Yb(OTf)3-catalyzed reactions of 5-alkylidene Meldrum's acids with phenols: One-pot assembly of 3,4-dihydrocoumarins, 4-chromanones, coumarins, and chromones

Article abstract of DOI:10.1021/jo052000t

The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel-Crafts C-alkylation/(O-acylation and Friedel-Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.

Full text of DOI:10.1021/jo052000t

tance are acylative and alkylative Friedel-Crafts cyclizations
from which a variety of carbo- and heterocycles have been
fashioned.3
Yb(OTf)3-Catalyzed Reactions of 5-Alkylidene
Meldrum’s Acids with Phenols: One-Pot
Assembly of 3,4-Dihydrocoumarins,
5-Alkylidene Meldrum’s acids are biselectrophilic species and
useful precursors in a variety of transformations.4 However,
examples of electrophilic aromatic substitution of arenes with
Meldrum’s acid derivatives are scarce. Benzylidene Meldrum’s
acids have been shown to participate in intramolecular Friedel-
Crafts acylations when treated with concentrated H2SO4 or
TFA.5 The biselectrophilic nature of 5-alkylidene Meldrum’s
acids in the design of multiple bond-forming synthetic strategies
with phenols was exploited in only one instance; Nair described
the preparation of 3,4-dihydrocoumarins from the reaction of
Meldrum’s acid with aldehydes and phloroglucinol.6 This
reaction seemed, however, limited to the highly nucleophilic
phloroglucinol, and the synthetic scope of this multicomponent
reaction was not subsequently defined.7
4-Chromanones, Coumarins, and Chromones
Eric Fillion,* Aaron M. Dumas, Bryan A. Kuropatwa,
Neil R. Malhotra, and Tamsyn C. Sitler
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
ReceiVed September 23, 2005
Our group has previously established that Meldrum’s acid
derivatives are powerful acylating agents in metal triflate-
catalyzed intramolecular Friedel-Crafts reactions,8 and this
approach was applied to the synthesis of benzocyclic ketones.
Herein, we describe the Yb(OTf)3-catalyzed reactions of 5-al-
kylidene Meldrum’s acids with phenols for the one-pot assembly
of 3,4-dihydrocoumarins, 4-chromanones, coumarins, and
(3) (a) Heaney, H. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 2, pp 753-
768. For recent examples, see: (b) Evans, D. A.; Fandrick, K. R.; Song,
H.-J. J. Am. Chem. Soc. 2005, 127, 8942-8943. (c) Tran, Y. S.; Kwon, O.
Org. Lett. 2005, 7, 4289-4291. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 10204-10205. (e) Cui, D.-M.; Zhang, C.; Kawamura, M.;
Shimada, S. Tetrahedron Lett. 2004, 45, 1741-1745. (f) Ishikawa, T.;
Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6, 2361-
2364. (g) Fillion, E.; Beingessner, R. L. J. Org. Chem. 2003, 68, 9485-
9488. (h) Hanessian, S.; Papeo, G.; Angiolini, M.; Fettis, K.; Beretta, M.;
Munro, A. J. Org. Chem. 2003, 68, 7204-7218. (i) Cui, D.-M.; Kawamura,
M.; Shimada, S.; Hayashi, T.; Tanaka, M. Tetrahedron Lett. 2003, 44,
4007-4010.
(4) For reviews on Meldrum’s acid, see: (a) Gaber, A. E.-A. O.; McNab,
H. Synthesis 2001, 2059-2074. (b) Chen, B.-C. Heterocycles 1991, 32,
529-597. (c) Strozhev, M. F.; Lielbriedis, I. EÄ .; Neiland, O. Ya. Khim.
Geterotsikl. Soedin. 1991, 579-599. (d) McNab, H. Chem. Soc. ReV. 1978,
7, 345-358.
(5) (a) Campaigne, E.; Frierson, M. R. J. Heterocycl. Chem. 1979, 16,
235-237. (b) Van Allan, J. A.; Reynolds, G. A. J. Heterocycl. Chem. 1972,
9, 669-673. (c) Synthesis of 3-carboxycoumarins from the cyclization of
o-methoxybenzylidene Meldrum’s acid derivatives: Armstrong, V.; Soto,
O.; Valderrama, J. A.; Tapia, R. Synth. Commun. 1988, 18, 717-725.
(6) Nair, V. Synth. Commun. 1987, 17, 723-727.
The Yb(OTf)3-catalyzed annulation reactions of phenols with
5-alkylidene Meldrum’s acids enabled the synthesis of
structurally diverse heterocycles in high isolated yields. A
series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubsti-
tuted 4-chromanones, coumarins, and 2-substituted chromones
were readily and efficiently assembled, including the natu-
rally occurring coumarins citropten, scoparone, and ayapin.
Addition of phenols to biselectrophilic 5-alkylidene Mel-
drum’s acids proceeded through two distinct multibond-
forming modes: Friedel-Crafts C-alkylation/O-acylation and
Friedel-Crafts C-acylation/O-alkylation. The regioselectivity
of the catalytic annulation reaction was controlled by the
degree of substitution on the alkylidene moiety.
(7) (a) For an application of Nair’s protocol see: Kumar, A.; Singh, B.
K.; Tyagi, R.; Jain, S. K.; Sharma, S. K.; Prasad, A. K.; Raj, H. G.; Rastogi,
R. C.; Watterson, A. C.; Parmar, V. S. Bioorg. Med. Chem. 2005, 13, 4300-
4305. The synthesis of benzo[f]quinoline derivatives via the reaction of
2-aminonaphthalene with various benzylidene Meldrum’s acids has been
reported, see: (b) Wang, X.-S.; Zhang, M.-M.; Zeng, Z.-S.; Shi, D.-Q.;
Tu, S.-J.; Wei, X.-Y.; Zong, Z.-M. Tetrahedron Lett. 2005, 46, 7169-
7173. (c) Kozlov, S. N.; Basalaeva, L. I.; Ol’khovik, V. K.; Kalechits, G.
V.; Matveenko, Yu. V. Russ. J. Gen. Chem. 2003, 73, 1434-1440. (d)
Kozlov, N. G.; Basalaeva, L. I.; Tychinskaya, L. Yu. Russ. J. Org. Chem.
2002, 38, 1166-1170. (e) Strods, Ya. A.; Tsiekure, V. P.; Kampars, V. EÄ .;
Lielbriedis, I. EÄ .; Neiland, O. Ya. Khim. Geterotsikl. Soedin. 1978, 1369-
1372. (f) Strods, Ya. A.; Lielbriedis, I. EÄ .; Neiland, O. Ya. IzV. Akad. Nauk
LatV. SSR, Ser. Khim. 1978, 225-228. (g) Strods, Ya. A.; Lielbriedis, I.
EÄ .; Neiland, O. Ya. Khim. Geterotsikl. Soedin. 1977, 977-979. (h) Strods,
Ya. A.; Kampare, R. B.; Lielbriedis, I. EÄ .; Neiland, O. Ya. Khim. Geterotsikl.
Soedin. 1977, 973-976.
The Friedel-Crafts acylation and alkylation reactions are the
most powerful processes for direct functionalization of aromatics
through C-H bond conversion into a C-C bond.1 A multitude
of inter- and intramolecular variants are available to effect this
synthetically significant transformation.2 Of particular impor-
(1) For reviews, see: (a) Yonezawa, N.; Hino, T.; Ikeda, T. Recent Res.
DeVel. Synth. Org. Chem. 1998, 1, 213-223. (b) Heaney, H. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon
Press: Oxford, UK, 1991; Vol. 2, pp 733-752. (c) Olah, G. A.;
Krishnamurti, R.; Prakash, G. K. S. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds; Pergamon Press: Oxford, UK, 1991; Vol.
3, pp 293-339. (d) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation
Chemistry: A Century of DiscoVery; Marcel Dekker: New York, 1984. (e)
Olah, G. A. Friedel-Crafts Chemistry; John Wiley and Sons: New York,
1973. (f) Popp, F. D.; McEwen, W. E. Chem. ReV. 1958, 58, 321-401.
(2) Larock, R. ComprehensiVe Organic Transformations, 2nd ed.; Wiley-
VCH: New York, 1999; pp 129-133 and 1422-1433.
(8) (a) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144-
13145. (b) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem.
2005, 70, 1316-1327. (c) Fillion, E.; Fishlock, D. Org. Lett. 2003, 5, 4653-
4656.
10.1021/jo052000t CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
J. Org. Chem. 2006, 71, 409-412
409

TABLE 1. Synthesis of 4-Substituted 3,4-Dihydrocoumarins
chromones. These heterocycles are important pharmacophores
present in diverse bioactive compounds.9
As depicted in Scheme 1, we initially studied the reaction of
5-alkylidene Meldrum’s acids with phenols under Lewis acid
catalysis. 3,4-Dihydrocoumarins and 4-chromanones could
potentially be accessed by this strategy.
SCHEME 1. Synthetic Strategy for the Preparation of
3,4-Dihydrocoumarins and 4-Chromanones
We began our study by reacting 3,5-dimethoxyphenol (1a)
with 5-ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (2a) in the
presence of Yb(OTf)3 (10 mol %) in refluxing CH3NO2. After
1.5 h, the reaction was complete and 5,7-dimethoxy-4-methyl-
3,4-dihydrocoumarin (3a) was isolated in 80% yield (Table 1,
entry 1).10 Under the same reaction conditions, Sc(OTf)3
provided 3a in 55% yield, and decomposition of the Meldrum’s
acid reagent was observed with Mg(OTf)2. Alternatively, excess
TFA promoted the reaction, albeit in lower yield. In the absence
of a catalyst, the starting materials were recovered. From these
results, Yb(OTf)3 was the optimal catalyst for this transformation
and was used throughout the study. As shown in Table 1, 1a
reacted with a number of 5-alkylidene Meldrum’s acids to afford
3,4-dihydrocoumarins in good yields (entries 2-5). 3,4-
Dimethoxyphenol (1b) and sesamol (1c) were also potent
nucleophiles in this Lewis acid-catalyzed domino transformation,
regioselectively forming dihydrocoumarins 3f-h (Table 1,
entries 6-8). Of note, 3-methoxyphenol was unreactive toward
2a,11 but 3i was generated from 3-methoxy-2-methylphenol (1d)
in 61% yield (Table 1, entry 9).
a Dihydrocoumarin 3a was formed in 70% yield when the reaction of
1a with 2a was promoted by TFA (5 equiv) in CH3NO2 at 100 °C for 1.5
h. b The reaction was run over 2 h. c The reaction was run over 2.5 h.
synthesis was extended to other substituted alkylidenes (Table
2, entries 2 and 3). Unfortunately, this protocol was limited to
electron-rich phenol 1a, and all attempts to react 3-methoxy-
phenol, 3,5-dimethylphenol, and phenols 1b-d with 2f failed.
The synthesis of 4,4-dimethyl-3,4-dihydrocoumarins was then
explored. These compounds have been previously prepared via
the one-pot protic acid-promoted reaction of 3,3-dimethylacrylic
acid or methyl 3,3-dimethyl acrylate with phenols.10e,f However,
treatment of phenol 1a with 5-(1-methylethylidene) Meldrum’s
acid (2f) did not provide the expected dihydrocoumarin. Instead,
5,7-dimethoxy-2,2-dimethyl-4-chromanone (4a) was formed in
83% yield (Table 2, entry 1). This unprecedented chromanone
TABLE 2. 2,2-Disubstituted 5,7-Dimethoxy-4-chromanone
Synthesis
(9) For a review on chromanones and chromones, see: (a) Saengchantara,
S. T.; Wallace, T. W. Nat. Prod. Rep. 1986, 3, 465-475. For reviews on
coumarins, see: (b) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.;
Uriarte, E. Curr. Med. Chem. 2005, 12, 887-916. (c) Murray, R. D. H.
Nat. Prod. Rep. 1995, 12, 477-505. (d) Murray, R. D. H. Nat. Prod. Rep.
1989, 6, 591-624.
(10) One-pot synthesis of 3,4-dihydrocoumarins from cinnamic acids and
phenols, see: (a) Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T.
Tetrahedron 2005, 61, 9291-9297 and references therein. (b) Li, K.;
Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881-2883. (c) Singh,
I.; Prasad, A. K.; Sharma, A. K.; Saxena, R. K.; Olsen, C. E.; Cholli, A.
L.; Samuelson, L. A.; Kumar, J.; Watterson, A. C.; Parmar, V. S. Bioorg.
Med. Chem. 2003, 11, 529-538. (d) Shukla, M. R.; Patil, P. N.;
Wadgaonkar, P. P.; Joshi, P. N.; Salunkhe, M. M. Synth. Commun. 2000,
30, 39-42. From methyl 3,3-dimethyl acrylate and 3,5-dimethoxyphenol:
(e) Song, X.; Siahaan, T. J. Bioorg. Med. Chem. Lett. 2002, 12, 3439-
3442. From 3,3-dimethylacrylic acid and phenols: (f) Amsberry, K. L.;
Borchardt, R. T. J. Org. Chem. 1990, 55, 5867-5877.
a Chromanone 4a was formed in 83% yield when the reaction of 1a
with 2f was promoted by TFA (5 equiv) in CH3NO2 at 100 °C for 1.5 h.
The synthesis of coumarins and chromones by the reaction
of phenols with 5-(1-methoxyalkylidene) Meldrum’s acids was
(11) Meldrum’s acid 2 decomposed in the course of the reaction, but
the phenol remained unreacted.
410 J. Org. Chem., Vol. 71, No. 1, 2006

TABLE 4. Synthesis of Chromones
then pursued (Scheme 2). It was postulated that the Lewis acid
catalyst, in addition to promoting the acylation/alkylation, would
further induce methanol elimination to produce unsaturated
heterocycles.
SCHEME 2. Synthetic Strategy for the Preparation of
Coumarins and Chromones
a Chromone 6a was formed in 72% yield when the reaction of 1a with
2j was promoted by TFA (5 equiv) in CH3NO2 at reflux for 1.5 h.
The addition of 1a to 5-(methoxymethylene) Meldrum’s acid
(2i) catalyzed by Yb(OTf)3 proceeded smoothly and yielded 5,7-
dimethoxycoumarin (5a) in 88% yield (Table 3, entry 1).12
Phenols 1b and 1c reacted cleanly with 2i (Table 2, entries 2
and 3). Citropten (5a), scoparone (5b), and ayapin (5c) are
naturally occurring coumarins isolated from a number of
sources.13
dichloroethane gave bromocoumarin 5e in 67% yield, ac-
companied by a minor amount of 5a (eq 2). Interestingly, 1e
and 2i engaged in an unprecedented atom-transfer reaction in
the presence of TfOH in 1,2-dichloroethane and 3-bromocou-
marin 5f was isolated in 38% yield, in addition to 41% of
coumarin 5a (eq 3).
TABLE 3. Yb(OTf)3-Catalyzed Coumarin Synthesis
a Coumarin 5a was formed in 64% yield when the reaction of 1a with
2i was promoted by TFA (5 equiv) in CH3NO2 at 100 °C for 1.5 h.
Reacting phenol 1a with 5-(1-methoxyethylidene) Meldrum’s
acid 2j furnished chromone 6a in 77% yield (Table 4, entry 1).
A similar result was obtained with 1c. The application of this
method to the synthesis of flavones was unsuccessful.
Finally, the compatibility of this methodology with bromide
and amino substituted phenols was investigated. As depicted
in eq 1, the reaction of 2-bromo-3,5-dimethoxyphenol 1e with
2i gave solely debrominated coumarin 5a in 82% yield. This
result may be rationalized by the known reversible electrophilic
substitution of electron-rich arenes by metal triflates.14 It was
theorized that CH3NO2 was acting as bromonium scavenger (via
its aci form) and that a non-nucleophilic solvent would decrease
the debromination rate. Indeed, carrying out the reaction in 1,2-
The compatibility of anilines was demonstrated by the
synthesis of 3j and 5g from 3-(dimethylamino)phenol (1f).
Lewis basic phenol 1f inhibited Yb(OTf)3 and the reaction did
not proceed. However, the domino process was successful when
promoted by excess TFA (eqs 4 and 5).
In conclusion, we have disclosed a mild and catalytic
procedure for the reaction of phenols with alkylidene Meldrum’s
acids. Excess TFA was demonstrated to be a complementary
alternative to Yb(OTf)3. The present protocol is operationally
simple and versatile in terms of the precursors and resulting
J. Org. Chem, Vol. 71, No. 1, 2006 411

TLC. The tube was removed from the bath and allowed to cool;
the contents were rinsed into a separatory funnel with EtOAc. The
organic layer was washed twice with water and once with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The products were purified by silica gel chromatography,
using EtOAc:petroleum ether (35-60 °C).
heterocycles. 3,4-Dihydrocoumarins, 4-chromanones, coumarins,
and chromones are assembled in a single synthetic operation in
good yields. Further research is ongoing to establish the reaction
mechanism and apply this methodology to other systems.
Experimental Section
General Procedure for Trifluoroacetic Acid-Promoted Reac-
tion of Phenols with 5-Alkylidene Meldrum’s Acid. An oven-
dried Schlenk tube cooled under nitrogen was charged with phenol
(1.0 equiv) and 5-alkylidene Meldrum’s acid (1.5 equiv). TFA (5
equiv) was then added, and immediately washed into the flask with
MeNO2; sufficient solvent was used such that the total volume made
the reaction 0.4 M in phenol. The remainder of the procedure is
identical to the previous procedure, with the addition of a saturated
NaHCO3 wash of the organic phase before using water and brine.
General Procedure for Yb(OTf)3-Catalyzed Reaction of
Phenols with 5-Alkylidene Meldrum’s Acids. All reactions were
performed with 100 mg of phenol. To a resealable, oven-dried
Schlenk tube cooled under nitrogen was added Yb(OTf)3 (10 mol
%) in a glovebox. Outside of the box, phenol (1.0 equiv) and
5-alkylidene Meldrum’s acid (1.5 equiv) were added to the Schlenk
tube under N2, and the residue was washed into the flask with
MeNO2; sufficient solvent was used such that the reaction was 0.4
M in phenol. The flask was placed in an oil bath at 100 °C and
allowed to stir until the reaction was complete as monitored by
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada (NSERC),
the Canadian Foundation for Innovation, the Ontario Innovation
Trust, and the University of Waterloo. We gratefully acknowl-
edge Boehringer Ingelheim (Canada) Ltd. (Young Investigator
Award to E.F.) and AstraZeneca Canada Inc. (AstraZeneca
Award to E.F.) for unrestricted support of this research. A.M.D.
thanks the Government of Ontario for an OGS scholarship.
B.A.K. and N.R.M. are indebted to NSERC for an USRA
scholarship.
(12) Catalytic one-pot synthesis of coumarins from alkynoates and
phenols: (a) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc.
2003, 125, 4518-4526. (b) Kitamura, T.; Yamamoto, K.; Kotani, M.;
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1895. (c) Oyamada, J.; Jia, C.; Fujiwara, Y.; Kitamura, T. Chem. Lett. 2002,
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6305-6306. From acrylates and phenols: (f) Aoki, S.; Oyamada, J.;
Kitamura, T. Bull. Chem. Soc. Jpn. 2005, 78, 468-472. From propiolic
acids and phenols: (g) Kotani, M.; Yamamoto, K.; Oyamada, J.; Fujiwara,
Y.; Kitamura, T. Synthesis 2004, 1466-1470. Catalytic Pechmann con-
densation: (h) De, S. K.; Gibbs, R. A. Synthesis 2005, 1231-1233.
(13) Fan, C.; Wang, W.; Wang, Y.; Qin, G.; Zhao, W. Phytochemistry
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Supporting Information Available: Experimental procedures
and NMR spectra for 3a-j, 4a-c, 5a-g, and 6a,b. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Bisi Castellani, C.; Perotti, A.; Scrivanti, M.; Vidari, G.
Tetrahedron 2000, 56, 8161-8166. (b) Bisi Castellani, C.; Carugo, O.;
Giusti, M.; Leopizzi, C.; Perotti, A.; Invernizzi Gamba A.; Vidari, G.
Tetrahedron 1996, 52, 11045-11052.
JO052000T
412 J. Org. Chem., Vol. 71, No. 1, 2006