Cascade synthesis of 3-alkenylcoumarins by palladium-catalyzed reaction of phenols and ethyl propiolate

Article abstract of DOI:10.1246/cl.2012.705

A highly effective cascade process giving 3-alkenylcoumarins is furnished by a series of reactions involving palladaarylation of ethyl propiolate with phenols, intramolecular transesterification to 3-coumarylpalladium species, its alkyne insertion, and protonation. [Pd(OAc)2(dppe)] is an effective catalyst for the synthesis of 3-alkenylcoumarins from phenols and ethyl propiolate.

Full text of DOI:10.1246/cl.2012.705

doi:10.1246/cl.2012.705
Published on the web June 23, 2012
705
Cascade Synthesis of 3-Alkenylcoumarins by Palladium-catalyzed Reaction
of Phenols and Ethyl Propiolate
Tsugio Kitamura,* Kotaro Tatemoto, Mariko Sakai, and Juzo Oyamada
Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering,
Saga University, 1 Honjo-machi, Saga 840-8502
(Received March 16, 2012; CL-120231; E-mail: kitamura@cc.saga-u.ac.jp)
A highly effective cascade process giving 3-alkenylcoumar-
ins is furnished by a series of reactions involving pallada-
arylation of ethyl propiolate with phenols, intramolecular
transesterification to 3-coumarylpalladium species, its alkyne
insertion, and protonation. [Pd(OAc)2(dppe)] is an effective
catalyst for the synthesis of 3-alkenylcoumarins from phenols
and ethyl propiolate.
pallada-arylation/
intramolecular
transesterification
O
+
O
OH
R
R
Pd
+
E
E
alkyne
insertion
E= CO2Et
O
O
R
E
Direct functionalization of C-H bonds forming new C-C
bonds has attracted much attention as a significant subject in
organic synthesis,1 because such direct functionalization of C-H
bonds does not require any prefunctionalization of the C-H
bonds transforming into reactive C-halogen bonds, and con-
sequently it reduces reaction steps to furnish highly efficient
synthetic processes. Hydroarylation of alkynes can formally be
regarded as a reaction where both aryl and hydrogen moieties of
an aromatic compound add across a triple bond. It is a highly
efficient reaction with high atom economy and provides
aromatic alkenes through a direct introduction of a double bond
into an aromatic C-H bond.2 Very recently, we have further
developed a direct synthesis of arylbutadienes by means of C-H
bond functionalization methodology,3 where two molecules of
ethyl propiolate are formally incorporated into an aromatic C-H
bond.
On the other hand, coumarin and its derivatives widely
occur in nature, particularly in plants, and most of them show
useful biological activities.4 In addition to the biological
properties, a coumarin unit is an important chromophore of
organic materials, indicating many applications to cosmetics,
optical brighteners, and dispersed fluorescent and laser dyes.4
Due to the useful applications much attention has been paid to
the synthesis of functionalized coumarin derivatives.4 Especial-
ly, the outstanding fluorescence of the coumarin chromophore
has been clarified by introduction of unsaturated substituents at
the 3 position, bringing about the extension of the ³ system.5
Very recently, it has been reported 3-alkenylcoumarins bearing
electron-withdrawing groups on the alkenyl moiety serve as
useful intermediates in the synthesis of 6H-dibenzo[b,d]pyran-6-
one, which is an important core of many natural products.6
Introduction of a substituent at the 3 position of coumarins
has been achieved so far by the following reactions: Heck-
type Pd-catalyzed cross-coupling reactions using 3-bromocou-
marins,5a the Friedel-Crafts acylation of coumarin-3-acetic acid
followed by reduction and dehydration,7 the Horner-Emmons
reaction of coumarylmethylphosphonate derived from salicyl-
aldehyde,8 the Knoevenagel condensation reaction of 2-hydro-
xybenzaldehydes with diethyl 2-pentenedicarboxylate,9 and the
conventional reactions of 3-formylcoumarin such as the Horner-
Wadsworth-Emmons reaction, the Wittig reaction, and the
Scheme 1.
Knoevenagel condensation.6 However, there are several draw-
backs in these methods. Each of the above-mentioned reactions
required a complicated substrate as a starting material, and
required several synthetic steps to introduce the unsaturated
substituent at the 3 position of coumarins. It would be the best
synthetic process if target 3-alkenylcoumarins could be prepared
by one-pot synthesis using simple substrates. Thus, we consid-
ered a cascade process affording the alkenylcoumarins, as
illustrated in Scheme 1. Synthesis of 3-alkenylcoumarins may
be furnished by insertion of an alkyne into a coumarin-
palladium bond of a coumarylpalladium complex, which is
formed by coumarin synthesis from a phenol and propiolates. In
this paper, we report a highly efficient cascade synthesis of 3-
alkenylcoumarins directly from phenols and ethyl propiolate
with the aid of [Pd(OAc)2(dppe)] [dppe: 1,2-bis(diphenylphos-
phino)ethane] as a catalyst.
Although we already have suitable reaction conditions for
the synthesis of coumarins,10 it is essential to use a bidentate
phosphine ligand to promote the alkyne insertion of the
intermediate coumarylpalladium complex.3 First, we examined
the reaction of 2-naphthol (1a) and ethyl propiolate (2) to
optimize the reaction conditions. The results are given in
Table 1. When the reaction of 1a (2 mmol) with 2 (2 mmol) was
carried out in the presence of a catalytic amount (0.5 mol %) of
[Pd(OAc)2(dppe)] in TFA (0.5 mL) and CH2Cl2 (1 mL) at 30 °C
for 5 h, alkenylcoumarin 3a was obtained in 44% yield, together
with coumarin 4a in 26% yield (Entry 1). The yield and
selectivity of 3a were improved by using an excessive quantity
of 2 to 1a (Entries 2 and 3), giving the highest yield (82%) of 3a
(Entry 3). In order to search for a better ligand, we screened the
following ligands: 1,3-bis(diphenylphosphino)propane (dppp),
1,1-bis(diphenylphosphino)methane (dppm), 1,1¤-bis(diphenyl-
phosphino)ferrocene (dppf), 1,2-bis(diphenylphosphino)benzene
(dppbz), and (R)-2,2¤-bis(diphenylphosphino)-1,1¤-binaphthyl
(BINAP). Unfortunately, better yield and selectivity were not
obtained (Entries 4-8).
By using the optimized conditions (Table 1, Entry 3) in
hand, a wide range of phenol derivatives 1 were converted into
the corresponding 3-alkenylcoumarin derivatives 3. The results
Chem. Lett. 2012, 41, 705-707
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

706
Table 1. Optimization of the reaction conditionsa
Table 2. Scope for Pd-catalyzed alkenylcoumarin formationa
Pd catalyst
OH
0.4 mol%
OH
O
O
+
CO2Et
[Pd(OAc)2(dppe)]
solvent
CO2Et
1a
2
TFA, CH2Cl2
CO2Et
R
R
3
1
2
O
O
O
O
+
Time
/h
Yield
/%c
OC2Et
Solv.b
A
Entry
1
1
Product
3a
4a
O
O
5
82
1a
1a
2
3a
/% /%
4
Entry
Pd catalyst
CO2Et
(4a: 10)
/mmol /mmol
3a
1
2
3
4
5
6
7
8
2
2
2
6
6
6
6
6
6
[Pd(OAc)2(dppe)]
[Pd(OAc)2(dppe)]
[Pd(OAc)2(dppe)]
[Pd(OAc)2(dppp)]
[Pd(OAc)2(dppm)]
[Pd(OAc)2(dppf)]
[Pd(OAc)2(dppbz)]
44
59
82
16
9
26
35
10
10
27
33
19
4
O
O
2
3
B
B
12
12
47
1b
1c
1.2
1.2
1.2
1.2
1.2
1.2
1.2
CO2Et
(4b: 24)
3b
O
O
O
94
CO2Et
8
+
O
3c
57
[Pd(OAc)2(R-BINAP)] 11
CO2Et
CO2Et
aReaction conditions: Pd catalyst (0.005 mmol), 1a, 2, TFA
(0.5 mL), CH2Cl2 (1 mL), 30 °C, 5 h. Yields (%) represent
isolated ones by column chromatography. See Supporting
Information (SI) for details.13
O
O
4
A
12
77
1d
3d
O
O
5
6
B
B
B
C
A
A
12
12
5
61
39
39
1e
1f
1g
1h
1i
CO2Et
3e
O
are given in Table 2. The reaction of 3,5-dimethylphenol (1b)
afforded alkenylcoumarin 3b in 47% yield, together with the
formation of coumarin 4b (Entry 2). Interestingly, 3,4-dimeth-
ylphenol (1c), 3,4,5-trimethylphenol (1d), and 4-tert-butylphe-
nol (1e) reacted highly selectively to give the corresponding
coumarins 3c-3e in 94, 77, and 61% yields, respectively (Entries
3-5). In the case of 1c, a regioisomeric mixture (1:1) of 3c was
formed. Next, we examined the reaction of alkoxyphenols under
similar conditions (Entries 6-10). The reaction of 3-methoxy-
phenol (1f) gave alkenylcoumarins 3f in 39% yield. A similar
reaction with 3,5-dimethoxyphenol (1g) afforded alkenylcou-
marin 3g in 39% yield. A better yield (57%) of alkenylcoumarin
3h was obtained in the case of 3,4-dimethoxyphenol (1h), albeit
coumarin 4d was also formed. The reaction of 3,4,5-trimethoxy-
phenol (1i) selectively gave the corresponding alkenylcoumarin
3i in 70% yield. Similarly, the reaction of 2-methoxy-4-
methylphenol (1j) gave alkenylcoumarin 3j selectively in 48%
yield. This alkenylcoumarin-formation reaction was applied
to polycyclic phenols such as 1-naphthol (1k), 7-methoxy-2-
naphthol (1l), and phenanthrol (1m) (Entries 11-13). Differently
from 2-naphthol (1a), 1-naphthol (1k) resulted in a low
selectivity to give alkenylcoumarin 3k and coumarin 4e in 50
and 28% yields, respectively. The reaction of 1l gave alkenyl-
coumarin 3l in 71% yield, together with coumarin 4f (6%). The
reaction of 1m afforded alkenylcoumarin 3m selectively in 58%
yield.
MeO
MeO
O
CO2Et
CO2Et
3f
O
O
7
(4c: 21)
3g
O
OMe
MeO
O
O
8
5
57
MeO
MeO
CO2Et
CO2Et
(4d: 22)
3h
3i
O
9
12
12
70
MeO
OMe
OMe
10
48
1j
O
O
CO2Et
CO2Et
3j
11
12
13
A
A
A
12
5
50
1k
1l
O
O
O
(4e: 28)
3k
O
71
CO2Et
(4f: 6)
3l
OMe
5
58
1m
O
O
CO2Et
The presence of a substituent at the terminal position of
propiolate 2 inhibited the reaction. For example, the reaction of
ethyl phenylpropiolate did not occur at all.
A possible mechanism for the reaction of phenols 1 with 2
in the presence of a palladium complex is shown in Scheme 2.
First, [Pd(OAc)2(dppe)] is thought to undergo ligand exchange
with TFA in TFA to form a cationic palladium species,11 which
coordinates with ethyl propiolate (2) to activate it. Next, the
activated 2 reacts with phenol 1 via electrophilic aromatic
3m
aReaction conditions: Pd catalyst (0.005 mmol), 1 (1.2 mmol),
2 (6 mmol), TFA, CH2Cl2, 30 °C. Solvent A: TFA (0.5 mL),
CH2Cl2 (1 mL); solvent B: TFA (0.5 mL), CH2Cl2 (0.5 mL);
solvent C: TFA (0.25 mL), CH2Cl2 (0.75 mL). Isolated yields
by column chromatography. The yield of coumarin 4 is shown
in a parenthesis. See SI for details.13
b
c
Chem. Lett. 2012, 41, 705-707
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

707
Ph2
P
References and Notes
1
P
P
For recent reviews, see: a) V. Ritleng, C. Sirlin, M. Pfeffer,
Chem. Rev. 2002, 102, 1731. b) G. Dyker, Angew. Chem., Int.
Ed. 1999, 38, 1698. c) F. Kakiuchi, N. Chatani, Adv. Synth.
Catal. 2003, 345, 1077. d) A. E. Shilov, G. B. Shul’pin, Chem.
Rev. 1997, 97, 2879. e) C. Jia, T. Kitamura, Y. Fujiwara, Acc.
Chem. Res. 2001, 34, 633. f) F. Kakiuchi, S. Murai, Acc. Chem.
Res. 2002, 35, 826. g) R. H. Crabtree, J. Chem. Soc., Dalton
Trans. 2001, 2437. h) Y. Guari, S. Sabo-Etienne, B. Chaudret,
Eur. J. Inorg. Chem. 1999, 1047. i) F. Kakiuchi, T. Kochi,
Synthesis 2008, 3013. j) X. Chen, K. M. Engle, D.-H. Wang,
J.-Q. Yu, Angew. Chem., Int. Ed. 2009, 48, 5094. k) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem., Int. Ed.
2009, 48, 9792. l) D. A. Colby, R. G. Bergman, J. A. Ellman,
Chem. Rev. 2010, 110, 624.
PdL2
L
Pd(OCOCF3)2
P
Ph2
3
P
2
PdL
P
H+L
O
P
P
P
O
CO2Et
PdL
Pd P
R
4
CO2Et
1
H+
2
a) T. Kitamura, Eur. J. Org. Chem. 2009, 1111. b) C. Nevado,
A. M. Echavarren, Synthesis 2005, 167. c) H. C. Shen,
Tetrahedron 2008, 64, 3885. d) X. Wang, L. Zhou, W. Lu,
Curr. Org. Chem. 2010, 14, 289.
O
O
P
Pd
H+
R
OH
CO2Et
P
R
P
3
4
J. Oyamada, T. Kitamura, Chem. Commun. 2008, 4992.
a) J. D. Hepworth, in Comprehensive Heterocyclic Chemistry,
ed. by A. R. Katritzky, C. W. Rees, Pergamon Press, Oxford,
1984, Vol. 3, Chap. 2.24, pp. 737-883. doi:10.1016/B978-
008096519-2.00046-1. b) U. Matern, P. Lüer, D. Kreusch, in
Polyketides and Other Secondary Metabolites Including Fatty
Acids and Their Derivatives in Comprehensive Natural Products
Chemistry, ed. by U. Sankawa, Pergamon Press, Oxford, 1999,
Vol. 1, pp. 623-635. c) J. D. Hepworth, C. D. Gabbutt, B. M.
Heron, in Comprehensive Heterocyclic Chemistry II, ed. by A.
McKillop, Pergamon Press, Oxford, 1996, Vol. 5, Chap. 5.08,
pp. 351-468. doi:10.1016/B978-008096518-5.00111-8. d) J.
Staunton, in Comprehensive Organic Chemistry, ed. by P. G.
Sammes, Pergamon Press, Oxford, 1979, Vol. 4, Part 18.2,
pp. 629-658. e) Coumarins: Biology, Applications and Mode of
Action, ed. by R. O’Kennedy, R. D. Thornes, Wiley, New York,
1997. f) R. D. H. Murray, J. Méndez, S. A. Brown, The Natural
Coumarins, Occurrence, Chemistry, and Biochemistry, Wiley,
New York, 1982. g) M. Zahradnik, The Production and
Application of Fluorescent Brightening Agents, Wiley, New
York, 1982.
LPd
CO2Et
O
O
P
R
P
L
LPd
EtOH
P
2
Scheme 2.
substitution and immediately cyclizes by intramolecular trans-
esterification to give a 3-coumarylpalladium species. Although
the protonation of this coumarylpalladium species produces
coumarin 4, the coordination with 2 makes a new route to 3-
alkenylcoumarin 3. In this complex, the bidentate phosphine
ligand (dppe) plays an important role. The presence of this
bidentate ligand forces the cis relationship between the coumaryl
group and 2 and this structural relation favors the insertion of
alkyne 2 into the C-Pd bond. If a bidentate ligand is not present,
alkyne 2 will be located trans to the coumaryl group due to
steric hindrance, where the coumarylpalladium intermediate
undergoes protonation to yield coumarin 4.10 To confirm this
postulation, we examined the reaction in the presence of
Pd(OAc)2 without any bidentate phosphine ligands. The reaction
of 1a with 2 was conducted in the presence of 0.4 mol %
Pd(OAc)2 in TFA and CH2Cl2 at 30 °C for 5 h. The products
isolated were 3a and 4 in 20 and 56% yields, respectively.
Apparently this result indicates that the presence of the bidentate
ligand is essential for this alkenylcoumarin formation. Finally,
the protonation of the resulting (coumarylvinyl)palladium
species gives 3-alkenylcoumarin 3, regenerates the cationic
palladium species, and closes the catalytic cycle.12
In summary, we have demonstrated for the first time an
effective cascade process involving pallada-arylation of ethyl
propiolate (2) with phenols 1, intramolecular transesterification
to 3-coumarylpalladium species, its alkyne insertion, and pro-
tonation leading to 3-alkenylcoumarins 3. In this reaction, two
molecules of 2 are formally incorporated into the ortho C-H
bond of 1. [Pd(OAc)2(dppe)] is an effective catalyst for the
synthesis of 3-alkenylcoumarins 3 from phenols 1 and ethyl
propiolate (2). Due to the wide applications of 3-alkenylcou-
marins, this efficient synthetic method will be attractive in
biological and material fields.
5
a) M.-S. Schiedel, C. A. Briehn, P. Bäuerle, Angew. Chem., Int.
Ed. 2001, 40, 4677. b) G.-J. Kim, K. Lee, H. Kwon, H.-J. Kim,
Org. Lett. 2011, 13, 2799.
6
7
I. R. Pottie, P. R. Nandaluru, W. L. Benoit, D. O. Miller, L. N.
Dawe, G. J. Bodwell, J. Org. Chem. 2011, 76, 9015.
A. Yu. Bochkov, V. N. Yarovenko, M. M. Krayushkin, T. A.
Chibisova, T. M. Valova, V. A. Barachevskii, V. F. Traven’, I. P.
Beletskaya, Russ. J. Org. Chem. 2008, 44, 595.
8
9
T. Janecki, R. Bodalski, Synthesis 1989, 506.
a) S. Padmanabhan, K. V. Gavaskar, D. J. Triggle, Synth.
Commun. 1996, 26, 3121. b) I. Rodriguez, S. Iborra, F. Rey, A.
Corma, Appl. Catal., A 2000, 194-195, 241.
10 a) J. Oyamada, C. Jia, Y. Fujiwara, T. Kitamura, Chem. Lett.
2002, 380. b) T. Kitamura, K. Yamamoto, M. Kotani, J.
Oyamada, C. Jia, Y. Fujiwara, Bull. Chem. Soc. Jpn. 2003, 76,
1889. c) M. Kotani, K. Yamamoto, J. Oyamada, Y. Fujiwara, T.
Kitamura, Synthesis 2004, 1466. d) J. Oyamada, T. Kitamura,
Tetrahedron 2006, 62, 6918. e) T. Kitamura, J. Oyamada, T.
Tsubota, Nat. Protoc. 2007, 2, 845.
11 A. Marson, A. B. van Oort, W. P. Mul, Eur. J. Inorg. Chem.
2002, 3028.
12 A referee suggested the possibility of direct coupling of
coumarin 4 with 2, but the reaction of 4a with 2 resulted in
the recovery of 4a under the present conditions.
13 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
Chem. Lett. 2012, 41, 705-707
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/