Palladium-Catalyzed Cyclocarbonylation-Decarboxylation of Diethyl(2-iodoaryl)malonates with Vinyl Ketones Affording Functionalized Enolic 2-Acyl-3,4-dihydronaphthalenones

Article abstract of DOI:10.1021/ol900859n

A wide variety of enolic tautomers of functionalized 2-acyl-3,4- dihydronaphthalen-1(2H)-ones were obtained in moderate to excellent yields by the palladium-catalyzed cyclocarbonylation-decarboxylation of diethyl(2-iodoaryl)malonates with vinyl ketones an

Full text of DOI:10.1021/ol900859n

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3278-3281
Palladium-Catalyzed
Cyclocarbonylation-Decarboxylation of
Diethyl(2-iodoaryl)malonates with Vinyl
Ketones Affording Functionalized Enolic
2-Acyl-3,4-dihydronaphthalenones
Zhaoyan Zheng and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
howard.alper@uottawa.ca
Received April 20, 2009
ABSTRACT
A wide variety of enolic tautomers of functionalized 2-acyl-3,4-dihydronaphthalen-1(2H)-ones were obtained in moderate to excellent yields by
the palladium-catalyzed cyclocarbonylation-decarboxylation of diethyl(2-iodoaryl)malonates with vinyl ketones and carbon monoxide. The reaction
may proceed via the formation of a keto-diester, followed by oxidative addition, CO insertion, intramolecular cyclization, and decarboxylation
to give the enolic substituted 2-acyldihydronaphthalenones.
3,4-Dihydronaphthalen-1(2H)-one, known as R-tetralone, and
its derivatives continue to occupy an important place in
organic and medicinal chemistry because of the presence of
this moiety in a number of natural products1 and synthetic
pharmaceuticals.2 2-Acyl-3,4-dihydronaphthalenones are key
building blocks for the construction of many bioactive
products such as (()brasiliquinone B3 and tetrahydronaph-
thalene.4 Classical approaches for the synthesis of 2-acyl-
3,4-dihydronaphthalenones include the condensation of the
corresponding 3,4-dihydronaphthalenone with aldehydes,
followed by oxidation of the resultant ketols with Jones
reagent.5 Acylation of R-tetralone using boron trifluoride
etherate or diethyl carbonate followed by treatment with
sodium acetate in refluxing methanol completes the synthetic
process.3,6 These methods need to start from the correspond-
ing tetralone and require multistep reactions. Routes to highly
substituted 2-acyl-3,4-dihydronaphthalenones are more com-
(2) (a) Deshpande, M. N.; Cain, M. H.; Patel, S. R.; Singman, P. R.;
Brown, D.; Gupta, A.; Barkalow, J.; Callen, G.; Patel, K.; Koops, R.;
Chorghade, M.; Foote, H.; Pariza, R. Org. Process Res. DeV. 1998, 2, 351.
(b) Vukics, K.; Fodor, T.; Fischer, J.; Fellegvari, I.; Levai, S. Org. Process
Res. DeV. 2002, 6, 82. (c) Zelle, R. E.; Hancock, A. A.; Buckner, S. A.;
Basha, F. Z.; Tietje, K.; DeBernardis, J. F.; Meyer, M. D. Bioorg. Med.
Chem. Lett. 1994, 4, 1319. (d) Moore, G.; Levacher, V.; Bourguignon, J.;
Dupas, G. Tetrahedron Lett. 2001, 42, 261. (e) Alamansa, C.; Gomez, L. A.;
Cavalcanti, F. L.; Rodriguez, R.; Carceller, E.; Bartroli, J.; Garcia-Rafanell,
J.; Forn, J. J. Med. Chem. 1993, 36, 2121. (f) Wachter, G. A.; Hartmann,
R. W.; Sergejew, T.; Grun, G. L.; Ledergerber, D. J. Med. Chem. 1996,
39, 834.
(1) (a) Jiao, P.; Swenson, D. C.; Gloer, J. B.; Campbell, J.; Shearer,
C. A. J. Nat. Prod. 2006, 69, 1667. (b) Barrett, A. G. M.; Blaney, F.;
Campbell, A. D.; Hamprecht, D.; Meyer, T.; White, A. J. P.; Witty, D.;
Williams, D. J. J. Org. Chem. 2002, 67, 2735. (c) Wipf, P.; Jung, J. K.;
Rodriguez, S.; Lazo, J. S. Tetrahedron 2001, 57, 283. (d) Ragot, J. P.;
Alcaraz, M. L.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 4921. (e)
Laurent, D.; Guella, G.; Mancini, I.; Roquebert, M. F.; Farinole, F.; Pietra.
F Tetrahedron 2002, 58, 9163. (f) Quang, D. N.; Hashimoto, T.; Tanaka,
M.; Baumgartner, M.; Stadler, M.; Asakawa, Y. J. Nat. Prod. 2002, 65,
1869. (g) Wu, T. S.; Tsai, Y. L.; Damu, A. G.; Kuo, P. C.; Wu, P. L. J.
Nat. Prod. 2002, 65, 1522. (h) Basavaiah, D.; Reddy, R. J. Org. Biomol.
Chem. 2008, 6, 1034.
(3) Patil, M. L.; Borate, H. B.; Ponde, D. E.; Deshpande, V. H.
Tetrahedron 2002, 58, 6615.
(4) Vera, W. J.; Banerjee, A. K. ArkiVoc 2007, 8.
(5) (a) Yoshioka, M.; Sawada, H.; Saitoh, M.; Hasegawab, T. J. Chem.
Soc., Perkin Trans. 1990, 1, 1097.
(6) Anderson, A. G.; Greef, H. F. J. Am. Chem. Soc. 1952, 74, 5203
.
10.1021/ol900859n CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

plicated and are accompanied by the formation of byprod-
ucts.7
Pd(OAc)2, 0.135 mmol of tri(2,6-dimethoxyphenyl)phosphine
(TDMPP) and 3.0 mmol of Et3N in 8.0 mL of THF at 120
°C for 24 h. These conditions mirror those used for the
synthesis of isoquinolin-1(2H)-ones.18 The desired dihy-
dronaphthalenone 3a was obtained in 47% yield (Table 1,
entry 1). The use of triphenylphosphine (PPh3) and trim-
tolylphosphine ((m-toly)3P) as ligands afforded 3a in 74%
and 70% yield, respectively (Table 1, entries 2 and 3), while
tricyclohexylphosphine (PCy3) afforded 3a in only 26% yield
(Table 1, entry 4). Performing the same reaction using
bidentate phosphine ligands resulted in the isolation of 3a
in 59% and 37% yield (Table 1, entries 5 and 6). When
employing the bulky and electron-rich monophosphine,
Xphos (2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphe-
nyl) and Davephos (2-dicyclohexylphosphine-2′-(N,N-dim-
ethylamino)biphenyl), the product yields for 3a increased
to 82% and 85% yield, respectively (Table 1, entries 7 and
8). These results show that the ligand employed plays an
important role in this transformation.
Transition-metal-catalyzed reactions are useful for the
construction of heterocyclic and carbocyclic systems.8 The
palladium-catalyzed cyclocarbonylation reaction provides
efficient access to a wide variety of carbonyl-containing
heterocycles.9 We previously demonstrated that palladium-
catalyzed cyclocarbonylation can be used for the synthesis
of thiochroman-4-ones,10 ring-fused isoquinolinones,11 lac-
tones,12 2(5H)-furanones,13 1,3-oxazin-4-ones,14 1,3-ben-
zothiazin-2-ones,15 quinazolin-4(3H)-ones16 and different
ring-sized lactams.17 Recently, we developed a novel cy-
clocarbonylation process, followed by decarboxylation,
which provides an effective approach for the one-step
synthesis of substituted heterocyclic isoquinolin-1(2H)-
ones.18 This result prompted us to extend this type of
cyclocarbonylation-decarboxylation reaction method to the
synthesis of carbocycles. Herein, we report the successful
application of this palladium-catalyzed cyclocarbonylation-
decarboxylation to the synthesis of variously substituted
2-acyl-4-carboxylic acid ethyl ester-3,4-dihydronaphthalen-
1(2H)-ones.
The yield of dihydronaphthalen-1(2H)-ones 3a was also
dependent on the nature of the base. The presence of an
inorganic base, such as K2CO3 and Cs2CO3, only afforded
trace amounts of 3a (Table 1, entries 9 and 10). The more
hindered amine base N,N-diisopropylethylamine is less
effective than triethylamine since it gave 3a in 62% yield
(Table 1, entry 11). A further increase in the yield was
achieved by reducing the pressure of carbon monoxide from
400 to 200 psi. (Table 1, entry 12). Lower temperatures
resulted in incomplete consumption of the starting materials
(Table 1, entry 14). On the basis of the above studies, the
reaction conditions using Pd(OAc)2 and Xphos in the
presence of Et3N at 120 °C in THF for 24 h, under a pressure
of 200 psi CO, were employed as the standard reaction
conditions for other substrates.
The reaction of diethyl(2-iodoaryl)malonate (1a) with
methyl vinyl ketone (2a) was chosen as a model system for
the optimization of the reaction conditions (Table 1). Initially,
Table 1. Optimization of the Reaction Conditions for the
Reaction of Diethyl(2-iodoaryl)malonate with Methyl Vinyl
Ketonea
A wide variety of vinyl ketones react with various
diethyl(2-iodoaryl)malonates under the optimized reaction
conditions to give the cyclocarbonylation products stereo-
selectively (Table 2). The stereochemistry of the products
was determined by NOE experiments.
temp
(°C)
CO
(psi)
yield
(%)b
entry
catalyst system
base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
1
2
3
4
5
6
7
8
Pd(OAc)2/TDMPP
Pd(OAc)2/PPh3
Pd(OAc)2/(m-toly)3P
Pd(OAc)2/PCy3
Pd(OAc)2/dppb
Pd(OAc)2/dppp
120
120
120
120
120
120
120
120
120
120
120
120
120
100
400
400
400
400
400
400
400
400
400
400
400
200
100
200
47
74
70
26
59
37
82
85
trace
18
Diethyl(2-iodophenyl)malonate 1a reacted with ethyl vinyl
ketone 2b and amyl vinyl ketone 2c to give 3b and 3c in
85% and 81% yield, respectively (Table 2, entries 2 and 3).
Phenyl vinyl ketone 2d also reacted well with 1a to afford
the corresponding 3d in 93% yield (Table 2, entry 4).
Similarly, 4-substituted vinyl ketone also underwent the
cyclocarbonylation reaction. Benzalacetone 2f reacted with
1a under the standard conditions to give 3f in 77% yield
(Table 2, entry 6). Chalcone 2g afforded the corresponding
product 3g in 67% yield (Table 2, entry 7). It is noteworthy
here that 3f and 3g were obtained as a single diastereomer.
However, when methyl propenyl ketone 2e was employed
as the reactant, a mixture of diastereomers of dihydronaph-
thalene-1(2H)-one was obtained in 68% yield. The reaction
of 1a with cyclic ketones, such as cyclohexenone 2h and
cycloheptanone 2i, also occurred in a highly stereoselective
fashion to give the corresponding ring-fused dihydronaph-
thalene-1(2H)-ones 3h and 3i in 70% and 74% yield,
respectively (Table 2, entries 8 and 9). Performing the same
Pd(OAc)2/Dave phos Et3N
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Pd(OAc)2/X-phos
Et3N
9
K2CO3
CsCO3
i-Pr2NEt
Et3N
Et3N
Et3N
10
11
12
13
14
62
87
80
81
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), Pd cat. (0.03
mmol), phosphine ligand (0.135 or 0.07 mmol), base (3.0 mmol), CO 100,
200, or 400 psi, 120 or 100 °C, THF (8.0 mL). b Isolated yield.
diethyl(2-iodoaryl)malonate 1a (1.0 mmol) and methyl vinyl
ketone 2a (1.2 mmol) were treated under a pressure of 400
psi carbon monoxide in the presence of 0.03 mmol of
Org. Lett., Vol. 11, No. 15, 2009
3279

Table 2. Cyclocarbonylation-Decarboxylation of
Scheme 1. Proposed Reaction Mechanism
Diethyl(2-iodophenyl)malonates 1 and Vinyl Ketones 2a
reaction using PPh3 instead of Xphos as the ligand resulted
in the isolation of 3h in 57% yield. The palladium-catalyzed
cyclocarbonylation-decarboxylation was also successfully
extended to the reaction of a diethyl(2-iodophenyl) malonate
derivative having electron-donating dimethoxy substituents
1b with 2a to form the corresponding product 3j in 96%
yield (Table 2, entry 10). In a similar manner, 1b underwent
carbonylation with 2d and 2h afford 3k and 3l in 84% and
81% yield, respectively (Table 2, entries 11 and 12).
The NMR spectra of 3 shows that they exist in the keto
form before work-up, but they isomerize to the enol form
on passing through a silica gel column for purification. The
13C NMR spectrum of crude 3a displays two carbonyl carbon
at δ 206.1 and 198.7, but the 13C NMR spectrum of purified
1
3a shows only a carbonyl carbon at δ 196.5, and the H
NMR spectrum has a hydroxyl singlet at δ 16.24. Similar
enolic tautomerism of 2-acyl-1-tetralones has been reported
in the literature.19
A possible reaction mechanism for the formation of 2-acyl-
3,4-dihydronaphthalen-1(2H)-ones 3 is outlined in Scheme
(7) Pazˇicky´, M.; Semak, V.; Ga´sˇpa´r, B.; B´ılesˇova´, A.; Salisˇova´, M.;
Boha´cˇ, A. ArVikoc 2008, 225.
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96, 935. (c) Rubin, M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265.
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Negishi, E., Ed.; John Wiley and Sons: New York, 2002; Vol. 2. (b) Tsuji,
J. Palladium Reagents and Catalysts: InnoVations in Organic Synthesis;
John Wiley and Sons: New York, 1995. (c) Tsuji, J. Palladium Reagents
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(11) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987.
(12) (a) Cao, H.; Xiao, W. J.; Alper, H. AdV. Synth. Catal. 2006, 348,
1807. (b) Li, Y.; Alper, H. Org. Lett. 2006, 8, 5199. (c) El Ali, B.; Okuro,
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a Diethyl(2-iodophenyl)malonates 1 (1.0 mmol), vinyl ketones 2 (1.2
mmol), Pd(OAc)2 (0.03 mmol), Xphos (0.135 mmol), Et3N (3.0 mmol),
CO 200 psi, THF (8.0 mL), 120 °C, 24 h. b Isolated yield. c structures of
major isomer are represented. d PPh3 as ligand.
(14) Larksarp, C.; Alper, H. J. Org. Chem. 1999, 64, 9194.
(15) Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612.
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Z. Y.; Alper, H. Org. Lett. 2008, 10, 829.
3280
Org. Lett., Vol. 11, No. 15, 2009

1. It is conceivable that the reaction starts by Michael
addition of the vinyl ketone with diethyl(2-iodoaryl)malonate
in the presence of a base giving a keto-diester intermediate
4,20 which then undergoes oxidative addition to provide in
situ generated palladium (0),21 leading to the arylpalladium
complex 5. Insertion of carbon monoxide into the aryl
carbon-palladium bond of 5 could afford the aroylpalladium
iodide complex 6, and subsequent intramolecular attack of
the enolate carbon on the palladium atom in 6 may afford a
seven-membered palladacycle 7.22 Reductive elimination of
7 may lead to the substituted diester 2-acetylcyclohexanone
compound 8 and regenerate the palladium(0) species. Com-
pound 8 may subsequently undergo base-induced decar-
boalkoxylation18 to afford the dihydronaphthalen-1(2H)-ones
9, which isomerizes to give the enolic tautomer 3 on silica
gel.
In conclusion, we have developed an effective one-pot
three-component reaction for the synthesis of functionalized
enolic 2-acyl-3,4-dihydronaphthalen-1(2H)-ones. The reac-
tion tolerates a variety of substitutions and affords 2-acyl-
1-tetralones in moderate to excellent yields. In addition, the
present method demonstrates that the Pd-catalyzed cyclo-
carbonylation-decarboxylation can also been extended to the
construction of carbocycles.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
support of this research.
(17) (a) Lu, S. M.; Alper, H. J. Am. Chem. Soc. 2008, 130, 6451. (b)
Lu, S. M.; Alper, H. Chem-Eur. J. 2007, 13, 5908. (c) Lu, S. M.; Alper,
H. J. Am. Chem. Soc. 2005, 127, 14776.
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(19) Yoshioka, M.; Nishioka, T.; Hasegawa, T. J. Org. Chem. 1993,
58, 278.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H NMR, 13C
(20) Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J. Tetrahedron
Lett. 2001, 42, 8395.
NMR, DEPT, NOESY and COSY spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) McCrindle, R.; Ferguson, G.; Arsenault, G. J.; McAlees, A. J.;
Stephenson, D. K. J. Chem. Res., Synop. 1984, 360.
(22) Roesch, K. R.; Zhang, H. M.; Larock, R. C. J. Org. Chem. 2001,
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OL900859N
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