Heck Arylation of 1,2-Cyclohexanedione and 2-Ethoxy-2-cyclohexenone

Full text of DOI:10.1021/jo980221b

4158
J . Org. Chem. 1998, 63, 4158-4162
We herein report that C3-arylation of ketol 1 can be
Heck Ar yla tion of 1,2-Cycloh exa n ed ion e
accomplished under traditional Heck arylation conditions
in the presence of water. This reaction constitutes, to
our knowledge, the first example of an arylation of an
enol proposed to proceed by a Heck reaction mechanism.1
Arylation of 2-ethoxy-2-cyclohexenone (4) and subsequent
cleavage of the alkoxy group provides an alternative
procedure to obtain 3.
a n d 2-Eth oxy-2-cycloh exen on e
Neeraj Garg, Mats Larhed, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry,
Uppsala Biomedical Centre, Uppsala University, Box 574,
SE-751 23 Uppsala, Sweden
Received February 6, 1998
Resu lts
Reactions of 1 (1 equiv) and aryl bromides 2a -h (4
equiv) with a catalytic amount palladium acetate as
precatalyst and triphenyl phosphine as ligand deliver
3a -h in moderate yields (eq 1 and Table 1). The
reactions were conducted with diisopropylethylamine as
base in aqueous DMF9 (DMF/water 85/15) at 100 °C. No
diarylation product was observed. With smaller amounts
of aryl bromide or water, considerably lower yields were
observed. Aromatic bromides carrying electron-with-
drawing groups, with the exception of 2g, failed to
produce arylated cyclohexane-1,2-diones. Furthermore,
with aryl iodides as coupling partners a fast formation
of biaryls predominated and no product from arylation
of 1 was detected.10,11
Palladium-catalyzed arylation of enol ether 4 with
electron-rich 2a -c,f occurred smoothly (eq 2 and Table
2). Interestingly, even the electron-poor aryl bromides
(2i-m ) were useful as arylating agents with 4, provided
the more hindered tri-o-tolylphosphine was employed as
supporting ligand (Table 2).10,12 High isolated yields of
the C3-arylated enol ethers 5a -c,f,i-m were obtained
with complete regioselectivity. Further deethylation of
5f,m to afford 3 could also be efficiently achieved (eq 3).13
Since the sharp temperature profiles associated with
microwave in-situ heating might help to minimize the
In tr od u ction
The intermolecular Heck reaction is of the utmost
importance in organic synthesis.1 The reaction allows
regioselective arylation at the terminal â-position of both
electron-deficient olefins such as R,â unsaturated carbon-
yl compounds and of electron-rich enol ethers. The
â-arylation of enol ethers, which relies on chelate control,2
delivers aryl acetaldehydes after hydrolysis and â-aryl-
ation of the enol ether methyl R-methoxyacrylate, and
subsequent hydrolysis provides aryl substituted R-keto
acid derivatives.3
In a medicinal chemistry oriented research project4
access to direct methods for the attachment of cyclic
corestructures with combined hydrogen bond accepting
and donating properties5 were needed. In particular, a
convenient synthetic route to 3-aryl-1,2-cyclohexanedi-
ones6,7 3 from aryl halides was desired. On the basis that
the enol form of 1,2-cyclohexanedione (1) encompasses
an R,â-unsaturated system,8 we were prompted to com-
mence a study of the Heck arylation of 1.1
(1) For reviews on the Heck reaction see: (a) Heck, R. F. Org React.
1982, 27, 345. (b) Heck, R. F. Comprehensive Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon Press: Oxford 1991; Vol. 4, p
833. (c) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379. (d) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (e)
Tsuji, J . Palladium Reagents and Catalysts: Innovations in Organic
Chemistry; J ohn Wiley & Sons: Chichester, 1995; p 125. (f) Soderberg,
B. C. Comprehensive Organometallic Chemistry II; Hegedus, L. S.,
Volume Ed., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon
Press: Oxford 1995; Vol. 12, p 259. (g) J effery, T. Advances in Metal-
Organic Chemistry; Liebeskind, L. S., Ed.; J AI Press Inc: Greenwich
1996; Vol. 5, p 153. (h) Bra¨se, S.; de Meijere, A. Metal-catalyzed Cross-
Coupling Reactions; Stang, P. J ., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 1997; p 99.
(7) 1,2-Diketones have found widespread use in the syntheses of
different heterocyclic compounds. For some examples, see the following.
(a) Bredereck, H.; Gompper, R.; von Schuh, H. G.; Theilig, G. Angew.
Chem. 1959, 71, 753. (b) Porter, A. E. A. Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J ., McKillop, A.,
Eds.; Pergamon Press: Oxford 1984; Vol. 3, p 157. (c) Christl, M.;
Kraft, A. Angew. Chem., Int. Ed. Engl. 1988, 27, 1369. (d) Gupta, A.
K.; Fu, X.; Snyder, J . P.; Cook, J . M. Tetrahedron 1991, 47, 3665. (e)
Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 493.
(2) (a) Andersson, C.-M.; Larsson, J .; Hallberg, A. J . Org. Chem.
1990, 55, 5757. (b) Larhed, M.; Andersson, C.-M.; Hallberg, A. Acta
Chem. Scand. 1993, 47, 212. (c) Badone, D.; Guzzi, U. Tetrahedron
Lett. 1993, 34, 3603. (d) Larhed, M.; Andersson, C.-M.; Hallberg, A.
Tetrahedron 1994, 50, 285. (e) Larhed, M.; Hallberg, A. J . Org. Chem.
1997, 62, 7858.
(3) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1987, 28, 3039.
(4) Hulte´n, J .; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello,
G.; Bouzide, A.; Åqvist, J .; Classon, B.; Danielson, U. H.; Karle´n, A.;
Kvarnstro¨m, I.; Samuelsson, B.; Hallberg, A. J . Med. Chem. 1997, 40,
885.
(5) For carboxylic acid group isosteres see: (a) Korolkovas, A.
Essentials of Medicinal Chemistry; J ohn Wiley & Sons: Chichester
1988; p 81. (b) Silverman, R. B. The Organic Chemistry of Drug Design
and Drug Action; Academic Press: San Diego 1992; p 20.
(6) Relatively few examples are documented for the preparation of
3-aryl-1, 2-cyclohexanediones. Oxidations: (a) Goldblum, A.; Mechou-
lam, R. J . Chem. Soc., Perkin Trans. 1 1977, 1889. (b) Kawada, K.;
Gross, R. S.; Watt, D. S. Synth. Commun. 1989, 19, 777. (c) Horiuchi,
C. A.; Kiyomiya, H.; Takahashi, M.; Suzuki, Y. Synthesis 1989, 785.
Photolysis: (d) Feigenbaum, A.; Pete, J .-P.; Scholler, D. J . Org. Chem.
1984, 49, 2355. (e) Feigenbaum, A.; Pete, J .-P.; Scholler, D. J . Org.
Chem. 1986, 51, 4424. Conjugate addition: (f) Tomboulian, P.;
Bloomquist, C. A. A. J . Org. Chem. 1959, 24, 1239. (g) Charonnat, J .
A.; Mitchell, A. L.; Keogh, B. P. Tetrahedron Lett. 1990, 31, 315.
(8) (a) Schwarzenbach, G.; Wittwer, C. Helv. Chim. Acta 1947, 30,
663. (b) Hesse, G.; Krehbiel, G. Ann. 1955, 593, 35.
(9) For examples of Heck reactions proceeding in water or in water/
organic solvent mixtures, see: (a) Bumagin, N. A.; More, P. G.;
Beletskaya I. P. J . Organomet. Chem. 1989, 371, 397. (b) Zhang, H.-
C.; Daves, G. D., J r. Organometallics 1993, 12, 1499. (c) J effery, T.
Tetrahedron Lett. 1994, 35, 3051. (d) Kiji, J .; Okano, T.; Hasegawa,
T. J . Mol. Catal. A: Chem. 1995, 97, 73. (e) Crisp, G. T.; Gebauer, M.
G. Tetrahedron 1996, 52, 12465. See also ref 20.
(10) Attempts to use iodobenzene or 1-iodonaphthalene in the
coupling reactions with 1,2-cyclohexanedione (1) and 2-ethoxy-2-
cyclohexenone (4) were unsuccessful. In all reactions, with or without
phosphine ligands (triphenylphosphine or tri-o-tolylphosphine), the
formation of biaryls strongly dominated. We believe that the slow
arylation of 1 and 4 may be attributed to difficulties in the migratory
insertion and a fast concomitant biaryl generation with aryl iodides
as arylating agents.
(11) It has been suggested that the reactivity and stoichiometry of
the oxidative addition products of aryl iodides and bromides are
substantially different. Wolfe, J . P.; Buchwald, S. L. J . Org. Chem.
1996, 61, 1133.
(12) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier,
T. H.; O¨ fele, K.; Beller, M. Chem. Eur. J . 1997, 3, 1357 and references
cited there.
(13) Garg, N.; Gogoll, A.; Westerlund, C.; Sundell, S.; Karle´n, A.;
Hallberg, A. Tetrahedron 1996, 52, 15209.
S0022-3263(98)00221-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/21/1998

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4159
Ta ble 1. P a lla d iu m -Ca ta lyzed Ar yla tion of
1,2-Cycloh exa n ed ion e (1) w ith Ar yl Br om id esa
Ta ble 2. P a lla d iu m -Ca ta lyzed Ar yla tion of
2-Eth oxy-2-cycloh exen on e (4) w ith Ar yl Br om id esa
a
The 1,2-cyclohexanedione (1) (1.0 equiv, 1.0 mmol), aryl
bromide (4.0 equiv), Pd(OAc)2 (0.05 equiv), Ph3P (0.12 equiv), and
i-Pr2NEt (4.0 equiv) were heated at 100 °C under nitrogen in
aqueous DMF. >95% Purity by GC-MS.
heat-induced decomposition of labile starting compound
1,14,15 we decided to assess this heating technique16 under
otherwise identical Heck reaction conditions (except for
reaction scale). Upon continuous microwave treatment,
the transformations were complete within 10 min17
a
The 2-ethoxy-2-cyclohexenone (4) (1.0 equiv, 0.20 mmol), aryl
bromide (4.0 equiv), Pd(OAc)2 (0.05 equiv), Ar3P (0.12 equiv), and
i-Pr2NEt (4.0 equiv) were heated at 100 °C under nitrogen in
b
aqueous DMF. >95% Purity by GC-MS. The phosphine ligand
was Ph3P. c The reaction was performed on a 2.0 mmol scale. d The
phosphine ligand was (o-tol)3P.
(14) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665.
(15) 1,2-Cyclohexanedione is known to be thermally unstable. Fluka
Catalogue, Chemica, BioChemika, Analytika, Norge/Sverige, 1997/98,
p 439.
rather than several hours. But the yields of 3c and 3f
were only slightly improved (Table 3). As was the case
with the thermal version of the reaction, electron-poor

4160 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Ta ble 3. P a lla d iu m -Ca ta lyzed Ar yla tion of 1 or 4 w ith
Ar yl Br om id es u n d er Micr ow a ve Hea tin ga
diketone or
enol ether
aryl
bromide
time
(min)
power
(W)
isolated yield, %,
of 3 or 5a
1
1
4
4
2c
2f
2c
2f
10
10
12
10
40
50
40
50
3c 69
3f 66
5c 57
5f 70
a
A mixture of the diketone 1 or enol ether 4 (1.0 equiv, 0.20
mmol), aryl bromide (4.0 equiv), Pd(OAc)2 (0.05 equiv), Ph3P (0.12
equiv), i-Pr2NEt (4.0 equiv), and aqueous DMF were continuously
irradiated for 10-12 min under nitrogen in a sealed Pyrex tube.
>95% Purity by GC-MS.
arylating derivatives afforded no coupling products. Two
microwave-assisted reactions with olefin 4 were also
conducted (Table 3). After a reaction time of 10-12 min,
arylation with 2c and 2f provided 5c and 5f in 57% and
70% isolated yields, respectively.17
Sch em e 1
Discu ssion
We believe that the reaction of 1 with aryl bromides
proceeds via formation of an aryl palladium π-complex
and subsequent insertion of the enol double bond as
depicted in Scheme 1.18 The arylated ketols 3 are
thereafter liberated by direct PdH elimination (path A)19
or alternatively, a palladium enolate is created and
eventually a syn-â-elimination provides free 3 (path B).20
It is possible that the hydrogen bonding proton of the
enol,21 prior to π-complex formation, is replaced by a
palladium atom which coordinates to the carbonyl oxygen
atom and forms a stable palladium 1,2-diketonate com-
plex.22,23 We cannot exclude that such an olefinic pal-
ladium diketonate complex constitutes the reactive ole-
finic substrate that is attacked by the arylpalladium
species and undergoes migratory insertion.24 The ability
of the carbonyl oxygen to undergo hydrogen bonding or
coordinate to palladium seems important since neither
(16) (a) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991,
20, 1. (b) Mingos, D. M. P.; Whittaker, A. G. Chemistry Under Extreme
or Non-Classical Conditions; van Eldik, R., Hubbard, C. D., Eds.; J ohn
Wiley & Sons: New York, and Spektrum Akademischer Verlag:
Heidelberg, 1997; p 479. (c) Galema, S. A. Chem. Soc. Rev. 1997, 26,
233. (d) Langa, F.; de la Cruz, P.; de la Hoz, A.; D´ıaz-Ortiz, A.; D´ıez-
Barra, E. Contemp. Org. Synth. 1997, 373. For microwave-assisted
Pd-catalyzed coupling reactions see: (e) Larhed, M.; Lindeberg, G.;
Hallberg, A. Tetrahedron Lett. 1996, 37, 8219. (f) Larhed, M.; Hallberg,
A. J . Org. Chem. 1996, 61, 9582. (g) Larhed, M.; Hoshino, M.; Hadida,
S.; Curran, D. P.; Hallberg, A. J . Org. Chem. 1997, 62, 5583. (h) D´ıaz-
Ortiz, A.; Prieto, P.; Va´zquez. Synlett 1997, 269. (i) Li, J .; Mau, A.
W.-H.; Strauss, C. R. J . Chem. Soc., Chem. Commun. 1997, 1275. (j)
Wali, A.; Muthukumaru Pillai, S.; Satish, S. React. Kinet. Catal. Lett.
1997, 60, 189.
(17) The substantially shorter reaction times obtained under mi-
crowave heating is probably arising from rapid heating to high
temperatures under pressurized conditions, rather than a result of a
specific microwave effect. (a) Ha´jek, M. Collect. Czech. Chem. Com-
mun. 1997, 62, 347. (b) Larhed, M., Ph.D. Thesis, Uppsala University,
Oct. 1997. See also ref 14.
(18) Nonprotected enamines were recently reported to undergo
intramolecular Heck reactions. Chen, C.-Y.; Lieberman, D. R.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J . J . Org. Chem. 1997, 62, 2676.
(19) A â-elimination over carbon and oxygen from a R-hydroxy
σ-complex, to give a carbonyl group and a palladium hydride, has been
proposed in the catalytic cycle of the Wacker process. Ba¨ckvall, J . E.,
Åkermark, B.; Ljunggren, S. O. J . Am. Chem. Soc. 1979, 101, 2411.
(20) Genet, J . P.; Blart, E.; Savignac, M. Synlett 1992, 715.
(21) The electrostatic repulsion between the coplanar carbonyl
dipoles has been suggested to be more important for the enolization of
cyclohexanone25 nor 1,3-cyclohexanedione23 were found
to undergo arylation under our reaction conditions.
The limited yields of 3a -h (Table 1), we believe, are
mainly attributed to a concomitant decomposition of the
ketol 1. A control experiment where 1 was subjected to
the Heck reaction conditions, but without the aryl
bromide, demonstrated that 1 was slowly decomposed
into unidentified compounds.15 Apparently, the utiliza-
tion of the microwave flash heating technique to promote
formation of 3 in favor of decomposition was only
moderately successful (Table 3).
Intermolecular palladium-catalyzed direct substitution
of halides in oxidative addition complexes for soft carbon
(24) To investigate if the reaction mixture was depleted of palladium
catalyst, experiments were performed with higher concentration of
precatalyst (10% Pd(OAc)2 and 24% Ph3P). No increase in the yields
were detected. Furthermore, addition of ZnCl2, MgCl2, MgBr2, and
NiCl2 did not improve the yields.
1
than the stabilization of the enol form by hydrogen bonding.
Hammond, G. S. Steric effects in Organic Chemistry; Newman, M. S.,
Ed.; J ohn Wiley and Sons: New York 1956; p 450.
(25) We were aware of only one report on palladium-catalyzed
intermolecular R-arylation of simple ketones while performing the
synthetic work. (a) Hou, D.; Mas, J . L. U.S. Patent, 4992591, 1991.
Chem. Abstr. 1991, 115, 28927z. After the completion of our laboratory
work, four reports conducted under similar palladium-catalyzed condi-
tions appeared in the literature. (b) Satoh, T.; Kawamura, Y.; Miura,
M.; Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 6, 1740. (c)
Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 11108. (d)
Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119, 12382.
(e) Åhman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.; Buchwald,
S. L. J . Am. Chem. Soc. 1998, 120, 1918. In the general methods for
direct R-arylation (a, c, d, and e) the use of a strong base is obligatory.
(22) For examples of isolated five-membered Pd(II) 1,2-diketonate
complexes see: (a) Morita, H.; Sakurai, H.; Shimomura, S.; Kawaguchi,
S. Transition Met. Chem. 1977, 2, 210. (b) Morita, H.; Shimomura,
S.; Kawaguchi, S. Bull. Chem. Soc., J pn. 1979, 52, 1838. (c) Greaves,
S. J .; Griffith, W. P. Polyhedron 1988, 7, 1973. (d) Griffith, W. P.;
Mostafa, S. I. Polyhedron 1992, 11, 2997.
(23) The pKa value for 1,2-cyclohexanedione was determined to be
9.9 by the potentiometric method. This pKa value was in good
agreement with the literature value (10.3). 1,3-cyclohexanedione is a
stronger acid (pKa ) 5.3). Beil. 7, E III, 3209.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4161
th a t a n a p p r op r ia te sep tu m is u tilized a s a p r essu r e r elief
d evice. The pKa of 1 was determined by an alkalimetric
titration (KOH) with a computerized instrument.31 TLC was
carried out using precoated silica gel plates (60F254 80.2 mm,
Merck) in 15-30% diethyl ether in isohexane, and the spots were
detected with UV light. Column chromatography was carried
out using silica gel (Merck G60) and gradient elution using
diethyl ether and isohexane. The elemental analyses were
performed by MikroKemi AB, Uppsala, Sweden.
nucleophiles, such as malonate or â-keto esters, is not
facile. The presence of a cyano group26 combined with
strong bases, e.g. t-BuOK or NaH, is reported to be
essential for successful reactions (Takahashi aryla-
tion).27,28 Therefore, it seems less likely that 3 is derived
from a direct halide displacement by an enolate anion.25,29
Moreover, no arylated products were traced in reactions
where NaH had been employed as base.
Ma ter ia ls. 1,2-Cyclohexanedione (1) was obtained from
Sigma, and palladium(II) acetate was purchased from Merck-
Schuchardt. 2-Ethoxy-2-cyclohexenone (4) was prepared as
described in this section but is also sold by Aldrich. Triph-
enylphosphine (Merck) was recrystallized from 95% ethanol, and
diisopropylethylamine (Fluka) was stored over potassium hy-
droxide. All other reagents obtained from commercial sources
were used without further purification. Products 3b,6d 3f,6c,d,f
and 5f6e have been synthesized and characterized by other
authors.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Hyd r oxy-
3-a r yl-2-cycloh exen on es (3a -h ). A mixture of 1 (1.0 mmol,
112 mg), aryl bromide (4.0 mmol), diisopropylethylamine (4.0
mmol, 515 mg), Pd(OAc)2 (0.05 mmol, 11.2 mg), Ph3P (0.12 mmol,
31.5 mg), and water (0.75 mL) in DMF (4.25 mL) was degassed
under a nitrogen flow for 5 min. The reaction mixture was
stirred and heated at 100 °C for an appropriate time (see Table
1). The reaction mixture was allowed to cool and was poured
into a saturated aqueous ammonium chloride solution. The
aqueous layer was extracted with diethyl ether, and the com-
bined organic phases were washed with saturated aqueous
ammonium chloride, dried over MgSO4, filtered, and concen-
trated at reduced pressure. The residue was purified on a silica
gel column to give pure 3a -h .
The formation of the arylated enol ethers 5 can be
explained with an analogous reaction sequence as in
Scheme 1. In this coupling, the C3-functionalized prod-
uct 5 is probably liberated after isomerization via a
palladium-enolate followed by syn-â-elimination.20 No-
tably, the reaction conditions for arylation of both 1 and
4 are identical (except for the choice of ligand with the
electron-deficient aryl bromides).
In conclusion, we propose that the palladium-catalyzed
reaction of 1,2-cyclohexanedione with aryl bromides in
aqueous DMF proceeds via Heck arylation of the enol
form of the dione. The simple procedure, good functional
group tolerance, and availability of the starting materials
render the palladium-catalyzed arylation of 1,2-cyclohex-
anedione and 2-ethoxy-2-cyclohexenone valuable comple-
ments to other existing methods6 for the preparation of
3-aryl-1,2-cyclohexanediones.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
capillary melting point apparatus and are uncorrected. 1H NMR
spectra were recorded (in δ scale) at 400 MHz. 13C NMR spectra
were recorded at 100.4 MHz using 1H-decoupled modes. Chemi-
cal shifts were indirectly referenced to TMS by the solvent signal
(CHCl3: 7.26 and CDCl3: 77.0). Signal assignments were made
from homonuclear and heteronuclear correlated spectra. Low
resolution MS spectra (EI+) were measured at an ionization
potential of 70 eV. The mass detector was interfaced with a gas
The experiments with NaH as base were conducted as
described above (but in absence of water).
2-Hydr oxy-3-(3-m eth ylph en yl)-2-cycloh exen on e (3c). Yel-
low semisolid, 134 mg (66%). 1H NMR (CDCl3): 7.53 (s, 1H,
Ar), 7.52 (d, J ) 7.8 Hz, 1H, Ar), 7.29 (t, J ) 7.8 Hz, 1H, Ar),
7.14 (d, J ) 7.3 Hz, 1H, Ar), 6.71 (s, 1H, OH), 2.79 (t, J ) 5.9
Hz, 2H, H-4), 2.63 (t, J ) 6.6 Hz, 2H, H-6), 2.38 (s, 3H, Me),
2.15-2.09 (m, 2H, H-5). 13C NMR (CDCl3): 195.5, 143.4, 137.7,
137.0, 129.1, 128.7, 128.4, 128.1, 125.3, 35.8, 28.9, 22.6, 21.6.
IR (CH2Cl2): 3417, 1665, 1626, 1374 cm-1. MS m/z (% relative
intensity): 202 (M+, 100), 187 (71), 174 (23), 159 (13), 115 (22),
91 (17). Anal. Calcd for C13H14O2: C, 77.2; H, 6.9. Found: C,
77.7; H, 7.1. HRMS calcd 202.0994. Found 202.0994.
P r ep a r a tion of 2-Eth oxy-2-cycloh exen on e (4). 1,2-Cy-
clohexanedione (40 mmol, 4.48 g), p-toluenesulfonic acid mono-
hydrate (1.05 mmol, 200 mg), and 20 mL of 99.5% ethanol were
dissolved in 120 mL of dry benzene in a 250-mL flask equipped
with a Dean-Stark trap.32 The reaction mixture was heated to
boiling, and the azeotrope (benzene, ethanol and water) was
removed for 16 h. The residual solution was washed with 10%
aqueous sodium hydroxide which had been saturated with
sodium chloride and water and was thereafter concentrated at
reduced pressure. Column chromatography of the crude liquid
yielded 2.36 g (42%) pure product.
chromatograph equipped with
a
HP-1 (25 m × 0.20 mm)
capillary column. High-resolution MS analyses (EI+, mean value
of three determinations) were performed by Mr E. Nilsson,
Instrumentstationen, Kemicentrum, Lund, Sweden. Infrared
spectra were recorded on a FTIR spectrophotometer. All pal-
ladium-catalyzed reactions were carried out in heavy-walled
Pyrex tubes, sealed with a screw cap fitted with a Teflon gasket.
The microwave treatment was performed with a MicroWell 10
single-mode cavity30 from Labwell AB, SE-753 19 Uppsala,
Sweden. The Pyrex tubes used in the microwave experiments
(8 mL, l ) 150 mm) were sealed with a silicon septum. It is not
recommended to repeat these reactions in a multimode domestic
microwave oven producing nonuniform irradiation.16b Ca u tion !
It is im p or ta n t to n ote th a t w h en ca r r yin g ou t m icr ow a ve-
h ea ted r ea ction s in closed vessels it is p ossible to gen er -
a te qu ite la r ge p r essu r es, a n d th er efor e it is im p er a tive
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Eth oxy-3-
a r yl-2-cycloh exen on es (5a -c,f,i-m ). A mixture of 4 (0.20
mmol, 28.0 mg), aryl bromide (0.80 mmol), diisopropylethyl-
amine (0.80 mmol, 103 mg), Pd(OAc)2 (0.010 mmol, 2.24 mg),
phosphine ligand (0.024 mmol, see Table 2), and water (0.15 mL)
in DMF (0.85 mL) was degassed under a nitrogen flow for 5 min.
The reaction mixture was stirred and heated at 100 °C for an
appropriate time (see Table 2). The reaction mixture was
allowed to cool and was poured into cold water. The aqueous
layer was extracted with diethyl ether, and the combined organic
phases were washed with water, dried over MgSO4, filtered, and
concentrated at reduced pressure. The residue was purified on
a silica gel column to give pure 5a -c,f,i-m .
(26) See ref 1e, p 244.
(27) (a) Uno, M.; Seto, K.; Takahashi, S. J . Chem. Soc., Chem.
Commun. 1984, 932. (b) Uno, M.; Seto, K.; Masuda, M.; Ueda, W.;
Takahashi, S. Tetrahedron Lett. 1985, 26, 1553. (c) Sakamoto, T.;
Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36,
1664. (d) Sakamoto, T.; Kondo, Y.; Suginome, T.; Ohba, S.; Yamanaka,
H. Synthesis 1992, 552.
(28) Intermolecular arylations of soft carbon nucleophiles lacking
cyano groups have been reported with aryl lead(IV) compounds, (a)
Donnelly, D. M. X.; Finet, J .-P.; Rattigan, B. A. J . Chem. Soc., Perkin
Trans. 1 1993, 1729, or with a copper(I) catalyst. (b) Okuro, K.;
Furuune, M.; Miura, M.; Nomura, M. J . Org. Chem. 1993, 58, 7606.
(29) For examples of Pd-catalyzed intramolecular arylations of
enolate anions (from â-diketones or monoketones) see: (a) Ciufolini,
M. A.; Qi, H.-B.; Browne, M. E. J . Org. Chem. 1988, 53, 4151. (b) Piers,
E.; Marais, P. C. J . Org. Chem. 1990, 55, 3454. (c) Piers, E.; Renaud,
J . J . Org. Chem. 1993, 58, 11. (d) Muratake, H.; Hayakawa, A.;
Natsume, M. Tetrahedron Lett. 1997, 38, 7577. (e) Muratake, H.;
Natsume, M. Tetrahedron Lett. 1997, 38, 7581.
(31) The operation of this type of instrument for the determination
of pKa and log P has been described in detail. Avdeef, A. Lipophilicity
in Drug Action and Toxicology; Pliska, V., Testa, B., van de Water-
beemd, H., Eds.; VCH: Weinheim, 1996; p 109.
(30) Stone-Elander, S. A.; Elander, N.; Thorell, J .-O.; Solås, G.;
Svennebrink, J . J . Label. Cmpds. Radiopharm. 1994, 10, 949.
(32) Gannon, W. F.; House, H. O. Org. Synth. 1960, 40, 41.

4162 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
2-Eth oxy-3-(3-m eth ylp h en yl)-2-cycloh exen on e (5c). Yel-
low oil, 38 mg (83%). 1H NMR (CDCl3): 7.34 (s, 1H, Ar), 7.33
(d, J ≈ 8 Hz, 1H, Ar), 7.26 (t, J ) 7.5 Hz, 1H, Ar), 7.14 (d, J )
7.3 Hz, 1H, Ar), 3.70 (q, J ) 6.8 Hz, 2H, CH2CH3), 2.75 (t, J )
5.9 Hz, 2H, H-4), 2.56 (t, J ) 6.6 Hz, 2H, H-6), 2.37 (s, 3H, Me),
2.08 (m, 2H, H-5), 1.10 (t, J ) 6.8 Hz, 3H, CH2CH3). 13C NMR
(CDCl3): 196.1, 148.0, 144.4, 137.5, 129.2, 128.6, 128.0, 127.9,
125.1, 67.9, 38.7, 30.9, 22.6, 21.4, 15.4. IR (CH2Cl2): 2996, 2972,
1673, 1602, 1454 cm-1. MS m/z (% relative intensity): 230 (M+,
100), 215 (22), 201 (33), 187 (49), 171 (39), 131 (63), 115 (75), 91
(45). Anal. Calcd for C15H18O2·1/4 H2O: C, 76.8; H, 7.9. Found:
C, 76.9; H, 7.7. HRMS calcd 230.1307. Found 230.1306.
Clea va ge of 5f a n d 5m To P r ovid e 3f a n d 3m . To a
solution of 5f or 5m (0.10 mmol) in dichloromethane (2.0 mL)
was added boron tribromide (0.12 mmol, 0.12 mL 1.0 M solution
in dichloromethane) dropwise during 5 min at -78 °C. The
reaction mixture was stirred at -78 °C for 1 h and then kept in
a refrigerator for 3 h at -12 °C. The reaction mixture was
thereafter poured into cold saturated aqueous ammonium
chloride and extracted with diethyl ether. The combined organic
layer was washed with saturated aqueous ammonium chloride,
dried over MgSO4, filtered, and concentrated at reduced pres-
sure. The residue was purified on a silica gel column to give
pure 3f or 3m .
Gen er a l P r oced u r e for th e Micr ow a ve-Assisted P r ep a -
r a tion of 3c, 3f, 5c, a n d 5f. A mixture of 1 or 4 (0.20 mmol),
aryl bromide (0.80 mmol), diisopropylethylamine (0.80 mmol, 103
mg), Pd(OAc)2 (0.010 mmol, 2.24 mg), Ph3P (0.024 mmol, 6.29
mg), and water (0.18 mL) in DMF (1.2 mL) was placed in a Pyrex
tube and was degassed under a nitrogen flow for 5 min. The
tube was sealed with
a silicon septum, positioned in the
MicroWell 10 microwave reactor, and the sample was irradiated
with a suitable power for an appropriate time (see Table 3). The
reaction mixture was allowed to cool for 5 min and was
thereafter poured into cold saturated aqueous ammonium
chloride. The aqueous layer was extracted with diethyl ether,
and the combined organic phases were washed with saturated
aqueous ammonium chloride, dried over MgSO4, filtered, and
concentrated at reduced pressure. The crude product was
purified on a silica gel column as described earlier.
Ack n ow led gm en t. We thank the Swedish Natural
Science Research Council for financial support. We also
thank Dr. Nicholas Bonham for performing the pKa
determination and Dr. Adolf Gogoll for assistance in the
NMR analyses.
Cleavage of compound 5f gave 16 mg (84%) of pure isolated
3f using the procedure described above.
2-H yd r oxy-3-(4-(t r iflu or om e t h yl)p h e n yl)-2-cycloh e x-
en on e (3m ). White solid, 23 mg (90%), mp ) 109-111 °C. H
1
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 3a ,b, 3d -h , 5a ,b, 5f, and 5i-m (4 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
NMR (CDCl3): 7.83 (d, J ) 8.3 Hz, 2H, Ar), 7.64 (d, J ) 8.3 Hz,
2H, Ar), 6.84 (s, 1H, OH), 2.80 (t, J ) 6.1 Hz, 2H, H-4), 2.66 (t,
J ) 6.8 Hz, 2H, H-6), 2.15 (m, 2H, H-5). 13C NMR (CDCl3):
195.4, 144.1, 140.7, 129.7, 128.5, 125.9, 125.0, 35.7, 28.5, 22.5.
IR (CH2Cl2): 3075, 1668, 1635, 1454 cm-1. MS m/z (% relative
intensity): 256 (M+, 100), 228 (39), 187 (72), 159 (20), 151 (22).
Anal. Calcd for C13H11F3O2: C, 60.9; H, 4.3. Found: C, 61.2;
H, 4.5.
J O980221B