A novel palladium-catalyzed dicarbonylation process leading to coumarins

Article abstract of DOI:10.1021/jo702243m

(Chemical Equation Presented) A novel approach to coumarin derivatives has been developed starting from readily available 2-(1-hydroxyprop-2-ynyl)phenols, based on an unprecedented palladium-catalyzed dicarbonylation process. Reactions were carried out in

Full text of DOI:10.1021/jo702243m

SCHEME 1
A Novel Palladium-Catalyzed Dicarbonylation
Process Leading to Coumarins
Bartolo Gabriele,*,† Raffaella Mancuso,‡
Giuseppe Salerno,‡ and Pierluigi Plastina‡
Dipartimento di Scienze Farmaceutiche, UniVersita` della
Calabria, 87036 ArcaVacata di Rende (Cosenza), Italy, and
Dipartimento di Chimica, UniVersita` della Calabria,
87036 ArcaVacata di Rende (Cosenza), Italy
of 3-[(methoxycarbonyl)methyl]coumarins 5 in good to high
yields, according to eq 2.
b.gabriele@unical.it
ReceiVed October 17, 2007
The possibility to obtain particularly important functionalized
coumarins in one step by carbonylation of readily available
substrates4 appears to be of particular synthetic interest,5-9 also
in view of the considerable importance of this class of
heterocyclic compounds.10 In fact, coumarin derivatives are
known to possess a wide range of biological activities, including
anticancer, anti-HIV, antiacetylcholinesterase, antifungal, anti-
oxidant, antihelmintic, anticoagulant, antibacterial, antiviral, and
anticlotting activity, and find extensive application in pharma-
ceuticals, fragrances, agrochemicals, additives in food and
A novel approach to coumarin derivatives has been devel-
oped starting from readily available 2-(1-hydroxyprop-2-
ynyl)phenols, based on an unprecedented palladium-catalyzed
dicarbonylation process. Reactions were carried out in the
presence of catalytic amounts of PdI2 in conjunction with
an excess of KI in MeOH as the solvent at room temperature
and under 90 atm of CO to give 3-[(methoxycarbonyl)-
methyl]coumarins in good to high isolated yields (62-87%).
(3) 2-(1-Hydroxyprop-2-ynyl)phenols 4, bearing a terminal triple bond,
are sufficiently stable to be isolated at the pure state and to be used as
substrates.
(4) Substrates 4 were easily prepared by the Grignard reaction between
2-hydroxybenzaldehydes or 2-hydroxyaryl ketones and ethynylmagnesium
bromide. See the Supporting Information for details.
We have recently reported a new and convenient approach
to 2-benzofuran-2-ylacetic esters 2 starting from readily available
(2-allyloxyaryl)-2-yn-1-ols 1 according to eq 1.1
(5) Coumarins (2H-1-benzopyran-2-ones, 2H-chromen-2-ones) have been
classically synthesized by several routes, such as the reaction of 2-hydroxy-
benzaldehydes or 2-hydroxyaryl alkyl ketones with carboxylic anhydrides
[Kostanecki-Robinson reaction: (a) Kostanechi, S. v.; Ro´zycki, A. Ber.
Dtsch. Chem. Ges. 1901, 34, 102-112. (b) Baker, W.; Eastwood, F. M. J.
Chem. Soc. 1929, 51, 2897-2907. (c) Heilbron, I. M.; Hey, D. H.; Lythgoe,
B. J. Chem. Soc. 1936, 58, 295-300. (d) Shah, D. N.; Shah, N. M. J. Am.
Chem. Soc. 1955, 77, 1699-1700] and the reaction of â-keto esters with
phenols [von Pechmann reaction: (e) von Pechmann, H.; Ber. Dtsch. Chem.
Ges. 1884, 17, 929-979. (f) Sethna, S. M.; Phadke, R. Org. React. 1953,
7, 1-58. (g) Horning, E. C. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, pp 281-285]. Other classical coumarins syntheses include
the Perkin [(h) Johnson, J. R. Org. React. 1942, 1, 210-265], Knoevenagel
[(i) Jones, G. Org. React. 1967, 15, 204-599. (j) Brufola, G.; Fringuelli,
F.; Piermatti, O.; Pizzo, F. Heterocycles 1996, 43, 1257-1266], Reformatsky
[(k) Shriner, R. L. Org. React. 1942, 1, 15-46. (l) Rathke, M. W. Org.
React. 1975, 22, 423-460. (m) Fu¨rstner, A. Synthesis 1989, 571-590],
and Wittig [(n) Maerker, A. Org. Synth. 1934, 14, 270-291. (o) Narasimhan,
N. S.; Mali, R. S.; Barve, M. V. Synthesis 1979, 906-909. (p) Yavari, I.;
Hekmet-Shoar, R.; Zonouzi, A. Tetrahedron Lett. 1998, 39, 2391-2392]
reactions.
Formation of 2 occurred through the concatenation of two
catalytic cycles: the first one, corresponding to deallylation of
1 with formation of free phenols 3, catalyzed by Pd(0), and the
second one, corresponding to a heterocyclization-alkoxycarbo-
nylation sequence, catalyzed by Pd(II) (sequential homobime-
tallic catalysis, Scheme 1).2
We have now found that, under appropriate conditions, 2-(1-
hydroxyprop-2-ynyl)phenols 4, bearing a terminal triple bond,3
can selectively undergo a dicarbonylation process with formation
(6) For some examples of classical syntheses of 3-[(alkoxycarbonyl)-
methyl]coumarins, see: (a) Ferroud, D.; Collard, J.; Klich, M.; Dupuis-
Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg.
Med. Chem. Lett. 1999, 9, 2881-2886. (b) Sun, W.-C.; Gee, K. R.;
Haugland, R. P. Bioorg. Med. Chem. Lett. 1998, 8, 3107-3110. (c) Feng,
Y.; Burgess, K.; Pledger, D.; Cairns, N.; Linthicum, D. S. Bioorg. Med.
Chem. Lett. 1998, 8, 881-884. (d) Parmar, V. S.; Singh, S.; Rathore, J. S.
J. Indian Chem. Soc. 1987, 64, 254-257. (e) Chodankar, N. K.; Joshi, S.
D.; Sequeria, S.; Seshadri, S. Indian J. Chem. Sect. B 1987, 26, 427-430.
(f) Goya, S.; Takadate, A.; Fujino, H.; Otagiri, M.; Uekama, K. Chem.
Pharm. Bull. 1982, 30, 1363-1369.
† Dipartimento di Scienze Farmaceutiche.
‡ Dipartimento di Chimica.
(1) Gabriele, B.; Mancuso; R.; Salerno, G.; Costa, M. AdV. Synth. Catal.
2006, 348, 1101-1109. (b) Gabriele, B.; Mancuso, R.; Salerno, G.; Veltri,
L. Chem. Commun. 2005, 271-273.
(2) Free phenols 3 with R2 ) alkyl could not be used directly as substrates
for the heterocyclization-alkoxycarbonylation process, owing to their
instability. On the other hand, unprotected phenols with R2 ) Ar were
sufficiently stable to be used as substrates, but better results were still
obtained by forming them in situ starting from their allylated precursors.
10.1021/jo702243m CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/14/2007
756
J. Org. Chem. 2008, 73, 756-759

cosmetics, and insecticides.10a-i,11,12 Moreover, coumarins find
application as dyes in laser technology, fluorescent indicators,
optical brighteners, and photosensitizers.10a,13
The first experiments were carried out with 2-(hydroxyprop-
2-ynyl)phenol 4a, which was initially allowed to react under
TABLE 1. Reactions of 2-(Hydroxyprop-2-ynyl)phenol 4a with CO
and MeOH in the Presence of the PdI2-KI Catalytic System in
MeOH as the Solvent
4a/KI/PdI2
T
PCO
t
convn of yield of yield of
entry molar ratio (°C) (atm) (h) 4aa (%) 2ab (%) 5ab (%)
1c
100:100:1 100
100:100:1 100
30
60
60
60
60
60
60
60
60
60
90
15
15
1
2
2
2
2
2
2
100
100
90
81
65
63
90
100
35
20
(58)
(35)
20
10
8
(27)
(48)
53
58
46
49
65
60
19
2c
(7) For some very recent developments in the synthesis of coumarins,
see: (a) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069-3072. (b)
Valizadeh, H.; Shockravi, A.; Gholipur, H. J. Heterocycl. Chem. 2007, 44,
867-870. (c) Shi, Y. L.; Shi, M. Org. Biomol. Chem. 2007, 5, 1499-
1504. (d) Kumar, S.; Saini, A.; Sandhu, J. S. ArkiVok 2007, 18-23. (e)
Selvakumar, S.; Chidambaram, M.; Singh, A. P. Catal. Commun. 2007, 8,
777-783. (f) Reddy, B. M.; Patil, M. K.; Lakshmanan, P. J. Mol. Catal.
A:Chem. 2006, 256, 290-294. (g) Maheswara, M.; Siddaiah, V.; Damu,
G. L. V.; Rao, Y. K.; Rao, C. V. J. Mol. Catal. A:Chem. 2006, 255, 49-
52. (h) Baldoumi, V.; Gautam, D. R.; Litinas, K. E.; Nicolaides, D. N.
Tetrahedron 2006, 62, 8016-8020. (i) Oyamada, J.; Kitamura, T. Tetra-
hedron 2006, 62, 6918-6925. (j) Manhas, M. S.; Ganguly, S. N.;
Mukherjee, A. K. J.; Bose, A. K. Tetrahedron Lett. 2006, 47, 2423-2425.
(k) Liu, Y.; Mills, A. D.; Kurth, M. J. Tetrahedron Lett. 2006, 47, 1985-
1988. (l) Santana, L.; Uriarte, E.; Gonzalez-Diaz, H.; Zagotto, G.; Soto-
Otero, R.; Mendez-Alvarez. E J. Med. Chem. 2006, 49, 1149-1156.
(8) Only a few transition metal-catalyzed approaches to the synthesis of
coumarins have been reported. For representative examples, see ref 9 and:
(a) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc. 2003, 125,
4518-4526. (b) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2001, 40, 1286-1288. (c) Jia, C.; Piao, D.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992-1995. (d) Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc. 1996, 118, 6305-6306. (e) Catellani, M.; Chiusoli, G.
P.; Fagnola, M. C.; Solari, G. Tetrahedron Lett. 1994, 35, 5919-5922.
(9) To our knowledge, only very few reports on coumarin synthesis by
a direct carbonylation approach have appeared in the literature so far: (a)
Cao, H.; Xiao, W. J. Can. J. Chem. 2005, 83, 826-831. (b) Kadnikov, D.
V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423-9432. (c) Yoneda, E.;
Sugioka, T.; Hirao, K.; Zhang, S. W.; Takahashi, S. J. Chem. Soc., Perkin
Trans. 1 1998, 477-483. (d) Catellani, M.; Chiusoli, G. P.; Fagnola, M.
C.; Solari, G. Tetrahedron Lett. 1994, 35, 5923-5926. None of these
methods, however, led to 3-[(alkoxycarbonyl)methyl]coumarins by direct
dicarbonylation of acyclic substrates.
3c
100:100:1
100:100:1
200:100:1
200:100:1
200:100:1
200:100:1
200:10:1
60
25
25
25
40
60
25
25
25
4c
5c
6d
7d
8d
9d
10d
11d
5
20
28
9
5
6
200:200:1
200:100:1
2
2
13
62
75
a Determined by GLC. b GLC yield (isolated yield) based on 4a.
c Substrate concentration was 0.22 mmol/mL of MeOH. d Substrate con-
centration was 0.50 mmol/mL of MeOH.
conditions similar to those previously used for the conversion
of (2-allyloxyphenyl)-2-yn-1-ols 1 into 2-benzofuran-2-ylacetic
esters 2 (PdI2 as the catalyst in conjunction with an excess of
KI, 4a/KI/PdI2 molar ratio ) 100:100:1, in MeOH as the solvent
at 100 °C and under 30 atm of CO). After 15 h, a mixture of
carbonylated products, that is, the benzofuran-2-acetic methyl
ester 2a (58% isolated yield) together with 3-[(methoxycarbo-
nyl)methyl]coumarin 5a (27% isolated yield), was obtained at
total substrate conversion (eq 3 and Table 1, entry 1).
(10) (a) Murray, R. D. H.; Me´ndez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry, and Biochemistry; Wiley: New York,
1982. (b) Coumarins: Biology, Applications, and Mode of Action;
O’Kennedy, R., Thornes, R. D., Eds.; John Wiley & Sons: New York,
1997. (c) Murray, R. D. H. Prog. Chem. Org. Nat. Prod. 2002, 83, 1-673.
(d) Kulkarni, M. V.; Kulkarni, G. M.; Lin, C. H.; Sun, C. M. Curr. Med.
Chem. 2006, 13, 2795-2818. (e) Kostova, I. Curr. HIV Res. 2006, 4, 347-
363. (f) Kostova, I. Mini-ReV. Med. Chem. 2006, 6, 365-374. (g) Borges,
F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887-916. (h) Lacy, A.; O’, Kennedy, R. Curr. Pharm. Design
2004, 10, 3797-3811. (i) Yu, D.; Suzuki, M.; Xie, L.; Morris-Natscke, S.
L.; Lee, K.-H. Med. Res. ReV. 2003, 23, 322-345. (j) Trenor, S. R.; Shultz,
A. R.; Love, B. J.; Long, T. E. Chem. ReV. 2004, 104, 3059-3077.
(11) For very recent examples on the pharmacological activity of
coumarins, see: (a) Jacquot, Y.; Laios, L.; Cleeren, A.; Nonclercq, D.;
Bermont, L.; Refouvelet, B.; Boubekeur, K;, Xicluna, A.; Leclercq, G.;
Laurent, G. Bioorg. Med. Chem. Lett. 2007, 15, 2269-2282. (b) Hadji-
pavlou-Litina, D.; Kontogiorgis, C.; Pontiki, E.; Dakanali, M.; Akoumianaki,
A.; Katerinopoulos, H. E. J. Enzym. Inhib. Med. Ch. 2007, 22, 287-292.
(c) Ruiz-Marcial, C.; Chilpa, R. R.; Estrada, E.; Reyes-Esparza, J.; Farina,
G. G.; Rodriguez-Fragoso, L. J. Pharm. Pharmacol. 2007, 59, 719-725.
(d) Garazd, M. M.; Muzychka, O. V.; Vovk, A. I.; Nagorichna, I. V.;
Ogorodniichuk, A. S. Chem. Nat. Compd. 2007, 43, 19-23. (e) Zhang, Q.
Y.; Qin, L. P.; He, W. D.; Van Puyvelde, L.; Maes, D.; Adams, A.; Zheng,
H. C.; De Kimpe, N. Planta Med. 2007, 73, 13-19.
(12) For recent examples on the pharmacological activity of [(3-
alkoxycarbonyl)methyl]coumarins, see: (a) Patterson, A. W.; Wood, W. J.
L.; Hornsby, M.; Lesley, S.; Spraggon, G.; Ellman, J. A. J. Med. Chem.
2006, 49, 6298-6307. (b) Wood, J. L.; Patterson, A. W.; Tsuruoka, H.;
Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527. (c)
Raj, H. G.; Parmar, V. S.; Jain, S. C.; Goel, S.; Himanshu, P.; Malhotra,
S.; Singh, A.; Olsen, C. E.; Wengel, J. Bioorg. Med. Chem. 1998, 6, 833-
839. (d) Raj, H. G.; Gupta, S.; Biswas, G.; Singh, S.; Singh, A.; Jha, A.;
Bisht, K. S.; Sharma, S. K.; Jain, S. C.; Parmar, V. S. Bioorg. Med. Chem.
1996, 4, 2225-2228.
Formation of the coumarin derivative was not observed in
the case of (2-allyloxyaryl)-2-yn-1-ols 1, bearing an internal
triple bond.1 Evidently, in the case of substrate 4a, bearing a
terminal triple bond, a second reaction route, corresponding to
dicarbonylation to give coumarin 5a, becomes competitive with
the heterocyclization-alkoxycarbonylation route leading to
benzofurans. This is in agreement with what we have already
observed in other PdI2-catalyzed carbonylation reactions of
alkynes, namely, that usually only terminal triple bonds undergo
PdI2-catalyzed dicarbonylation.14 Formation of the coumarin
derivative may occur through two different pathways (Scheme
2, anionic iodide ligands are omitted for clarity).15 The first
possibility (path a) corresponds to triple-bond insertion into the
Pd-C bond of a phenoxycarbonylpalladium intermediate fol-
lowed by alkoxycarbonylation. Alternatively, triple-bond inser-
tion into the Pd-C bond of a methoxycarbonylpalladium species
may occur, followed by CO insertion and intramolecular
nucleophilic displacement (path b). In either case, intermediate
6 and an H-Pd-I complex are formed, which, according to a
known reactivity,1,16 react to afford an allylpalladium intermedi-
ate with elimination of water. Protonolysis of the allylpalladium
(13) See, for example: (a) Zabradnik, M. The Production and Application
of Fluorescent Brightening Agents; John Wiley & Sons: New York, 1992.
(b) Sekar, N. Colourage 2003, 50, 55-56. (c) Maeda, M. Laser Dyes;
Academic Press: New York, 1984. (d) Brun, M.-P.; Bischoff, L.; Garbay,
C. Angew. Chem., Int. Ed. 2004, 43, 3432-3436.
J. Org. Chem, Vol. 73, No. 2, 2008 757

TABLE 2. Synthesis of 3-[(Methoxycarbonyl)methyl]coumarins
5a-d by PdI2/KI-Catalyzed Dicarbonylation of
2-(1-Hydroxyprop-2-ynyl)phenols 4a-da
SCHEME 2
entry
4
R1 R2
R3 t (h) conv of 4b (%)
5
yield of 5c (%)
12 4a
13 4b
14 4c
15 4c
16 4d
17 4d
H
H
H
H
H
H
H
OMe
H
H
H
H
H
8
8
8
100
100
71
100
68
5a
5b
5c
5c
5d
5d
87 (83)d
(81)e
42f
OMe
OMe 15
Cl
Cl
(70)g
47h
8
15
H
100
(74)i
a All reactions were carried out at room temperature in MeOH (0.5 mmol
of 4/mL of MeOH, 5 mmol scale based on 4) under 90 atm of CO in the
presence of PdI2 in conjunction with KI (4/KI/PdI2 molar ratio ) 200/100/
1). b Determined by GLC. c GLC yield (isolated yield) based on 4. d Ben-
zofuran-2-ylacetic acid methyl ester 2a was also formed in 10% isolated
yield (8% isolated). e (7-Methoxybenzofuran-2-yl)acetic acid methyl ester
2b was also formed in 9% isolated yield. f (5-Methoxybenzofuran-2-yl)acetic
acid methyl ester 2c was also formed in 8% GLC yield. g Benzofuran 2c
was also formed in 10% isolated yield. h (5-Chlorobenzofuran-2-yl)acetic
acid methyl ester 2d was also formed in 5% GLC yield. i Benzofuran 2d
was also formed in 6% isolated yield.
TABLE 3. Reactions of 2-(Hydroxy-1-methylprop-2-ynyl)phenol 4e
with CO and MeOH in the Presence of the PdI2-KI Catalytic
System in MeOH as the Solvent (0.50 mmol of 4e/mL of MeOH)
4e/KI/PdI2
T
PCO
t
convn of yield of yield of
entry molar ratio (°C) (atm) (h) 4ea (%) 2eb (%) 5eb (%)
complex by HI eventually leads to the coumarin derivative with
regeneration of PdI2.
18
19
20
21
22
23
200:100:1
100:100:1
100:50:1
100:10:1
100:10:1
100:10:1
25
40
40
40
40
40
90
60
60
60
90
90
8
2
2
2
2
67
31
51
80
79
95
45
5
9
19
15
18
20
17
28
57
61
71
Based on this initial result, we tried to selectively activate
the catalytic process toward the formation of the coumarin
derivative by suitably changing the reaction parameters (Table
1, entries 2-11). As can be seen, the selectivity toward 5a could
be significantly improved by raising the CO pressure, decreasing
the reaction temperature, and increasing the substrate concentra-
tion.
15
a Determined by GCL. b GLC yield based on 4e.
Under the final optimized conditions (4a/KI/PdI2 molar ratio
) 200:100:1, concentration of 4a ) 0.50 mmol/mL of MeOH,
T ) 25 °C, PCO ) 90 atm, t ) 8 h), coumarin 5a was obtained
in an isolated yield as high as 83%, benzofuran 2a being also
obtained in only 8% isolated yield (Table 2, entry 12). Under
these conditions, other 2-(1-hydroxyprop-2-ynyl)phenols 4b-
d, bearing a π-donor or an electron-withdrawing group on the
aromatic ring, afforded, after 8-15 h, the corresponding
coumarins in good yields (70-81%) and high selectivity (Table
2, entries 13, 15, and 17).
As expected in view of the higher steric hindrance on the
triple bond, substrates bearing an additional benzylic substituent
(R1 ) alkyl, phenyl) were slightly less reactive than the
analogous ones with R1 ) H. Thus, the reaction of 2-(1-hydroxy-
1-methylprop-2-ynyl)phenol 4e (R1 ) Me, R2 ) R3 ) H),
carried out under the same conditions as entry 12, led to the
corresponding coumarin and benzofuran derivatives (5e and 2e,
respectively) in 45% and 20% GLC yields at 67% substrate
conversion (Table 3, entry 18). In order to find the optimal
reaction conditions also for this substrate, we next tested its
reactivity at 40 °C under various conditions (Table 3, entries
19-23). Working under 60 atm of CO with a 4e/KI/PdI2 molar
ratio of 100/100/1, substrate conversion after 2 h was 31%, while
the GLC yields of the benzofuran and coumarin derivatives (2e
and 5e, respectively) were 17 and 5%, respectively. Interestingly,
the substrate conversion and products yields were higher by
working with lower KI/PdI2 ratios (entries 20 and 21). This is
conceivable, since, in the presence of a less coordinating triple
bond, iodide anions may compete more effectively for coordina-
tion to the metal center. As already observed for 4a, an increase
of the carbon monoxide pressure from 60 to 90 atm caused an
increase of the selectivity toward the coumarin derivative (entry
22). Under these latter conditions, substrate conversion reached
95% after 15 h, with GLC yields of 2e and 5e of 18 and 71%,
respectively (entry 23). As expected, the same reaction, carried
out at 25 °C rather than 40 °C, was slower but more selective
toward coumarin 5e: substrate conversion was 100% after 24
h, with GLC yields of 2e and 5e of 90% and 10%, respectively
(87% and 9% isolated, Table 4, entry 24). Similar results were
obtained with 4-chloro-2-(1-hydroxy-1-methylprop-2-ynyl)phe-
(14) (a) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P. J. Chem.
Soc., Perkin Trans. 1 1994, 84-87. (b) Bonardi, A.; Costa, M.; Gabriele,
B.; Salerno, G.; Chiusoli, G. P. Tetrahedron Lett. 1995, 36, 7495-7498.
(c) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem.
1995, 503, 21-28. (d) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa, M.;
Chiusoli, G. P. J. Chem. Soc., Perkin Trans. 1 1997, 147-154. (e) Gabriele,
B.; Salerno, G.; Costa, M.; Chiusoli, G. P. Chem. Commun. 1999, 1381-
1382. (f) Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M.; Massera, C. Eur.
J. Org. Chem. 2001, 4607-4613. (g) Gabriele, B.; Veltri, L.; Salerno, G.;
Costa, M.; Chiusoli, G. P. Eur. J. Org. Chem. 2003, 1722-1728. (h)
Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem.
2003, 687, 219-228. (i) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G.
P. Curr. Org. Chem. 2004, 8, 919-946.(j) Gabriele, B.; Salerno, G.; Costa,
Synlett 2004, 2468-2483. (k) Gabriele, B.; Salerno, G. PdI2. In e-EROS
(Electronic Encyclopedia of Reagents for Organic Synthesis); Crich, D.,
Ed.; Wiley-Interscience: New York, 2006.
(15) For a recent monograph on Pd-catalyzed cyclocarbonylation-
alkoxycarbonylation reactions, including a detailed mechanistic discussion,
see: Gabriele, B.; Salerno, G. Cyclocarbonylation. In: Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; Vol. II; pp 2623-2641.
(16) (a) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J. Mol.
Catal. A: Chem. 1996, 111, 43-48. (b) Ozawa, F.; Ishiyama, T.;
Yamamoto, S.; Kawagishi, S.; Murakami, H. Organometallics 2004, 23,
1698-1707.
758 J. Org. Chem., Vol. 73, No. 2, 2008

TABLE 4. Synthesis of 3-[(Methoxycarbonyl)methyl]coumarins
5e-g by PdI2/KI-Catalyzed Dicarbonylation of
2-(1-Hydroxyprop-2-ynyl)phenols 4e-ga
by column chromatography on silica gel using 8:2 hexane-AcOEt
(reaction crude deriving from 4a) or 7:3 hexane-AcOEt (reaction
crude deriving from the reactions of 4b, 4c, and 4d) as eluent. The
benzofuran derivatives 2a-d were eluted first in all cases: 2a was
a yellow oil (77.5 mg, 8% based on 4a, Table 2, entry 12); 5a was
a yellow solid, mp 77-78 °C (0.91 g, 83% based on 4a, Table 2,
entry 12); 2b was a yellow oil (100.3 mg, 9% based on 4b, Table
2, entry 13); 5b was a yellow solid, mp 108-110 °C (1.01 g, 81%
based on 4b, Table 2, entry 13); 2c was a yellow solid, mp 78-80
°C (109.8 mg, 10% based on 4c, Table 2, entry 15); 5c was a yellow
solid, mp 128-130 °C (0.87 g, 70% based on 4c, Table 2, entry
15); 2d was a yellow solid, mp 58-59 °C (65.8 mg, 6% based on
4d, Table 2, entry 17); 5d was a yellow solid, mp 128-129 °C
(0.93 g, 74% based on 4d, Table 2, entry 17).
entry
4
R1 R2 R3 t (h) convn of 4b (%)
5
yield of 5c (%)
24
25
26
4e Me
4f Me
4g Ph
H
H
H
H
24
Cl 24
24
100
100
100
5e
5f
5g
90 (87)d
(76)
H
66 (63)e
a All reactions were carried out at room temperature in MeOH (0.5 mmol
of 4/mL of MeOH, 5 mmol scale based on 4) under 90 atm of CO in the
presence of PdI2 in conjunction with KI (4/KI/PdI2 molar ratio ) 100/10/
1). b Determined by GLC. c GLC yield (isolated yield) based on 4. d (3-
Methylbenzofuran-2-yl)acetic acid methyl ester 2e was also formed in 9%
isolated yield. e (3-Phenylbenzofuran-2-yl)acetic acid methyl ester 2g was
also formed in 30% GLC yield (27% isolated).
2-Benzofuran-2-ylacetic acid methyl ester 2a was characterized
by comparison with literature data.1 Complete characterization data
for all the other products are given in the Supporting Information.
General Procedure for the Carbonylation of 2-(1-Hydroxy-
prop-2-ynyl)phenols 4e-g To Give Coumarins 5e-g (Table 4,
Entries 24-26). In a typical experiment, a 250 mL stainless steel
autoclave was charged with PdI2 (18.0 mg, 5.0 × 10-2 mmol), KI
(83.0 mg, 2.5 mmol), and a solution of 4 (5.0 mmol) in anhydrous
MeOH (10.0 mL). The autoclave was sealed, purged at room
temperature several times with CO with stirring (10 atm), and
eventually pressurized at 90 atm. After being stirred at room
temperature for 24 h, the autoclave was degassed. The solvent was
evaporated, and products were purified by column chromatography
on silica gel using 7:3 hexane-AcOEt (reaction crude deriving from
the reactions of 4e, 4f) or 9:1 hexane-acetone (reaction crude
deriving from the reaction of 4g) as eluent. The benzofuran
derivatives 2e and 2g were eluted first: 2e was a yellow oil (90.5
mg, 9% based on 4e, Table 4, entry 24); 5e was a yellow solid, mp
130-131 °C (1.01 g, 87% based on 4e, Table 4, entry 24); 5f was
a yellow solid, mp 55-56 °C (1.01 g, 76% based on 4f, Table 4,
entry 25); 2g was a yellow oil (360.3 mg, 27% based on 4g, Table
4, entry 26); 5g was a yellow solid, mp 120-121 °C (0.92 g, 63%
based on 4g, Table 4, entry 29). Complete characterization data
for all products are given in the Supporting Information.
nol 4f, bearing a chloro substituent on the aromatic ring (R3 )
Cl) (entry 25, Table 4), while the reaction was slightly less
selective in the case of 2-(1-hydroxy-1-phenylprop-2-ynyl)-
phenol 4g, bearing a phenyl rather than a methyl group at the
benzylic position (R1 ) Ph), as shown by entry 26 (Table 4).
In conclusion, we have reported a novel synthesis of
3-[(alkoxycarbonyl)methyl]coumarins 5 in good to high yields
starting from readily available 2-(1-hydroxyprop-2-ynyl)phenols
4, based on an unprecedented palladium-catalyzed dicarbony-
lation process.9 The selectivity of the process toward the
formation of the coumarin derivatives rather than toward
benzofuran derivatives 2 (deriving from a competitive hetero-
cyclization-alkoxycarbonylation process) turned out to be
highly dependent on both carbon monoxide pressure and
reaction temperature. Very good selectivities toward coumarins
5 could in fact be obtained working at room temperature and
under 90 atm of CO.
Experimental Section
Preparation of Substrates. Substrates were prepared and
characterized as described in the Supporting Information.
Acknowledgment. This work was supported by the Minis-
tero dell’Universita` e della Ricerca (Progetto di Ricerca di
Interesse Nazionale PRIN 2006031888, Roma, Italy).
General Procedure for the Carbonylation of 2-(1-Hydroxy-
prop-2-ynyl)phenols 4a-d To Give Coumarins 5a-d (Table 2,
Entries 12, 13, 15, and 17). In a typical experiment, a 250 mL
stainless steel autoclave was charged with PdI2 (9.0 mg, 2.5‚10-2
mmol), KI (415.0 mg, 2.5 mmol), and a solution of 4 (5.0 mmol)
in anhydrous MeOH (10.0 mL). The autoclave was sealed, purged
at room temperature several times with CO with stirring (10 atm),
and eventually pressurized at 90 atm. After being stirred at room
temperature for 8 h (4a, 4b) or 15 h (4c, 4d), the autoclave was
degassed. The solvent was evaporated, and products were purified
Supporting Information Available: General experimental
methods, preparation and characterization of substrates, character-
ization data, and copies of 1H and 13C NMR spectra for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702243M
J. Org. Chem, Vol. 73, No. 2, 2008 759