A new palladium-catalyzed addition: A mild method for the synthesis of coumarins

Full text of DOI:10.1021/ja961107i

J. Am. Chem. Soc. 1996, 118, 6305-6306
6305
A New Palladium-Catalyzed Addition: A Mild
Method for the Synthesis of Coumarins
Barry M. Trost* and F. Dean Toste
Department of Chemistry, Stanford UniVersity
position, but none of the desired coumarin. A dramatic change
occurred by switching to formic acid. Using 30% palladium
acetate and 50% sodium acetate at 50 °C, a 40% yield of the
Stanford, California 94305
ReceiVed April 4, 1996
1
0
coumarin 3a, mp 143-5 °C, was obtained. Reducing the
palladium acetate to 10% and the sodium acetate to 20% at 35
°C increased the yield to 82% (method A). To ascertain the
source of this effect, consideration of the reducing properties
Palladium(0) complexes in the presence of carboxylic acids
have proven to be an interesting catalyst system. In spite of
the absence of any discernable reaction between Pd(0) and the
carboxylic acid, this catalyst system effects cycloisomerizations
1
1
of formic acid toward Pd(+2) salts led to the notion that
perhaps a Pd(0) species was the actual catalyst. Indeed, using
2.5 mol % (dba) Pd ‚CHCl and 10 mol % sodium acetate in
1
2
of enynes, reductive cyclizations of enynes and diynes, and
semihydrogenation of alkynes.3 All of these reactions are best
interpreted as initiated by a hydropalladation with a hydridopal-
ladium carboxylate formed in equilibrium albeit at very low
concentration. In conjunction with a projected synthesis of
3
2
3
formic acid at 25 °C gave 3a in yields up to 88% (method B).
Although sodium acetate is not required, the reactions proceeded
faster and at lower temperature in its presence. The methyl
ethers are not required. Phloroglucinol (1b) reacts equally well
4
a
aflatoxins, our desire to find a mild route to coumarins led to
a new reaction involving this catalyst system which follows a
completely different course.
7
to give 5,7-dihydroxycoumarin, (3b) mp 270-272 °C, by
method B in 79% yield. Extension of the reaction to substituted
alkynoates was also examined. Running the reaction according
to method A with ethyl phenylpropynoate and ethyl 2-butynoate
led to the corresponding 4-substituted coumarins 6a, mp 164-5
Although coumarins retain a high degree of importance
5
because of their biological relevancy, improved methods of
synthesis have not evolved.4 One of the most attractive methods
6
12
13
is the Pechmann condensation and a variation wherein an
°C, and 6b, mp 168-170 °C, (eq 3) in 69% and 51% yields,
alkynoate replaces the more typical â-ketoester.7 The major
drawbacks of this protocol stem from the requirement of
stoichiometric amounts of strong Bronsted or Lewis acids at
high temperature that also frequently limit its scope.
We chose the reaction depicted in eq 1 as our test reaction,
respectively. In the latter case, switching to method B increased
the yield to 63%.
The regioselectivity was examined in the case of phenols 7a
and 7b (eq 4). In both cases, good selectivity for formation of
consistent with our goal directed toward the aflatoxins. The
initial concept was based upon an electrophilic palladation
8
,9
of the phenol 1a to give 4a (eq 2). Standard carbametalation
of the alkynoate to give 5a followed by protonolysis would give
the cinnamate 2a which, in turn, should readily cyclize to the
coumarin 3a. In the event, treatment of ethyl propynoate with
phenol 1a in acetic acid buffered with sodium acetate at room
temperature (rt) to 70° gave either starting material or decom-
(
1) Trost, B. M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116,
268. Trost, B. M.; Czeskis, B. A. Tetrahedron Lett. 1994, 35, 211. Trost,
B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421.
4
the new bond occurred para to the methoxy group. Using
method A, phenol 7a gave isolated yields of herniarin (8a), mp
(2) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32, 1613. Trost, B.
1
4
15
1
19-120 °C, and 9a, mp 80-82 °C, of 52% and 7%,
M.; Edstrom, E. D. Angew. Chem., Int. Ed. Engl. 1990, 29, 520. Trost, B.
M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255.
respectively. Using method B, phenol 7b gave isolated yields
of 8b, mp 139-142 °C, and 9b of 72% and 10%, respectively.
(
3) Trost, B. M.; Braslau, R. Tetrahedron Lett. 1989, 30, 4657.
16
(
4) (a) Marray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
The fact that the absence or presence of the methyl group had
essentially no effect on the regioselectivity suggests that
electronic more than steric effects account for the regioselec-
tivity.
This reaction succeeds where the Pechmann condensation is
claimed to perform poorly. For example, the synthesis of
umckalin methyl ether (10) required a four-step protocol from
Coumarins; Wiley: New York, 1982. (b) Hepworth, J. D. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A., Rees, C. W., Boulton, A. J.,
McKillop, A., Ed.; Pergamon Press: Oxford, 1984; Vol. 3, Chapter 2.24,
pp 799-810. (c) Staunton, J. In ComprehensiVe Organic Chemistry; Barton,
D. H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 4, Chapter
1
8.2, pp 651-653. (d) Livingstone, R. In Rodd’s Chemistry of Carbon
Compounds; Coffey, S., Ed.; Elsevier: Amsterdam, 1977; Vol. IV, Part E.
5) Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings of
(
the International Society of Coumarin InVestigators; Springer: Berlin, 1994.
(
6) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1.
(
7) Kaufman, K. D.; Kelly, R. C. J. Heterocyclic Chem. 1965, 2, 91.
(10) Caldwell, A. G.; Jones, E. R. H. J. Chem. Soc. 1945, 540. Mali, R.
S.; Yadav, V. J. Synthesis 1977, 465.
Fischer, E.; Nouri, O. Chem. Ber. 1917, 50, 693. Also, see: Ganguly, A.
K.; Joshi, B. J.; Kamat, V. N.; Manmade, A. H. Tetrahedron 1967, 23,
(11) cf: Tsuji, J.; Mandai, T. Synthesis 1996, 1.
(12) Ahluwalia, V. K.; Sunita Ind. J. Chem. B 1978, 16, 528.
(13) Dreyer, D. L.; Munderich, K. P. Tetrahedron 1975, 31, 287.
(14) Steck, N.; Bailey, B. K. Can. J. Chem. 1967, 47, 3577.
(15) Ahluwalia, V. K.; Sachdev, G. P.; Seshardi, T. R. Ind. J. Chem.
1967, 5, 461. Nrasinhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis 1979,
906.
4
777.
(
8) cf: Trost, B. M.; Fortunak, J. M. D. Organometallics 1982, 1, 7.
Fuchita, Y.; Hiraki, K.; Kamogawa, Y.; Suenaga, M.; Tohgoh, K.; Fujiwara,
Y. Bull. Chem. Soc. Jpn. 1989, 62, 1081.
(
9) Cyclopalladation is much more common than simple palladation.
See: Canty, A. J. ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Puddephatt, R. J., Eds.; Pergamon:
Oxford, 1995; Vol. 9, Chapter 5, pp 242-8.
(16) Das Gupta, A. K.; Chatterje, R. M.; Das Carp, K. R. J. Chem. Soc.
C 1969, 2618.
S0002-7863(96)01107-9 CCC: $12.00 © 1996 American Chemical Society

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306 J. Am. Chem. Soc., Vol. 118, No. 26, 1996
Communications to the Editor
Scheme 1. A Mechanistic Proposal
3
,4,5-trimethoxyphenol.17 The one-step palladium-catalyzed
observations of the effectiveness of (dba)3Pd2 in formic acid to
cycloisomerize enynes. Since this reaction is initiated by a
hydropalladation, the formation of HPdX appears likely. Scheme
1
8
21
reaction (method B) provided coumarin 10, mp 72-74 °C, in
4
6% yield unoptimized (eq 5).
1
outlines the proposed mechanism. Although this mechanistic
proposal supports the concept of a cis addition to produce
E-cinnamic esters, their known ease of E-Z isomerization
accounts for the isolation of the coumarin rather than the
5
E-cinnamates. Employing phenylsulfonylethyne which cannot
cyclize did produce the expected E-alkene (eq 8). The low
1
9
Ayapin (11) represents another difficult example and
required a four-step synthesis.20 As shown in eq 6, this
reactivity of the palladium phenoxide requires the alkyne to bear
an electron-withdrawing group. Further, the aryl ring must be
at least as electron rich as â-naphthol; for example, m-cresol
did not react. This proposal suggests a new way to effect direct
electrophilic aromatic substitution using catalytic “catalysts” in
contrast to the normal Lewis acid “catalyzed” reactions which,
almost invariably, require more than stoichiometric amounts of
coumarin, mp 225-227 °C,19 is available in 67% yield using
method B. The regioselectivity follows that observed in eq 4.
â-Naphthol is also reported as an unsuitable substrate for the
Pechmann condensation.6 In contrast to that observation, it
participates satisfactorily in this palladium-catalyzed version
whereby a single product 12, mp 139-142 °C,16 as shown in
eq 7 forms. Because of the partial solubility of â-naphthol in
“
catalyst”. Defining the types of substitutions that this more
atom economical approach allows will be the subject of future
work in these laboratories.
A sample experimental procedure follows. Ethyl propynoate
(2.6 mL, 26.0 mmol) was added to a solution of 3,5-dimethoxy-
phenol (2.00 g, 13.0 mmol), (dba)3Pd2‚CHCl3 (0.34 g, 0.325
mmol), and sodium acetate (0.11 g, 0.725 mmol) in 13 mL of
formic acid. The resulting brown/purple reaction mixture was
stirred at rt for 16 h, diluted with methylene chloride (25 mL),
washed with water (25 mL), 5% aqueous sodium bicarbonate
formic acid, use of sonication improved the isolated yield from
4
6% to 61%.
(25 mL), and brine (25 mL), dried (MgSO4), and concentrated
The mechanism of this new palladium-catalyzed reaction is
in Vacuo to give a brown solid. Flash chromatography (CH2-
Cl2) followed by recrystallization from methylene chloride-
hexanes afforded 2.51 g (77% yield) of 2,5-dimethoxycoumarin
quite interesting since it appears to involve Pd(0) rather than
Pd(+2). Use of palladium acetate in acetic acid does not effect
reaction, whereas replacing acetic acid by formic acid, which
can reduce Pd(+2) to Pd(0), leads to reaction. Indeed, in the
case of palladium acetate as a palladium source, Pd black formed
under the reaction conditions in the absence of substrate. In
addition, when using a Pd(0) complex as the precatalyst, both
acetic and formic acids led to catalytic cycles although the latter
gave more satisfactory results. Further, starting from a Pd(0)
complex gave faster reactions at lower temperatures. Control
experiments verify the absence of any reaction in the absence
of palladium. A ligand like 2-diphenylphosphinobenzoic acid
shuts down reaction. A reasonable rationale builds from our
1
0
as a yellow solid, mp 143-5 °C (lit mp 143-4 °C).
Acknowledgment. Generous continued support was provided by
the National Institutes of Health, General Medical Sciences, and the
National Science Foundation. Mass spectra were provided by the Mass
Spectrometry Facility at the University of California-San Francisco
supported by the NIH Division of Research Resources. Johnson
Matthey Alfa Aesar provided a generous loan of palladium salts.
JA961107I
(
21) Trost, B. M.; Li, Y. Unpublished results. cf: Trost, B. M.; Romero,
(
17) Ahluwalia, V. K.; Prakash, C.; Gupta, Y. K. Natl. Acad. Sci. Lect.
India) 1978, 1, 215; Chem. Abstr. 1979, 89, 179800y.
18) Wagner, H.; Bladt, S.; Abraham, D. J.; Lother, H. Tetrahedron Lett.
D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116, 4268.
(
(22) For some additions to phenol, see: Yamaguchi, M.; Hayashi, A.;
Hirama, M. J. Am. Chem. Soc. 1995, 117, 1151. Sartori, G.; Bigi, F.;
Pastorio, A.; Porta, C.; Arienti, A.; Maggi, R.; Moretti, N.; Gnappi, G.
Tetrahedron Lett. 1995, 36, 9177. Lewis, L. N.; Smith, J. F. J. Am. Chem.
Soc. 1986, 108, 2728.
(
1
974, 3807.
(
19) Crosby, D. G.; Berthold, R. V. J. Org. Chem. 1962, 27, 3083.
20) Fukui, K.; Nakayama, M. Bull. Chem. Soc. Jpn. 1962, 35, 1321.
(