Synthesis of coumarins via Pd-catalyzed oxidative cyclocarbonylation of 2-vinylphenols

Article abstract of DOI:10.1021/ol302725x

Palladium-catalyzed oxidative cyclocarbonylation of 2-vinylphenols constitutes a simple, direct method for the synthesis of coumarins. The reaction conditions, employing low pressures of CO, and air or 1,4- benzoquinone as the oxidant, are attractive in terms of environmental considerations and operational simplicity. Coumarins with a variety of functional groups were prepared in yields up to 85%.

Full text of DOI:10.1021/ol302725x

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5602–5605
Synthesis of Coumarins via Pd-Catalyzed
Oxidative Cyclocarbonylation
of 2‑Vinylphenols
Jamie Ferguson, Fanlong Zeng, and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry,
University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
howard.alper@uottawa.ca
Received October 2, 2012
ABSTRACT
Palladium-catalyzed oxidative cyclocarbonylation of 2-vinylphenols constitutes a simple, direct method for the synthesis of coumarins. The
reaction conditions, employing low pressures of CO, and air or 1,4- benzoquinone as the oxidant, are attractive in terms of environmental
considerations and operational simplicity. Coumarins with a variety of functional groups were prepared in yields up to 85%.
Coumarins (compounds containing the 2H-chromen-2-
one structure) are a ubiquitous class of natural products
in plants, animals, and microbiota.1 They show a broad
variety of biological activities, such as anticoagulant,2
antitumor,3 anti-inflammatory,4 antibiotic,5 anti-HIV-1,5
antidiabetic,6 and antidepressant6 activities. Consequently,
coumarins are used as synthetic building blocks in the
pharmaceutical, perfume, and agrochemical industries,
as well as additives in food and cosmetics.1 They can be
extracted from plants;a tedious process;or synthesized
by various means,7 many involving the condensation of
a carbonyl compound with a phenol derivative (e.g., the
Pechmann condensation). These classical methods usually
require harsh conditions (e.g., stoichiometric amounts of
strong acids), are not highly regiospecific, and lead to
difficult separations of product mixtures. Various cat-
alytic routes7 to coumarins include, for example, the Pd-
catalyzed oxidative reactions of phenols with propargylic
esters8a or ethyl acrylates;8b traditional Pd-catalyzed car-
bonylative cross-coupling of 2-iodophenols and alkynes;8c
and Ru-catalyzed ring-closing metathesis of esterified
2-vinylphenols.8d,e Here, we report a route to coumarins
via Pd-catalyzed oxidative cyclocarbonylation of 2-vinyl-
phenols. This method is a new, oxidative example from
within a class of transformations which are of genuine
industrial relevance and well established in the liter-
ature, namely, the alkoxycarbonylation of unsaturated
compounds.
Transition-metal-catalyzed oxidative carbonylation in-
volves the connection of two components through a carbo-
nyl group, with the assistance of an oxidant. It is synthetically
simple and efficient, since it avoids the use of halogenated or
otherwise activated substrates, is often accomplished under
mild reaction conditions, and does not require an added
(1) Kennedy, O.; Zhorenes, R. Coumarins: Biology, Applications and
Mode of Action; John Wiley and Sons: Chichester, 1997.
(2) O’Reilly, R. A.; Aggeler, P. M.; Leong, L. S. J. Clin. Invest. 1963,
42, 1542.
(3) Huang, X. Y.; Shan, Z. J.; Zhai, H. L.; Su, L.; Zhang, X. Y. Chem.
Biol. Drug Des. 2011, 78, 651.
(4) Lee, S. J.; Lee, U. S.; Kim, W. J.; Moon, S. K. Mol. Med. Rep.
2011, 4, 337.
(5) Vasconcelos, J. F.; Teixeira, M. M.; Barbosa-Filho, J. M.; Agra,
M. F.; Nunes, X. P.; Giulietti, A. M.; Ribeiro-dos-Santos, R.; Soares,
M. B. P. Eur. J. Pharmacol. 2007, 609, 126.
(6) Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh,
S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem. Lett. 2011, 21, 1937.
(7) For a review of catalytic approaches to coumarin synthesis, see:
Fedorov, A. Y.; Nyuchev, A. V.; Beletskaya, I. P. Chem. Heterocycl.
Compd. (N. Y., NY, U. S.) 2012, 48, 166.
(8) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1996, 118, 6305.
(b) Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T. Tetrahedron
2005, 61, 9291. (c) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2,
3643. (f) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992. (g) Park, K. H.; Jung, I. G.; Chung, Y. K.
Synlett 2004, 14, 2541. (d) Chatterjee, A. K.; Toste, F. D.; Goldberg,
S. D.; Grubbs, R. H. Pure Appl. Chem. 2003, 75, 421. (e) Van, T. N.;
Debenedetti, S.; De Kimpe, N. Tetrahedron Lett. 2003, 44, 4199.
r
10.1021/ol302725x
Published on Web 10/23/2012
2012 American Chemical Society

base or generate a stoichiometric HX byproduct. In fact,
water is the only stoichiometric byproduct when oxygen is
employed as the oxidant. Therefore, oxygen;and better
yet, air;is a rather ideal oxidant. However, not all oxida-
tive transformations are suited to using oxygen, and re-
agents such as quinones, peroxides, and salts of silver and
copper are often employed.9
Table 1. Optimization of the Oxidative Cyclocarbonylation of
2-Isopropenylphenol (1a)a
The oxidative alkoxycarbonylation of unsaturated com-
pounds has been extensively investigated in the literature.
There are many accounts of intramolecular oxidative
alkoxycarbonylations, for example, whereby cyclized prod-
ucts are obtained from hydroxy-functionalized alkenes
or alkynes.10 These transformations generally do not
require the activation of a CꢀH bond, since the product
is formed with the concurrent loss of hydrogen from amine
and/or alcohol nucleophiles. By contrast, the intermole-
cular Pd-catalyzed oxidative alkoxycarbonylation of term-
inal alkynes does involve sp CꢀH bond activation, and
alkyl 2-alkynoate esters are easily obtained under mild
conditions.11 The corresponding oxidative alkoxycarbo-
nylation of alkenes to R,β-unsaturated esters remains
challenging, however, since the necessary reaction condi-
tions typically transform the substrate into a complicated
mixture of products.12 In fact, very little has been pub-
lished on the selective synthesis of R,β-unsaturated esters
from alkenes and alcohols.13 Bianchini and co-workers
have made excellent contributions in this regard including
the preparation of methyl cinnamate in good selectivity
(up to 99%) from styrene and methanol, using Pd catalysts
with 1,4-benzoquinone, diphosphine ligands, and a protic
CO/O2
entry
(co)oxidant
ligand
dppb
(psi)
solvent
% 2a
1b
2
1,4-BQ
1,4-BQ
Cu(OAc)2
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQd
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
1,4-BQ
300/0
toluene
toluene
toluene
toluene
toluene
THF
38
<7
10
47
63
68
75
60
41
69
75e
67
54
61
0
300/0
3
300/0
4
dppb
300/0
5
dppb
100/0
6
dppb
100/0
7
8c
dppb
100/0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
dppb
100/0
9
dppb
100/0
10
11
12
13
14
15
16
17
18g
19h
20
21
22
23
24
25
26j
27
28k
29
30c
31c
dppe
100/0
phen
phen
dppf
100/0
100/0
100/0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
TMEDA
TMBDA
100/0
100/0
f
PR3
100/0
21
57
71
0
dppb
dppb
dppb
dppb
dppb
phen
phen
phen
phen
phen
phen
phen
phen
PPh3
Cytop292l
30/0
100/0
100/0
100/100
20/20
41
43
63
45
64
54
25j
65
55
74
41
37
100/100
100/20
100/20
100/20
100/20
20/20
acid cocatalyst under high CO pressure (800 psi).13d
A
similar reaction was carried out by Jiang and co-workers,
but with isomerization of the double bond.14 They ob-
tained alkyl-3-phenylbut-3-eneoates via Pd-catalyzed oxi-
dative allylic CꢀH carbonylation of R-methylstyrene
substrates, using a mixed quinone (BQ/DDQ) oxidant
system.
1,4-BQi
i
Cu(OAc)2
i
CuCl2
15/30
20/20 air
20/20 air
20/20 air
To our knowledge, our current work is the first report of
an intramolecular oxidative alkoxycarbonylation with net
a All reactions were performed at 1 mmol (1a) scale. Unless otherwise
indicated, the reaction conditions were as follows: Pd(OAc)2 (10%),
ligand (10%), (co)oxidant (1.5 equiv), 110 °C, 20 h. Yields are isolated
yields. b 4% Pd loading. c 20% ligand loading. d 3 equiv of oxidant. e 2a
was obtained in 60% isolated yield, plus a further 15% yield in a mixture
with the oxidized dimer 3. f A monophosphine heterocycle: 1-butyl-
2,2,6,6-tetramethylphosphinane. g The precatalyst was Pd(TFA)2
(10%). h The reaction mixture contained p-toluenesulfonic acid (2 equiv).
i 0.5 equiv of co-oxidant. j The precatalyst was PdCl2 (10%). From this
reaction, 4 was also obtained in 48% yield. k T = 140 °C. l 1,3,5,7-
Tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane.
(9) For a review of oxidative carbonylations with hydrocarbons, see:
Liu, Q.; Zhang, H.; Lei, A. Angew. Chem, Int. Ed. 2011, 50, 10788.
(10) (a) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. Curr.
Org. Chem. 2004, 8, 919. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285. McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111,
2981.
(11) (a) Tsuji, J.; Takahashi, M.; Takahashi, T. Tetrahedron Lett.
1980, 21, 849. (b) Izawa, Y.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc.
Jpn. 2004, 77, 2033.
(12) (a) Beller, M.; Tafesh, A. M. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Hermann, W. A., Eds.;
Wiley-VCH: Weinheim, 1996; p 187. (b) Sommazzi, A.; Garbassi, F.
Prog. Polym. Sci. 1997, 22, 1547. (c) Drent, E.; Budzelaar, P. H. M.
Chem. Rev. 1996, 96, 663.
(13) (a) El’man, A. R.; Boldyreva, O. V.; Slivinskii, E. V.; Loktev,
S. M. Bull. Russ. Acad. Sci. Div. Chem. Sci. (Engl. Transl.) 1992, 41, 435.
(b) Cometti, G.; Chiusoli, G. P. J. Organomet. Chem. 1979, 181, C14. (c)
Hallgren, J. E.; Matthews, R. O. J. Organomet. Chem. 1980, 192, C12–
C16. (d) Bianchini, C.; Mantovani, G.; Meli, A.; Oberhauser, W.;
sp2 CꢀH bond activation, whereby R,β-unsaturated lac-
tones (coumarins) are selectively formed from adjacent
vinyl and phenol groups on an aromatic ring. We discov-
ered this reaction while exploring alternative reaction con-
ditions to form saturated lactones from 2-vinylphenols, via
the Pd-catalyzed cyclocarbonylation we reported earlier.15
The R,β-unsaturated lactone was formed in low yields under
€
Bruggeller, P.; Stampfl., T. J. Chem. Soc., Dalton Trans. 2001, 690. (e)
Bianchini, C.; Lee, H. M.; Mantovani, G.; Meli, A.; Oberhauser, W.
New J. Chem. 2002, 26, 387. (f) Bajracharya, G. B.; Koranne, P. S.;
Tsujihara, T.; Takizawa, S.; Onitsuka, K.; Sasai, H. Synlett 2009, 2,
0310.
(14) Chen, H.; Cai, C.; Liu, X.; Li, X.; Jiang, H. Chem. Commun.
2011, 47, 12224.
(15) (a) Dong, C.; Alper, H. J. Org. Chem. 2004, 69, 5011. (b) Ye, F.;
Alper, H. Adv. Synth. Catal. 2006, 348, 1855.
Org. Lett., Vol. 14, No. 21, 2012
5603

certain conditions, sometimes as the main or only product,
even in the absence of an external oxidant. The addition of
an oxidant greatly improved yields, however, and several
were investigated in the course of optimizations.
Table 2. Optimized Oxidative Cyclocarbonylation of 2-Vinyl-
phenols to Coumarins
We chose 2-isopropenylphenol (1a) as a model substrate
to optimize the oxidative Pd-catalyzed cyclocarbonyl-
ation of 1a to 2a. Table 1 shows some of the conditions
that were tried. Acceptable yields of 2a were obtained with
palladium(II) acetate at a 10% catalyst loading. No reac-
tion took place in the absence of a palladium source. The
reaction was not enhanced by the use of a less coordinating
anion in the precatalyst (Table 1, entry 18) or by addition
of p-toluenesulfonic acid (Table 1, entry 19). A range
of solvents were tolerated, but best results were obtained
in acetonitrile (Table 1, entries 5ꢀ7, 11, 12). The optimal
pressure of CO depended upon the choice of oxidant. For
example, with 1,4-benzoquinone, 100 psi of CO appeared
to be the optimal pressure, whereas, with O2 or air, the
optimal CO pressure was around 1 or 2 atm.
The reaction requires a ligand, since essentially no
product is formed in the absence of one (Table 1, entries 2
and 3). An equimolar ratio of Pd/L worked best. In fact,
excess ligand actually appeared detrimental (Table 1,
entry 8). Monodentate phosphines performed rather
poorly (Table 1, entries 16, 30, and 31), and a longer chain
dinitrogen ligand, N,N,N0,N0-tetramethyldiaminobutane,
was completely ineffective (Table 1, entry 15). In contrast,
diphosphine or short-chain dinitrogen bidentate ligands all
worked fairly well (Table 1, entries 7, 10ꢀ14). When using
1,10-phenanthroline (phen) as the ligand in acetonitrile,
with 1,4-benzoquinone as the oxidant, 2a was obtained
in 60% isolated yield after column chromatography,
plus a further 15% yield that eluted in a 1:1 mixture
with the oxidized dimer 3 (Table 1, entry 11). Dimer 3
was only observed in this particular solvent/ligand/oxidant
combination.
a Isolated yields using the following experimental conditions: 1(1 mmol),
1,4-benzoquinone (1.5 mmol), Pd(OAc)2 (0.1 mmol), dppb (0.1 mmol),
CH3CN (5 mL), CO (100 psi), 110 °C, 20 h. b Isolated yields from the
following experimental conditions: 1 (1 mmol), Pd(OAc)2 (0.1 mmol), 1,10-
phenanthroline (0.1 mmol), CH3CN (5 mL), air (20 psi), CO (20 psi), 110 °C,
20 h. c The experiment was repeated once and gave the same result.
Another interesting outcome was found using PdCl2/
CuCl2 with CO/O2 (Table 1, entry 26), where the dimeric
diester 4 was formed in 48% yield, along with the expected
coumarin in 25% yield. This result seems to follow the
argument of Bianchini and co-workers13d that the presence
of a more strongly coordinating counteranion (i.e., chloride)
would hinder β-hydride elimination from the Pd-alkyl
intermediate and favor CO coordination to Pd, leading to
double carbonylation, followed by nucleophilic attack by
the phenol group of a second molecule of 1a.
We tried a range of oxidants and co-oxidants for the reac-
tions, and initially, it appeared that nothing could surpass
the results obtained with a slight excess of 1,4-benzoquinone
and moderate CO pressure. Therefore, we explored the
substrate scope under those conditions (Table 2). Obviously,
though, the use of oxygen and lower CO pressures would be
more ideal and green. Therefore, we were delighted to
discover that this reaction worked as well or better under
low pressures of CO and without 1,4-benzoquinone,
when we replaced low pressures of O2 with air (Table 1,
entry 29, and Table 2). We tried all substrates under these
lower-pressure, aerobic conditions for comparison.
As demonstrated in Table 2, 2-vinylphenolic substrates
with a variety of substitutions on the aromatic ring or vinyl
group could be transformed into the corresponding cou-
marins. Substituents at the 3-, 4-, and 5-positions were well
tolerated, especially under the optimized aerobic condi-
tions. However, steric crowding, by introduction of a fused
ring ortho to the hydroxyl group (1i), caused yields to
fall sharply for the transformation of 1i to 2i, using either
1,4-benzoquinone or air as the oxidant.
5604
Org. Lett., Vol. 14, No. 21, 2012

There were marked similarities, as well as clear differ-
ences, in the behavior of the two oxidative systems, as illus-
trated inTable 2. Inboth systems, a chloro-substituent (1d)
was better tolerated than bromo- (1e) in the 4-position
of the substrate. Also in both systems, methyl substitu-
tion was better tolerated in the 4-position (1g) than in the
5-position (1f). However, very different results were seen
regarding substitution at the R-position of the vinyl group.
When 1,4-benzoquinone was usedasthe oxidant, R-phenyl
substituted2bwas obtainedin 85% yield, whereas the yield
dropped to 58% for the unsubstituted 2c. Under aerobic
conditions, this trend was reversed: 2b was obtained in just
54% yield, while 2c was obtained in 85% yield. The reason
for this is unclear.
Scheme 1. Possible Mechanism of Oxidative Cyclocarbonylation
Related substrates, 2-allylphenol and 2-vinylaniline,
were each also subjected to the optimized reaction condi-
tions with 1,4-benzoquinone. None of the desired seven-
membered R,β-unsaturated lactone or six-membered
R,β-unsaturated lactam, respectively, was obtained.
2-Vinylaniline did form the urea dimer in low (7%)
yield.
A possible mechanism for the Pd-catalyzed intra-
molecular oxidative carbonylation of 2-vinylphenols is
outlined in Scheme 1. This pathway is analogous in
a number of respects to that proposed by Bianchini and
co-workers for the oxidative carbonylation of styrene in
methanol.13d
To begin the catalysis, a palladium phenoxide species is
generated by ligand exchange with an anionic ligand, with
the loss of HX. CO insertion into the PdꢀO bond affords
a phenoxycarbonyl palladium species. Alkene insertion
of the vinyl group into the PdꢀCO bond then generates
an alkylpalladium intermediate. The coumarin product is
finally released by β-hydride elimination, and the resulting
palladium(II) hydride, L2PdIIHX, may be reduced to a
palladium(0) species throughthe loss ofHX. Palladium(II)
is regenerated by the oxidant, either 1,4-benzoquinone or
molecular oxygen, to complete the catalytic cycle.
In conclusion, we have developed an efficient Pd-catalyzed
oxidative cyclocarbonylation of 2-vinylphenols to prepare
coumarins in high yields, using simple and mild conditions
(CO e 100 psi) with air or 1,4-benzoquinone as the oxidant.
This reaction constitutes a new route to a highly important
class of natural compounds. It is also, to our knowledge,
the first intramolecular oxidative carbonylation in which a
phenol has been coupled directly with a terminal alkene.
These results add value to the scope of Pd-catalyzed oxida-
tive carbonylations.
Acknowledgment. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
for support of this research.
Supporting Information Available. Experimental de-
tails and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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