2.4 Hz, 1 H), 8.47 (dd, J = 9.2, 2.4 Hz, 1 H), 8.22 (d, J = 7.6
Hz, 1 H), 7.94 (s, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1
H), 7.58 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H). 13C NMR (100
MHz, CDCl3+TFA): δ = 160.4, 156.8, 148.2, 144.8, 139.3, 134.6,
132.1, 131.2, 130.1, 129.0, 127.1, 125.5, 124.2, 119.5, 118.5.
HRMS (ESI-TOF): m/z calcd for C15H9N2O6 [M + H]+: 313.0461;
found. 313.0467.
6-Chloro-3-(2-nitrophenyl)-2H-chromen-2-one (Table 2,
Entry 8)
White solid (0.0832 g, 67% yield); mp 214–215 °C; Rf = 0.46 (30%
EtOAc–hexanes). 1H NMR (400 MHz, CDCl3 + TFA): δ = 8.20 (d,
J = 8.0 Hz, 1 H), 7.85 (s, 1 H), 7.77 (td, J = 8.0, 1.2 Hz, 2 H), 7.67
(td, J = 8.0, 1.2 Hz, 1 H), 7.62 (s, 1 H), 7.60 (dd, J = 8.8, 2.4 Hz, 1
H), 7.49 (dd, J = 8.0, 1.2 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H). 13C
NMR (100 MHz, CDCl3 + TFA): δ = 162.6, 151.6, 148.2, 140.6,
134.5, 132.9, 132.2, 131.4, 130.9, 129.3, 127.7, 125.4, 118.6,
110.3. HRMS (ESI-TOF): m/z calcd for C15H9ClNO4 [M + H]+:
302.0220; found: 302.0226.
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3-(4-Fluorophenyl)-4-methyl-2H-chromen-2-one (Table 2,
Entry 18)
White solid (0.0921 g, 88% yield); mp 183–184 °C; Rf = 0.30 (20%
EtOAc–hexanes). 1H NMR (400 MHz, CDCl3): δ = 7.68 (dd, J = 8.0,
1.2 Hz, 1 H), 7.55 (td, J = 8.0, 1.2 Hz, 1 H), 7.36 (t, J = 8.8 Hz, 2 H),
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(b) Pedrosa, L. F. Synlett 2008, 1581.
7.31–7.26 (m, 2 H), 7.14 (td, J = 8.8, 2.0 Hz, 2 H), 2.32 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 163.9, 161.4, 161.0, 152.7, 148.1,
132.07, 131.99, 131.6, 130.4 (d, J = 14.4 Hz), 126.4, 125.3, 124.5,
120.5, 117.0, 115.70, 115.5, 16.7. HRMS (ESI-TOF): m/z calcd for
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Akula, H. K.; Lakshman, M. K. Eur. J. Org. Chem. 2010, 2709.
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Palumbo, G. Synthesis 1995, 141. (d) Kawagoe, Y.; Moriyama, K.;
Togo, H. Tetrahedron 2013, 69, 3971. (e) Sardarian, A. R.; Zandi,
M.; Motevally, S. Acta Chim. Slov. 2009, 56, 729. (f) Morcillo, S.
P.; Alvarez de Cienfuegos, L.; Mota, A. J.; Justicia, J.; Robles, R.
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Chandrasekaran, S. J. Org. Chem. 2009, 74, 6291.
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(22) General Procedure
C
16H12FO2 [M + H]+: 255.0821; found: 255.0824.
3-(3,4-Dichlorophenyl)-4-methyl-2H-chromen-2-one (Table
2, Entry 19)
White solid (0.0901 g, 72% yield); mp 209–210 °C; Rf = 0.31 (20%
EtOAc–hexanes). 1H NMR (400 MHz, CDCl3 + TFA): δ = 7.76 (dd,
J = 8.4, 1.6 Hz, 1 H), 7.64 (td, J = 8.4, 1.6 Hz, 1 H), 7.55 (d, J = 8.4
Hz, 1 H), 7.45–7.41 (m, 2 H), 7.41 (d, J = 2.0 Hz, 1 H), 7.15 (dd, J =
8.4, 2.0 Hz, 1 H), 2.39 (s, 3 H). 13C NMR (100 MHz, CDCl3 + TFA):
δ = 163.2, 152.3, 151.4, 133.7, 133.2, 133.0, 132.7, 132.1, 130.9,
129.6, 125.6, 125.5, 124.6, 120.3, 117.3, 113.3, 16.9. HRMS (ESI-
TOF): m/z calcd for C16H11ClO2 [M + H]+: 305.0136; found:
305.0129.
4-Methyl-3-(2-nitrophenyl)-2H-chromen-2-one (Table 2,
Entry 20)
White solid (0.0957 g, 83% yield); mp 167–168 °C; Rf = 0.37 (30%
1
EtOAc–hexanes). H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.0
To a solution of Ph3P (0.62 mmol) in CH2Cl2 (4 mL) was added I2
(0.62 mmol) at 0 °C. The resulting solution was sequentially
Hz, 1 H), 7.72 (td, J = 7.6, 1.2 Hz, 1 H), 7.67 (dd, J = 8.0, 1.6 Hz, 1
H), 7.62–7.55 (m, 2 H), 7.40–7.32 (m, 3 H), 2.27 (s, 3 H). 13C NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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W. Phakhodee et al.
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Synlett
(100 MHz, CDCl3): δ = 159.9, 152.8, 148.8, 147.2, 133.8, 132.7,
131.9, 130.2, 129.8, 125.19, 125.17, 125.0, 124.6, 120.2, 117.2,
16.6. HRMS (ESI-TOF): m/z calcd for C16H12NO4 [M + H]+:
282.0766; found: 282.0767.
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(23) (a) Shen, W.; Mao, J.; Sun, J.; Sun, M.; Zhang, C. Med. Chem. Res.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F