Direct carbocyclizations of benzoic acids: Catalyst-controlled synthesis of cyclic ketones and the development of tandem aHH (acyl Heck-Heck) reactions

Article abstract of DOI:10.1002/chem.201403561

The formation of exo-methylene indanones and indenones from simple ortho-allyl benzoic acid derivatives has been developed. Selective formation of the indanone or indenone products in these reactions is controlled by choice of ancillary ligand. This new process has a low environmental footprint as the products are formed in high yields using low catalyst loadings, while the only stoichiometric chemical waste generated from the reactants in the transformation is acetic acid. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction, and utilized in the synthesis of donepezil. Carboxylic acids in aHH: Simple ortho-allyl benzoic acid derivatives have been utilized in an acyl Heck (aH) reaction to selectively form indanones and indenones. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction to form two sp ²-sp² bonds of (E)-trisubstituted olefins.

Full text of DOI:10.1002/chem.201403561

DOI: 10.1002/chem.201403561
Communication
&
Synthetic Methods
Direct Carbocyclizations of Benzoic Acids: Catalyst-Controlled
Synthesis of Cyclic Ketones and the Development of Tandem aHH
(acyl Heck–Heck) Reactions
Kelsey C. Miles, Chi “Chip” Le, and James P. Stambuli*[a]
Abstract: The formation of exo-methylene indanones and
indenones from simple ortho-allyl benzoic acid derivatives
has been developed. Selective formation of the indanone
or indenone products in these reactions is controlled by
choice of ancillary ligand. This new process has a low envi-
ronmental footprint as the products are formed in high
Figure 1. Examples of biologically active molecules that contain indanone
cores.
yields using low catalyst loadings, while the only stoichio-
metric chemical waste generated from the reactants in
the transformation is acetic acid. The conversion of the
active cyclization catalyst into the Hermman–Beller palla-
dacycle was exploited in a one-pot tandem acyl Heck–
Heck (aHH) reaction, and utilized in the synthesis of done-
pezil.
Due to the biological importance of this scaffold, several
metal-mediated processes have been developed including clas-
sical Friedel–Crafts chemistry, the carbonylation of arynes,[11]
carbocyclizations of ortho-halobenzaldehydes[12] and thioest-
ers[13] (Scheme 1). In general, all of the current methods to pre-
pare indanones or indenones have one or more of the follow-
ing unfavorable attributes: i) low atom economy; ii) poor regio-
selectivity; iii) high pressures of CO. The method reported
herein generates acetic acid as the only stoichiometric byprod-
uct, bypasses regioselectivity issues, and does not require the
use of CO. Moreover, the products formed from this reaction
can shuttle between exo-methylene indanones or indenones
depending upon the choice of catalyst.
The generation and subsequent functionalization of acylmetal
species is a useful approach to carbon–carbon bond forma-
tion.[1] Common methods to generate acylmetal species in-
clude the activation of acyl halides[2] or thioesters,[3] which are
typically prepared from the corresponding carboxylic acids.
The direct employment of carboxylic acids to generate acylme-
tal species would eliminate an extra synthetic step and lessen
the amount of chemical waste. Acylmetal species are also gen-
erated from the insertion of carbon monoxide (CO) into pre-ex-
isting metal–carbon bonds.[4] Despite the use of CO in large-
scale industrial processes, the development of carbonylation
methods that avoid the use of CO is important because of the
toxicity and handling issues associated with this gas.[5] In paral-
lel with our group’s work on the use of carboxylic acid deriva-
tives in synthetic methodology,[6] we have developed a catalytic
strategy to prepare indanones and indenones from benzoic
acids.
We investigated the activation and subsequent annulation
of ortho-allyl benzoic acids with acetic anhydride. As shown in
Scheme 2, formation of the benzoic acid to the anhydride, fol-
lowed by subsequent selective insertion of the palladium cata-
lyst would give the acylpalladium complex 3. Insertion of the
alkene into the palladium–acyl bond would give complex 4,
which could undergo b-hydride elimination to expel the carbo-
cyclization product 5. Elimination of acetic acid from 6 would
regenerate the palladium(0) complex and turnover the catalyst.
Isomerization of the exo-methylene indanone 5 could poten-
tially be isomerized to indenone 7 under controlled reaction
conditions. The formal transformation of the ortho-allylbenzoic
acid to the indanone could be regarded as an acyl-Heck reac-
tion. One of the challenges facing this chemistry is the ability
of palladium to selectively insert into the in situ generated an-
hydride (2). Previously, pivalic anhydride has been required in
intermolecular insertion reactions of this type, in order to favor
the specific CÀO bond.[14] However, we hypothesized that the
selectivity of the initial oxidative addition reaction could be
controlled by the stronger p-bonding interaction between the
palladium center and the more proximal alkene (Scheme 2).
The hypothesis proposed in Scheme 2 was tested by treat-
ing ortho-allylbenzoic acid 1 with acetic anhydride in the pres-
ence of 1 mol% Pd(OAc)2 and 1.2 mol% P(o-tol)3 in THF at am-
Among the compounds formed from metal-catalyzed carbo-
cyclization reactions, indanones and indenones are popular tar-
gets. These ketones are prevalent in many potent biologically
active molecules, such as Aricept,[7] indanorine,[8] indanocine,[9]
and the pterosin family of natural products (Figure 1).[10]
[a] K. C. Miles, C. Le, Prof. Dr. J. P. Stambuli
Department of Chemistry and Biochemistry
The Ohio State University
88 West 18th Avenue, Columbus, OH 43210 (USA)
E-mail: jamesstambuli@gmail.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403561.
Chem. Eur. J. 2014, 20, 11336 – 11339
11336
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
With the optimized conditions
in hand, a variety of ortho-allyl
benzoic acids were cyclized to
the corresponding exo-methyl-
ene indanones (Table 2). The
parent allylbenzoic acid sub-
strate was transformed into the
desired indanone in 88% yield.
Electron-donating groups did
not greatly affect the yield of in-
danone as methyl or methoxy
groups in various positions
about the aromatic ring were
converted to the corresponding
products in 86–92% yield (8–
12). Expectedly 2-allyl-5-hydroxy-
benzoic acid underwent cycliza-
Scheme 1. Common synthetic routes to indanones and indenones.
tion to indanone 13, with con-
comitant protection of the hy-
droxy group as an acetate in 82% yield. Submission of 2-allyl-
5-bromobenzoic acid under the reaction conditions required
the use of the less basic triphenylarsine ligand, in order to
avoid insertion of the palladium complex into the carbon–bro-
mine bond (14). Stronger carbon–halogen bonds, such as
carbon–chlorine (15) and carbon–fluorine (16 and 17) did not
require alternative ligands, providing high yields of indanone
products. o-Allylnaphthoic acid cyclized to indanone 18 in
75% yield, while the tosyl-protected indole cyclized to the an-
nulated indole product 19 in 50% yield.
The formation of the indenone product with the Pd(OAc)2/
PCy3 catalyst system, as discovered in the initial ligand screen
(Table 1, entry 5), was further examined. The reaction scope of
this carbocyclization to the corresponding indenones tolerated
a variety of functional groups and heterocyclic partners
(Table 3). Unsubstituted ortho-allylbenzoic acid was converted
to the indenone product 7 in 73% yield. The methyl-substitut-
Scheme 2. Proposed reaction mechanism for the carbocyclization reaction.
bient temperature (Table 1, entry 1). We were pleased to find
the cyclization proceeded smoothly to afford the correspond-
ing exo-methylene indanone (5) in 78% yield (entry 1). Heating
the reaction to 658C and increasing the P(o-tol)3 loading to
2 mol%, increased the yield to 89%. Although switching the
ancillary ligand to AsPh3 and PPh3 did not greatly improve the
yield, the use of PCy3 unexpectedly furnished 2-methyl inden-
one (7) as the major product (entries 3–5). The scope of this
process was examined further (vide infra). Omission of acetic
anhydride from the reaction conditions shut down the reaction
pathway to product (entry 6), while removal of the ligand
dropped the yield of indanone to 17% (entry 7). Replacement
of Pd(OAc)2 with [Pd(dba)2] resulted in diminished yields of the
indanone (entry 8), while no carbocyclization product was ob-
served with PdCl2 or without palladium (entry 9 and 10). In the
absence of palladium, quantitative conversion to the corre-
sponding anhydride 2 was observed. Preformation of the anhy-
dride 2, and submission to the catalytic reaction conditions
produces similar yield and selectivity to the in situ generated
anhydride.
Table 1. Initial reaction screening of the carbocyclization of ortho-allyl
benzoic acid.
Entry[a]
Pd
Ligand
Yield 5[b]
Yield 7[b]
1[c]
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
PdCl2
P(o-tol)3
P(o-tol)3
AsPh3
PPh3
PCy3
P(o-tol)3
none
P(o-tol)3
P(o-tol)3
P(o-tol)3
78
89
82
53
14
0
17
63
0
3
3
5
8
68
0
0
16
0
0
5
6[d]
7
8
9
10
none
0
[a] Reaction conditions: 2-allybenzoic acid (1 equiv), Ac2O (2 equiv),
Pd(OAc)2 (1 mol%), P(o-tol)3 (2 mol%), THF (1m), 658C, 18 h. [b] Yields de-
1
termined by H NMR spectroscopy using an internal standard. [c] Reaction
performed at 238C for 24 h with 1.2 mol% P(o-tol)3. [d] No Ac2O
Chem. Eur. J. 2014, 20, 11336 – 11339
www.chemeurj.org
11337
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
73% yield (28–30).[15] The slightly decreased yields of the in-
denone series with respect to the indanone series is likely
caused by the tandem reaction sequence of indenone forma-
tion, followed by isomerization. Thus, two reactions are re-
quired to form a single indenone product (Scheme 1).
We have demonstrated that exo-methylene indanone 10 iso-
merizes in the presence of PCy3 as ligand to give 21, while
little to no isomerization is seen in the presence of P(o-tol)3 as
ligand (Scheme 3). The isomerization required the addition of
acetic acid, which is presumably formed in situ under the reac-
tion conditions. Interestingly, these isomerization results are in
contrast to palladium-catalyzed isomerizations that employ
P(o-tol)3 as ligand.[6]
Table 2. Substrate scope of the carbocyclization of ortho-allyl benzoic
acids to exo-methylene indanones.[a]
[a] Yields are an average of two, one mmol reactions. [b] 3 equiv of Ac2O
used. [c] 2 mol% Pd(OAc)2 4 mol% AsPh3. [d] 2 mol% of Pd(OAc)2/
4 mol% P(o-tol)3 was used. [e] 5 mol% Pd(OAc)2, 10 mol% P(o-tol)3 in di-
oxane at 1008C.
Scheme 3. Conversion of exo-methylene indanone 10 to the corresponding
indenone 21.
The Pd(OAc)2/P(o-tol)3 catalyst system was monitored by
31P NMR spectrum and after several hours, a new resonance
appeared near 35 ppm. Independent synthesis of the Her-
mann–Beller palladacycle 31 confirmed the identity of the
complex that evoked this resonance. However, when the palla-
dacycle was subjected to the reaction conditions with acid 1 it
was not chemically competent and is likely the product of cat-
alyst decomposition. (Scheme 4).
ed benzoic acids provided indenone 20 and 21 in 75% yield.
Electron-deficient aryl chloride and aryl fluorides, as well as
a naphthoic derivative smoothly cyclized in 60–80% yields
(22–25). Electron-rich phenol substrate cyclized with concomi-
tant acetylation of the phenol, to provide 26 in 60% yield. A
sterically hindered disubstituted olefin also participated in the
carbocyclization reaction, giving 57% yield of the dihydrofluor-
enone derivative 27. Heterocyclic substrates were also reactive,
forming interesting thiophenyl and carbazole products in 48–
Previously, Hermann and Beller showed that their namesake
palladacycle is a robust catalyst that promotes the Heck reac-
tion of aryl halides and olefins with high turnover numbers.[17]
We exploited the known catalytic activity of this complex by
adding aryl halide and base to the crude indanone reaction
mixture post-carbocyclization to promote the formation of
a second sp2–sp2 carbon–carbon bond via a traditional Heck
reaction. The in situ generated Hermann–Beller catalyst elimi-
nated the need to add additional palladium for the second
Heck reaction. This one-pot reaction worked well and provided
(E)-selective acyl-Heck–Heck (aHH) products in 44–77% yields
(Table 4, 32–37). Notably, the known antiproliferative agent, in-
danorine (35),[8] was formed in 64% yield from the correspond-
ing o-allyl benzoic acid. The higher temperatures for the
second Heck reaction is indicative of reactions using this palla-
Table 3. Substrate scope of the carbocyclization of ortho-allyl benzoic
acids to indenones.[a]
[a] Yields are an average of two, one mmol reactions. [b] 3 mol% of
Pd(OAc)2/6 mol% P(Cy)3 in dioxane at 1008C. [c] 5 mol% Pd(OAc)2,
10 mol% P(Cy)3 in dioxane at 1008C. [d] 3 equiv of Ac2O used.
Scheme 4. Testing the potential catalytic activity of the Hermann–Beller pal-
ladacycle 31.
Chem. Eur. J. 2014, 20, 11336 – 11339
www.chemeurj.org
11338
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Acknowledgements
Table 4. One-pot aHH reactions form two sp2–sp2 carbon–carbon bonds
of trisubstituted olefins.
The Ohio State University is acknowledged for support of this
research.
Keywords: carboxylic acids · catalysis · cyclization · green
chemistry · palladium
[1] a) L. S. Hegedus in Transition Metals in the Synthesis of Complex Organic
Molecules, University Science Books, Mill Valley, CA, 1999; b) C. H. Jun,
E. A. Jo, J. W. Park, Eur. J. Org. Chem. 2007, 1869; c) E. Negishi, Handbook
of Organopalladium Chemistry for Organic Synthesis, Wiley-Interscience,
New York, 2002; d) M. C. Willis, Chem. Rev. 2010, 110, 725.
[2] a) J. M. Tour, E. I. Negishi, J. Am. Chem. Soc. 1985, 107, 8289; b) C. M. An-
dersson, A. Hallberg, J. Org. Chem. 1988, 53, 4257; c) R. K. Dieter, Tetra-
hedron 1999, 55, 4177; d) M. Kubota, D. M. Blake, J. Am. Chem. Soc.
1971, 93, 1368; e) Y. Zhang, T. Rovis, J. Am. Chem. Soc. 2004, 126, 15964.
[3] a) T. Fukuyama, S. C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050; b) H.
Tokuyama, S. Yokoshima, T. Yamashita, T. Fukuyama, Tetrahedron Lett.
1998, 39, 3189; c) J. M. Villalobos, J. Srogl, L. S. Liebeskind, J. Am. Chem.
Soc. 2007, 129, 15734; d) H. Yang, L. S. Liebeskind, Org. Lett. 2007, 9,
2993; e) phosphoric anhydrides have also been employed: K.-C. Lim, Y.-
T. Hong, S. Kim, Synlett 12, 1851.
[4] a) T. Morimoto, M. Fujioka, K. Fuji, K. Tsutsumi, K. Kakiuchi, Pure Appl.
Chem. 2008, 80, 1079; b) E. I. Negishi, C. Copꢁret, S. Ma, T. Mita, T. Sugi-
hara, J. M. Tour, J. Am. Chem. Soc. 1996, 118, 5904; c) C. Torborg, M.
Beller, Adv. Synth. Catal. 2009, 351, 3027; d) X.-F. Wu, H. Neumann, M.
Beller, Chem. Soc. Rev. 2011, 40, 4986; e) X.-F. Wu, H. Neumann, M.
Beller, Chem. Rev. 2013, 113, 1.
dacycle, and is also likely required because the formation of tri-
substituted olefins in Heck reactions is typically sluggish.
This newly developed one-pot acyl-Heck–Heck (aHH) reac-
tion was applied to the synthesis of donepezil, whose HCl salt
is marketed as Aricept by Pfizer for the treatment of Alzheim-
er’s disease.[18] Our aHH reaction allows a complementary syn-
thesis of donepezil that is more atom economical than previ-
ously reported.[19] Subjecting 4,5-dimethoxy-2-allylbenzoic acid
and 4-bromopyridine to the optimized one-pot reaction condi-
tions yielded the aHH product 39 in 60%. Quaternization of
the pyridine with benzyl bromide gave pyridinium 40 in 79%
yield. Hydrogenation of the alkene and pyridine ring in 40 fur-
nished donepezil (41) in 50% yield (Scheme 5).
[5] a) R. F. Coburn, H. J. Forman in Comprehensive Physiology, Wiley, Hobo-
ken, 2011; b) A. Ernst, J. D. Zibrak, New Engl. J. Med. 1998, 339, 1603.
[6] a) K. Kunchithapatham, C. C. Eichman, J. P. Stambuli, Chem. Commun.
2011, 47, 12679; b) S. M. Whittemore, R. J. Yoder, J. P. Stambuli, Organo-
metallics 2012, 31, 6124.
[7] D. S. Geldmacher, Expert Rev. Neurother. 2004, 4, 5.
[8] H. Shih, L. Deng, C. J. Carrera, S. Adachi, H. B. Cottam, D. A. Carson,
Bioorg. Med. Chem. Lett. 2000, 10, 487.
[9] a) X. H. Hua, D. Genini, R. Gussio, R. Tawatao, H. Shih, T. J. Kipps, D. A.
Carson, L. M. Leoni, Cancer Res. 2001, 61, 7248; b) L. M. Leoni, E. Hamel,
D. Genini, H. Shih, C. J. Carrera, H. B. Cottam, D. A. Carson, J. Natl.
Cancer Inst. 2000, 92, 217.
[10] A. I. Syrchina, A. A. Semenov, Chem. Nat. Compd. 1982, 18, 1.
[11] N. Chatani, A. Kamitani, M. Oshita, Y. Fukumoto, S. Murai, J. Am. Chem.
Soc. 2001, 123, 12686.
[12] a) R. C. Larock, M. J. Doty, S. Cacchi, J. Org. Chem. 1993, 58, 4579; b) W.
Tao, L. J. Silverberg, A. L. Rheingold, R. F. Heck, Organometallics 1989, 8,
2550.
[13] A. P. Thottumkara, T. Kurokawa, J. Du Bois, Chem. Sci. 2013, 4, 2686.
[14] L. J. Gooßen, K. Ghosh, Eur. J. Org. Chem. 2002, 3254.
[15] Compound 30 may be formed from a 6-endo cyclization, followed by
aromatization to the phenol, and subsequent acetylation.
Scheme 5. Synthesis of Donepezil via an aHH reaction.
In summary, we present a highly efficient, selective, and
functional group tolerant method to form exo-methylene inda-
nones and indenones from readily accessible substituted ben-
zoic acids. The reaction avoids the use of toxic carbon monox-
ide and produces acetic acid as the only stoichiometric by-
product. A simple change in ligand selectively controls the for-
mation of the indanone or indenone likely through an addi-
tional isomerization reaction. The conversion of this active
catalyst to the Hermann–Beller palladacycle was exploited as
the second catalyst in a one-pot acyl Heck–Heck coupling reac-
tion that forms two sp2–sp2 carbon–carbon bonds of trisubsti-
tuted olefins.
[16] H. J. Lim, C. R. Smith, T. V. RajanBabu, J. Org. Chem. 2009, 74, 4565.
[17] a) M. Beller, H. Fischer, W. A. Herrmann, K. ꢂfele, C. Brossmer, Angew.
Chem. 1995, 107, 1992; Angew. Chem. Int. Ed. Engl. 1995, 34, 1848;
b) W. A. Herrmann, C. Brossmer, K. ꢂfele, C.-P. Reisinger, T. Priermeier, M.
Beller, H. Fischer, Angew. Chem. 1995, 107, 1989; Angew. Chem. Int. Ed.
Engl. 1995, 34, 1844; c) W. A. Herrmann, C. Brossmer, C.-P. Reisinger,
T. H. Riermeier, K. ꢂfele, M. Beller, Chem. Eur. J. 1997, 3, 1357.
[18] H. Sugimoto, Y. Iimura, Y. Yamanishi, K. Yamatsu, J. Med. Chem. 1995, 38,
4821.
[19] N. Niphade, A. Mali, K. Jagtap, R. C. Ojha, P. J. Vankawala, V. T. Mathad,
Org. Process Res. Dev. 2008, 12, 731.
Received: May 16, 2014
Published online on July 22, 2014
Chem. Eur. J. 2014, 20, 11336 – 11339
www.chemeurj.org
11339
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim