Trifluoroacetic acid-mediated hydroarylation: Synthesis of dihydrocoumarins and dihydroquinolones

Article abstract of DOI:10.1021/jo0477650

(Chemical Equation Presented) Trifluoroacetic acid mediates the hydroarylation of alkenes to afford dihydrocoumarins and dihydroquinolones in good yield. Intermolecular hydroarylation of cinnamic acids by phenols is particularly facile, which leads to the

Full text of DOI:10.1021/jo0477650

SCHEME 1
SCHEME 2
Trifluoroacetic Acid-Mediated
Hydroarylation: Synthesis of
Dihydrocoumarins and Dihydroquinolones
Kelin Li, Lindsay N. Foresee, and Jon A. Tunge*
Department of Chemistry, 1251 Wescoe Hall Drive, 2010
Malott Hall, University of Kansas, Lawrence, Kansas
66045-7582 and The KU Chemical Methodologies and
Library Development Center of Excellence, University of
Kansas, 1501 Wakarusa Drive, Lawrence, Kansas 66047
tunge@ku.edu
Received December 21, 2004
hydroarylation of alkynes establishes the synthetic utility
of these C-H bond functionalization reactions.
In comparison to the hydroarylation of alkynes, the
catalytic addition of arenes to alkenes has received much
less attention. Thus, we were intrigued by reports that
Pd(OAc)2 in trifluoroacetic acid (TFA) effected the room
temperature hydroarylation of alkenes.1,4 With the goal
of investigating possible mechanistic differences between
alkyne and olefin hydroarylation, we began examining
the intra- and intermolecular hydroarylation of alkenes.
In the course of these studies we discovered that, in
contrast to literature reports, the hydroarylation of
cinnamic acids in trifluoroacetic acid is not palladium
catalyzed.
Trifluoroacetic acid mediates the hydroarylation of alkenes
to afford dihydrocoumarins and dihydroquinolones in good
yield. Intermolecular hydroarylation of cinnamic acids by
phenols is particularly facile, which leads to the conclusion
that previous reports of palladium-catalyzed hydroarylation
of cinnamic acids in trifluoroacetic acid are erroneous.
We began our study by repeating the reported proce-
dure for the hydroarylation of p-methoxycinnamic acid
2a with 3,4,5-trimethoxyphenol 1a in the presence of 1
mol % of Pd(OAc)2 in 4:1 TFA:CH2Cl2 (Scheme 2).1a,4a
Consistent with the literature report, a 96% yield of the
dihydrocoumarin derivative 3a was isolated. To deter-
mine the background rate of uncatalyzed hydroarylation,
we repeated this experiment in the absence of Pd(OAc)2.
Much to our surprise, a 99% yield of 3a was isolated after
16 h at ambient temperature. To confirm that there was
no difference in the qualitative rates of product formation
with or without Pd(OAc)2, the two reactions were moni-
Development of catalysts for the hydroarylation of
alkynes and olefins by the addition of a C-H bond across
a π-bond has received significant recent attention.1,2
These reactions are particularly interesting from the
standpoint of green chemistry because hydroarylation
exhibits perfect atom economy and relies on the use of
simple arene reactants (Scheme 1).3 Furthermore, the
ability to synthesize coumarins4 and chromenes5 through
(1) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992-1995. (b) Jia, C.; Lu, W.; Oyamada, J.;
Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc.
2000, 122, 7252-7263. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633-639.
1
tored by H NMR spectroscopy.6 Indeed product 3a was
observed in 30% and 29% conversion after a 3.5 h
reaction period in CF3CO2D with and without 5 mol %
of Pd(OAc)2, respectively. Thus, hydroarylation of cin-
namic acids is not palladium catalyzed in this case or
any other we have investigated.7
Having failed to validate the catalytic role of pal-
ladium, we turned our attention to the investigation of
TFA-mediated hydroarylation. We began by comparing
intermolecular and intramolecular procedures for hy-
droarylation of cinnamic acids with phenols. Coupling the
acid (1a) and phenol (2a) to form an ester (4a) prior to
(2) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59,
8859-8868. (b) Viciu, M. S.; Stevens, E. D.; Petersen, J. L.; Nolan, S.
P. Organometallics 2004, 23, 3752-3755. (c) Trost, B. M.; Toste, F.
D.; Greenman, K. J. Am. Chem. Soc. 2003, 125, 4518-4526. (d) Boele,
M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.;
de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002,
124, 1586-1587. (e) Song, C. E.; Jung, D.-u.; Choung, S. Y.; Roh, E.
J.; Lee, S.-g. Angew. Chem., Int. Ed. 2004, 43, 6183-6185. (f) Reetz,
M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 18, 3485-3496. (g)
Matsumoto, T.; Taube, D. J.; Periana, R. A.; Taube, H.; Yoshida, H. J.
Am. Chem. Soc. 2000, 122, 7414-7415. (h) Shi, Z.; He, C. J. Org. Chem.
2004, 69, 3669-3671.
(3) Aresta, M.; Armor, J. N.; Barteau, M. A.; Beckman, E. J.; Bell,
A. T.; Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon, D. A.; Domen, K.;
Dubois, D. L.; Eckert, J.; Fujita, E.; Gibson, D. H.; Goddard, W. A.;
Goodman, D. W.; Keller, J.; Kubas, G. J.; Kung, H. H.; Lyons, J. E.;
Manzer, L. E.; Marks, T. J.; Morokuma, K.; Nicholas, K. M.; Periana,
R.; Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L. D.;
Sen, A.; Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W. Chem.
Rev. 2001, 101, 953-996.
(5) (a) Pastine, S. J.; Sames, D. Org. Lett. 2003, 5, 4053-4055. (b)
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856-11857.
(6) The palladium-free reaction was conducted in a brand new NMR
tube and care was taken to avoid any exposure to palladium.
(7) We routinely treat slowly reacting substrates with Pd(OAc)2 and
have yet to observe any rate acceleration. Specific examples include
3b, 3c, 3d, 6a, 6c, and 6i.
(4) (a) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem.
2000, 65, 7516-7522. (b) Kitamura, T.; Yamamoto, K.; Kotani, M.;
Oyamada, J.; Jia, C.; Fujiwara, Y. Bull. Chem. Soc. Jpn. 2003, 76,
1889-1895.
10.1021/jo0477650 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/10/2005
J. Org. Chem. 2005, 70, 2881-2883
2881

TABLE 1. Hydroarylation of Cinnamic Acids
SCHEME 3
HO2CCHdCHAr2 with Phenols HOAr1
hydroarylation was not beneficial; however, product 3a
was obtained in high yield after 18 h at room temperature
1
(Method A, Scheme 3). The H NMR spectrum of this
reaction mixture after 3.5 h shows somewhat lower
conversion (22%) to 3a as compared to the intermolecular
reaction (30%, Method B). In addition to product 3a, new
resonances corresponding to 1a (6%) and 2a were appar-
ent, indicating that the aryl ester (4a) had been partially
hydrolyzed under the reaction conditions. Hydroarylation
of other substrates confirmed that intermolecular hy-
droarylation is more facile than the analogous intramo-
lecular hydroarylation. For example, intramolecular hy-
droarylation (Method A) with substrate 4b (X ) p-CMe3,
Y ) p-OMe) proceeded sluggishly to provide a 54% yield
of hydrocoumarin 3b after 2 days (Scheme 3). In contrast,
the intermolecular hydroarylation (Method B) of p-
methoxycinnamic acid 2a with phenol 1b provides 3b in
95% yield after 18 h.
A survey of a small subset of phenol reaction partners
shows that there is no obvious electronic requirement for
facile hydroarylation (Table 1). In contrast, cinnamic
acids that are less electron rich than p-methoxycinnamic
acid required elevated reaction temperatures to achieve
reasonable reaction rates. Furthermore, the potential for
regioselective hydroarylation was demonstrated by using
unsymmetrical 3-methyl-4-chlorophenol, which under-
went cyclohydroarylation to afford the product of addition
by the least substituted ortho-carbon (Scheme 4). Inter-
estingly, the regioselectivity is identical in the intramo-
lecular cyclization of the aryl cinnamate 4d.
The trifluoroacetic acid-catalyzed hydroarylation reac-
tion is not limited to the synthesis of dihydrocoumarins;
the analogous dihydroquinolones are readily prepared in
good yield by coupling anilines with cinnamic acids prior
to hydroarylation. For example, cinnamanilide 5a reacts
smoothly in TFA to provide dihydroquinolone 6a in 82%
yield after 23 h at ambient temperature (Scheme 5). In
contrast to the activity of phenols for the intermolecular
hydroarylation of alkenes, unprotected anilines do not
hydroarylate alkenes under our conditions. This is ex-
pected based on the favorable protonation of anilines by
trifluoroacetic acid, which will greatly decrease the
nucleophilicity of the arene. The electronics of the cin-
namic acid derivative are important in predicting the
conditions required for intramolecular hydroarylation.
While the electron-rich p-OMe (σp ) -0.268) substrate
provides dihydroquinolone 6a in good yield (82%) after
23 h at room temperature, the electron-deficient m-OMe
(σm ) +0.115) substituted 5c fails to react even at 50 °C.
The deactivating effect of the meta withdrawing sub-
a A ) intramolecular, B ) intermolecular. b Isolated yields. c 11:
1 mixture of regioisomers. d Reaction was run at 100 °C.
SCHEME 4
stituent can be overcome by incorporation of a sufficiently
electron donating para substituent (entry 6e). Further-
more, the electron-deficient p-chlorocinnamanilide (σp )
+0.232) substrate 5i undergoes the cycloisomerization
only at elevated temperature (100 °C) and requires
extended reaction times (5 d). However, the same reaction
2882 J. Org. Chem., Vol. 70, No. 7, 2005

SCHEME 5
SCHEME 6
TABLE 2. Hydroarylation of Aryl Cinnamides
Ar1NCOCHdCHAr2 (5)
generally proceeds in moderate yield (22-90%; 51%
average);8 dihydrocoumarin byproducts have also been
observed in Fries rearrangements of aryl 3-methylbut-
2-enoates catalyzed by methane sulfonic acid.9 Similarly,
the thermal (120-190 °C) cyclizations of cinnamanilides
have been reported in the presence of PPA.10 The results
of our investigation suggest that TFA may be a superior
acid for the Friedel-Crafts cyclization since both dihy-
drocoumarins and dihydroquinolones are formed in good
to excellent yield. Furthermore, TFA-catalyzed hydroary-
lation occurs, in most cases, at room temperature. These
relatively mild reaction conditions preclude dearylation
of the product dihydroquinolones which can occur under
the conditions of PPA-catalyzed hydroarylation.10
The mechanism of catalysis likely involves protonation
of the carbonyl, which activates the olefin toward nu-
cleophilic attack (Scheme 6).11 Thus, the more facile
intermolecular hydroarylation of phenols, as compared
to the intramolecular hydroarylation of aryl cinnamates,
is simply a result of the higher nucleophilicity of phenols.
Furthermore, the observation of ester cleavage under the
conditions of “intramolecular” cyclization suggests that
the reaction of aryl cinnamates may proceed intermo-
lecularly as well. The fact that the intra- and intermo-
lecular hydroarylation procedures afford product with
identical regioselectivity supports this hypothesis.
In conclusion, we have developed a highly atom eco-
nomical route to dihydrocoumarins and dihydroquino-
lones based on acid-mediated hydroarylation of alkenes.
The simplicity of this approach makes it particularly
attractive for use in combinatorial synthesis.
a Isolated yields. b 3.4:1 ratio of regioisomers.
Acknowledgment. We acknowledge support of this
work by the National Institutes of Health (KU Chemical
Methodologies and Library Development Center of
Excellence, P50 GM069663). L.N.F. gratefully acknowl-
edges support by the University of Kansas Chemistry
REU Program funded by NSF grant CHE-024401.
can be performed conveniently in a microwave reactor
at 180 °C, resulting in 50% conversion to product 6i in
15 min.
The success of the intramolecular hydroarylation is not
as dependent on the electronics of the aniline fragment,
with the p-methoxyanilide and m-methoxyanilide both
providing product within 24 h at room temperature.
While the electronics of the aniline fragment are not
crucial to the success of the hydroarylation, ultimately
the most facile hydroarylation occurs when both aniline
and cinnamic acid precursors contain electron-rich aro-
matic rings. In these cases, hydroarylation generally
occurs within 24-40 h at 24 °C and provides high yields
of dihydroquinolones. Prior to this work, the acid-
catalyzed cyclization of aryl cinnamates was largely
limited to catalysis by polyphosphoric acid (PPA), which
Supporting Information Available: Spectroscopic data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0477650
(8) Dupin, J.-F. E.; Chenault, J. Heterocycles 1983, 20, 2401-2404.
(9) Camps, F.; Coll, J.; Colomina, O.; Messeguer, A. J. Heterocycl.
Chem. 1985, 22, 363-368.
(10) (a) Johnston, K. M. Tetrahedron 1968, 24, 5595-5600. (b) Inglis,
S. R.; Stojkoski, C.; Branson, K. M.; Cawthray, J. F.; Fritz, D.;
Wiadrowski, E.; Pyke, S. M.; Booker, G. W. J. Med. Chem. 2004, 47,
5405-5417.
(11) A mechanism involving 6 π-electrocyclization is also possible:
Ogata, Y.; Takagi, K.; Ishino, I. J. Org. Chem. 1971, 36, 3975-3979.
J. Org. Chem, Vol. 70, No. 7, 2005 2883