A tandem palladium-catalyzed Heck-lactonization through the reaction of ortho-iodophenols with β-substituted acrylates: synthesis of 4,6-substituted coumarins

Article abstract of DOI:10.1016/j.tetlet.2008.03.037

Coumarins were obtained in one pot through a palladium-catalyzed Heck-lactonization reaction involving ortho-iodophenols and methyl crotonate or a Z-enoate derived from d-mannitol. These reactions were investigated under different conditions and palladium sources. In the more interesting cases, coumarins were prepared in water, using triethylamine as base and 1 mol % of PdCl₂ as catalyst.

Full text of DOI:10.1016/j.tetlet.2008.03.037

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Tetrahedron Letters 49 (2008) 3322–3325
A tandem palladium-catalyzed Heck-lactonization through the
reaction of ortho-iodophenols with b-substituted acrylates:
synthesis of 4,6-substituted coumarins
Talita de A. Fernandes, Rita de C. C. Carvalho, Tatiana M. D. Gonßcalves,
Alcides J. M. da Silva *, Paulo R. R. Costa *
ˆ ˆ
´ ´ ´
Laborato´rio de Quı´mica Bioorganica (LQB), Nucleo de Pesquisas de Produtos Naturais, Centro de Ciencias da Saude, Bl H, Ilha da Cidade Universitaria,
Universidade Federal do Rio de Janeiro, Rio de Janerio 21941-590, Brazil
Received 10 January 2008; revised 5 March 2008; accepted 6 March 2008
Available online 18 March 2008
Abstract
Coumarins were obtained in one pot through a palladium-catalyzed Heck-lactonization reaction involving ortho-iodophenols and
methyl crotonate or a Z-enoate derived from D-mannitol. These reactions were investigated under different conditions and palladium
sources. In the more interesting cases, coumarins were prepared in water, using triethylamine as base and 1 mol % of PdCl2 as catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and the aza-arylation of dihydronaphthalene and related
olefins by ortho-iodoanilin was also reported by the Lar-
ock’s group.9
The arylation of olefins by ArHgX in the presence of
stoichiometric amounts of PdCl2 was discovered by Heck1
in 1968 and the first catalytic versions of this reaction were
reported by Mizoroki, in 1971,2 and Heck, in 1972,3 using
ArI as a source of ArPdX species. Today the Heck reaction
is one of the most industrially important palladium-cata-
lyzed carbon–carbon coupling.4 The reaction of ortho-
iodoaniline with b-substituted enoates in the presence of
catalytic amounts of Pd(OAc)2 was also firstly reported
by Heck5 and in this case a tandem Heck-lactamization
reaction took place, leading to 4-substituted quinolones.
Surprisingly, coumarins were not obtained when ortho-
iodophenol was used as starting material.5 On the other
hand, the Pd(OAc)2 catalyzed reaction of methyl acrylate
with ortho-iodophenol led to the corresponding cinnamate
(Heck adduct, without lactonization).6
During the course of our work, Ulgheri et al. reported
the first and sole example of a tandem palladium-catalyzed
Heck-lactonization through the reaction of methyl cinna-
mate and para-methyl, ortho-bromophenol in the presence
of catalytic amounts of Pd(OAc)2.10 This letter prompted
us do disclose our own results on this reaction. As part
of a program aiming towards the synthesis of new bioactive
compounds, we became interested in the preparation of
coumarin derivatives.11,12 Therefore, we decided to reinves-
tigate5,10 the reaction between ortho-iodophenols (1a–d)
and acrylate derivatives as a strategy to prepare these com-
pounds. Enoates (Z)-2 and (E)-2,13 as well as methyl crot-
onate (3a) and methyl cynnamate (3b), were used as
substrates (Fig. 1).
The oxy-arylation of chromens by ortho-iodophenols
was reported by Larock7 and Kiss et al.8 The oxy-arylation
2. Results
These reactions were firstly studied (Scheme 1, Table 1)
under the conditions described by Kiss et al.8 for the oxy-
arylation of chromens by ortho-iodophenols (acetone,
Pd(OAc)2, Ag2CO3, PPh3).
*
Corresponding authors. Tel.: +55 21 256 26791; fax: +55 21 2562 6512
(P.R.R.C.).
E-mail address: lqb@nppn.ufrj.br (P. R. R. Costa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.037

Talita de A. Fernandes et al. / Tetrahedron Letters 49 (2008) 3322–3325
3323
Table 2
OH
R1
Yields of 4a and 5a in water and Et3N (3 equiv) as base
CO2Me
I
O
O
Entry
Olefin
Product
Catalyst
Yield (%)
CO2Et
1
Z-2
Z-2
Z-2
Z-2
3a
4a
4a
4a
4a
5a
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
71
71
48
73
44
R2
2a
3
1a, R1=H
1b, R1=Cl
1c, R1=CO2Et
1d, R1=NO2
3a, R2=Me
3b, R2=Ph
4b
5
(E
)-2 or (Z)-2
Reaction mixtures were heated to 80 °C for 40 h in the presence of
Fig. 1. ortho-Iodophenols and olefins used in this work.
10 mol % of catalyst, 3 equiv of Et3N, and water.
a
1 equiv of tetrabutylammonium bromide was added in this reaction.
1 mol % of catalyst was used.
b
OH
O
O
I
(entry 7) and 39% in DMF (entry 8). No reaction occurred
when K2CO3 was used as base in DMF (entry 9), but the
use of NaHCO3 in the presence of tetrabutylammonium
chloride led to 4a in 44% (entry 10). When PdCl2 was used
as a source of Pd[0] instead of Pd(OAc)2, the yield of 4a
decreased to 7% (entry 11) while the use of Pd(PPh3)4 led
to this product in 50% yield (entry 12). Finally the use of
3a as substrate using Pd(OAc)2 as catalyst led to 5a in
63% yield, but no reaction was observed for 3b (entries
13 and 14). All attempts to reduce the amount of Pd(OAc)2
under these conditions were unfruitful.
(Z)-2 or 3a
1a
R3
O
O
4a, R3 =
5a, R3 =Me
4a or 5a
Scheme 1. Palladium-catalyzed reaction between ortho-iodophenol 1a and
olefins (Z)-2 and 3. Synthesis of coumarins 4a and 5a.
Table 1
Reaction between ortho-iodophenol (1a) and olefins 2 and 3 Synthesis of
coumarins 4a and 5a
The data in Table 1 suggest that the reaction is favored
by a cationic mechanism as better yields were obtained
with silver salts.4 Therefore, we decided to investigate alter-
native protocols for accomplishing these reactions via a
cationic mechanism with the objective of avoiding the use
of the toxic reagents Ag2CO3 and PPh3.14 It has been sug-
gested that reaction in water goes through a cationic mech-
anism4 and for this reason the reaction of 1a with Z-2 and
3a in water was studied, using Et3N as base (Table 2).15
Coumarin 4a was obtained in good yield (71%) under
the conditions used in Table 2 (entry 1). The same yield
was obtained when tetrabutylammonium bromide was
used as an additive (entry 2), but decreased to 48% when
Pd(PPh3)4 was employed as the source of Pd[0] (entry 3).
The amount of catalyst could be reduced, and 73% yield
of 4a was obtained when 1 mol % of Pd(OAc)2 was used
as catalyst (entry 4). Under these conditions, 3a led to cou-
marin 5a in 44% yield (entry 5).
Entry
Olefin
Base
Catalyst
Product
Yield (%)
1
2
E-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
Z-2
3a
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
—
4a
4a
4a
4a
4a
4a
4a
—
4a
4a
4a
5a
—
SM
68
66
53
50
SM
41
39
SM
44
7
3a
4b
5c
6d
7
8c
9c
10e
11
12
13
14
Et3N
K2CO3
NaHCO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
50
63
SM
3b
Reaction mixtures were heated to 80 °C for 40 h in the presence of
10 mol % of catalyst, 0.2 equiv of PPh3, and 3 equiv of base in acetone at
70 °C.
a
2 equiv of Ag2CO3 was used in this reaction.
1 equiv of Ag2CO3.
DMF was used as a solvent instead of acetone.
MeCN was used as a solvent.
b
c
d
e
O
O
Tetrabutylammonium chloride was used as an additive.
OH
R3
+
Only unreacted enoate was isolated from the reaction
between 1a and E-2 in this condition (entry 1). In contrast,
a tandem Heck-lactonization took place when Z-2 was
used as starting material, resulting in the preparation of
coumarin 4a in 68% (entry 2). The yield was almost the
same in the presence of 2 instead of 3 equiv of Ag2CO3
(entry 3) but dropped off to 53% when 1 equiv was used
(entry 4). A yield of 50% of 4a was obtained when DMF
instead of acetone was used (entry 5) and no reaction
was observed in MeCN (entry 6). Ag2CO3 could be
replaced by Et3N, but the yield decreased to 41% in acetone
Z-2
R3
I
4b-d
O
1b-d
O
b, R3 = Cl; c, R3 = NO2; d, R3 = CO2Et
O
O
OH
+
3a
EtO2C
EtO2C
I
1d
5d
Scheme 2. Reaction between 1b–d with Z-2 and 3a.

3324
Talita de A. Fernandes et al. / Tetrahedron Letters 49 (2008) 3322–3325
Table 3
0.025 mmol), PPh3 (13.1 mg, 0.05 mmol), Ag2CO3
(207 mg, 0.75 mmol), and acetone (15 mL) was stirred at
70 °C for 40 h under inert atmosphere. It was cooled, fil-
tered through diatomaceous earth and washed with ethyl
acetate. The organic phase was washed with brine, dried
over Na2SO4 and filtered. The solvent was removed in vac-
uum and the residual mass was purified by column chroma-
tography (hexane–EtOAc, 9:1) to give 4a (68%).
Yields of 4a–d and 5d in acetone/Ag2CO3 and water/Et3N in the presence
of of Pd(OAc)2
Entry
Olefin
Product
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
Z-2
Z-2
Z-2
3a
4b
4c
4d
5d
4b
4c
4d
Acetonea
Acetone
Acetone
Acetone
H2Ob
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
23
68
52
39
78
59
50
Z-2
Z-2
Z-2
H2O
H2O
Et3N
Et3N
3.2. General procedure in water
Reaction mixtures were heated to 70 °C or 80 °C for 40 h in the presence
of 10 mol % of Pd(OAc)2, 3 equiv of base and the solvent.
A mixture of PdCl2 (0.9 mg, 0.005 mmol), enoate (Z-2,
300 mg, 1.5 mmol), ortho-iodophenol (1a, 110 mg,
0.5 mmol) and Et3N (0.208 mL, 1.5 mmol) in H2O (15 mL)
was stirred at 80 °C for 40 h under N2 atmosphere. The mix-
ture was allowed to cool, H2O (10 mL) was added, and it was
extracted with EtOAc (4 Â 40 mL). The organic phase was
washed with brine, dried over Na2SO4, and filtered through
diatomaceous earth. The solvent was removed in vacuum
and the residual mass was purified by column chromatogra-
phy (hexane–EtOAc, 9:1) to give 4a (84%).
a
Reactions in acetone were accomplished in the presence of 0.2 equiv of
PPh3.
b
Reactions in H2O were accomplished in the absence of PPh3.
Table 4
Yields of 4a–c using PdCl2 as catalyst in water
Entry
Olefin
Product
Catalyst
Yield (%)
1
Z-2
Z-2
Z-2
Z-2
4a
4a
4b
4c
PdCl2
PdCl2
PdCl2
PdCl2
81
84
90
51
2a
3a
4a
Acknowledgement
Reaction mixtures were heated to 80 °C for 40 h in the presence of
10 mol % of catalyst, 3 equiv of Et3N and water.
a
1 mol % of catalyst was used.
We thank CAPES, FAPERJ, FINEP, CNPq and the
program of Oncobiology-UFRJ for financial support and
fellowships.
In order to expand the scope of this reaction, ortho-iodo-
phenols 1b–d were also used as substrates (Scheme 2,
Table 3).
Supplementary data
The yields obtained under the conditions described by
Kiss (Pd(OAc)2, Ag2CO3, PPh3, and acetone) are com-
pared in Table 3 with those obtained in the presence of
Pd(OAc)2 in Et3N and H2O. Coumarin 4b was formed in
23% in the first condition (entry 1), and the yield was
improved to 78% for the reaction in water (entry 5). For
coumarins 4c (entries 2 and 6) and 4d (entries 3 and 7)
the yields were slightly lower in water. Coumarin 5d was
obtained in 39% from enoate 3a (entry 4).
We also tried to find a better catalyst for the reaction in
water and the yield was improved using PdCl2 instead
Pd(OAc)2 in H2O and Et3N (Table 4). Coumarin 4a was
obtained in 81% and 84% yields when, respectively, 10
and 1 mol % of PdCl2 were employed (entries 1 and 2).
The yield of coumarin 4b was also enhanced when
1 mol % of PdCl2 was used (entry 3). For coumarin 4c,
essentially the same yield was obtained (entry 4).
1H NMR and 13C NMR of compounds 4a–d, 5a and 5d.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2008.03.037.
References and notes
1. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
2. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
3. Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
4. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
5. Cortese, A. N.; Ziegler, C. B.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem.
1978, 43, 2952.
6. Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941.
7. Larock, R. C. U.S. Pat. Appl. No. 767,794, 1998.
´
8. Kiss, L.; Kurtan, T.; Antus, S.; Brunner, H. ARKIVOC 2003, 69.
9. Emrich, D. E.; Larock, R. C. J. Organomet. Chem. 2004, 689, 3756.
10. Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72, 6056.
11. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr.
Med. Chem. 2005, 12, 887.
12. For alternative procedures to synthesize coumarins through palla-
dium catalyzed reactions see: (a) Battistuzzi, G.; Cacchi, S.; De Salve,
I.; Fabrizi, G.; Parisi, L. M. Adv. Synth. Catal. 2005, 347, 308; (b)
Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423.
13. (a) Ferreira, A. R. G.; Vilela, G. V. M. D.; Amorim, M. B.; Perry, K.
P.; da Silva, A. J. R.; Dias, A. G.; Costa, P. R. J. Org. Chem. 2004, 69,
4013; (b) Domingos, J. L. D.; Vilela, G. V. M. D.; Costa, P. R. R.;
Dias, A. G. Synth. Commun. 2004, 34, 589.
Work is now in progress to prepare new coumarins from
other enoates and ortho-iodophenols and use new catalyst.
The mechanism of this reaction is also under evaluation.
3. Coumarins 4 and 516–21
3.1. General procedure in organic solvents
A mixture of ortho-iodophenol (1a, 55 mg, 0.25 mmol),
enoate (Z-2, 150 mg, 0.75 mmol), Pd(OAc)2 (5.6 mg,
14. (a) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751; (b)
Gruber, A. S.; Pozebon, D.; Monteiro, A. L.; Dupont, J. Tetrahedron

Talita de A. Fernandes et al. / Tetrahedron Letters 49 (2008) 3322–3325
3325
Lett. 2001, 42, 7345; (c) Reetz, M. T.; de Vries, J. G. Chem. Commun.
2004, 1559.
18. 4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-nitro-2H-chromen-2-one
(4c): White solid; mp: 153–157 °C. 1H NMR (200 MHz, CDCl3):
d = 1.56 (s, 3H, CH3), 1.61 (s, 3H, CH3), 3.88 (m, 1H, CH2), 4.65 (m,
1H, CH2), 5.41 (t, J = 6.8 Hz, 1H, CH), 6.82 (s, 1H, @CH), 7.52 (d,
J = 9.2 Hz, 1H, ArH), 8.41 (m, 2H, ArH). 13C NMR (50 MHz,
CDCl3): d = 24.9, 25.9, 69.0, 73.0, 111.1, 113.9, 117.3, 118.5, 119.8,
126.5, 143.7, 152.5, 157.2, 158.8. MS: m/z = 291 [M+].
´
15. (a) Botella, L.; Najera, C. J. Org. Chem. 2005, 70, 4360; (b)
Solabannavar, S. B.; Desai, U. V.; Mane, R. B. Green Chem. 2002,
4, 34.
16. (S)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2H-chromen-2-one
White solid; mp 132–135 °C. IR (KBr): 1721 cmÀ1
(4a):
1H NMR
.
(200 MHz, CDCl3): d = 1.53 (s, 3H, CH3), 1.57 (s, 3H, CH3), 3.80
(dd, J = 6.9, 8.3 Hz, 1H, CH2), 4.59 (dd, J = 7.2, 8.3 Hz, 1H, CH2),
5.39 (dt, J = 1.2, 7.0 Hz, 1H, CH), 6.72 (d, J = 1.2 Hz, 1H, @CH),
7.34 (m, 3H, ArH), 7.55 (m, 1H, ArH). 13C NMR (200 MHz, CDCl3):
d = 25.1, 25.9, 69.3, 73.0, 110.4, 111.5, 117.0, 117.3, 123.1, 124.2,
131.7, 153.3, 153.5, 160.5. MS: m/z = 246 [M+].
19. Methyl 4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-2H-chromene-6-
carboxylate (4d): Yellow solid. 1H NMR (200 MHz, CDCl3): d = 1.55
(s, 3H, CH3), 1.59 (s, 3H, CH3), 3.82 (m, 1H, CH2), 3.97 (s, 3H,
OCH3), 4.65 (m, 1H, CH2), 5.42 (t, J = 7.0 Hz, 1H, CH), 6.76 (s, 1H,
@CH), 7.42 (d, J = 8.4 Hz, 1H, ArH), 8.13 (s, 1H, ArH), 8.21 (dd,
J = 8.8, 1.8 Hz, 1H, ArH). 13C NMR (50 MHz, CDCl3): d = 25.2,
25.9, 52.5, 69.3, 73.0, 110.7, 112.4, 117.0, 117.6, 125.4, 126.2, 132.7,
153.2, 156.4, 159.8, 165.4. MS: m/z = 304 [M+].
17. 6-Chloro-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-2-one
(4b): White solid; mp 129–130 °C. 1H NMR (200 MHz, CDCl3):
d = 1.53 (s, 3H, CH3), 1.57 (s, 3H, CH3), 3.81 (dd, J = 6.7, 8.4 Hz,
1H, CH2), 4.59 (dd, J = 7.2, 8.4 Hz, 1H, CH2), 5.31 (dt, J = 1.2,
6.9 Hz, 1H, CH), 6.73 (d, J = 1.2 Hz, 1H, @CH), 7.32 (d, J = 8.8 Hz,
1H, ArH), 7.38 (d, J = 2.3 Hz, 1H, ArH), 7.50 (dd, J = 2.3, 8.8 Hz,
1H, ArH). 13C NMR (200 MHz, CDCl3): d = 25.1, 26.0, 69.2, 72.9,
110.7, 112.8, 118.3, 118.8, 122.9, 129.7, 131.7, 152.0, 152.3, 159.9. MS:
m/z = 280, 282 [M+].
20. 4-Methyl-2H-chromen-2-one (5a): 1H NMR (200 MHz, CDCl3):
d = 2.45 (s, 3H, CH3), 6.31 (s, 1H, @CH), 7.33 (m, 2H, ArH), 7.52
(d, J = 7.1 Hz, 1H, ArH), 7.61 (d, J = 7.9 Hz, 1H, ArH).
21. Methyl 4-methyl-2-oxo-2H-chromene-6-carboxylate (5d): 1H NMR
(200 MHz, CDCl3): 2.51 (d, J = 1.3 Hz, 3H, CH3), 3.97 (s, 3H,
OCH3), 6.36 (d, J = 1.2 Hz, 1H, @CH), 7.38 (d, J = 8.6 Hz, 1H,
ArH), 8.20 (dd, J = 8.6, 2 Hz, 1H, ArH), 8.32 (d, J = 2 Hz, 1H, ArH).