A novel palladium-catalyzed arylation - dehydroaromatization reaction: Synthesis of 7-aryltetralones

Article abstract of DOI:10.1021/ol051290x

(Chemical Equation Presented) A new one-pot room-temperature palladium-catalyzed synthesis of 7-aryltetralones was discovered. This tandem process includes a palladium-catalyzed γ-selective arylation of the enone 4 followed by a dehydrogenation-aromatization of the initial cross-coupling product.

Full text of DOI:10.1021/ol051290x

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3881-3884
A Novel Palladium-Catalyzed
Arylation Dehydroaromatization
−
Reaction: Synthesis of 7-Aryltetralones
Georgy N. Varseev and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received June 2, 2005
ABSTRACT
A new one-pot room-temperature palladium-catalyzed synthesis of 7-aryltetralones was discovered. This tandem process includes a palladium-
catalyzed -selective arylation of the enone 4 followed by a dehydrogenation-aromatization of the initial cross-coupling product.
γ
The palladium-catalyzed R-arylation of ketones and ester
derivatives has greatly expanded the repertoire of useful
methods in organic chemistry.1,2 Key parameters for this
transformation include the use of sterically hindered and
electron-rich phosphine ligands and a suitable solvent.
Important recent discoveries in this regard were made by
the Buchwald3 and Hartwig groups.4 The arylation can be
run with the carbonyl compound directly in the presence of
a base. Alternatively, preformed enolates such as trialkylsilyl
enol ethers can be arylated in the presence of ZnF2 or
Zn(OtBu)2 as addititives.4 Thus, the potential applications
seem countless.
systems of type A (Figure 1). Besides possible regioisomers,
for each pathway stereoisomers (cis/trans) might form.
The parent substrate, enone 4, was prepared essentially
according to the literature by the copper-catalyzed 1,4-
addition of 2-(3-bromopropyl)-1,3-dioxolane5 (2) followed
by acid-induced deprotection-cyclization of the ketoacetal
3 (Scheme 1).6,7
Initially, we examined the regioselective formation of the
two possible triisopropylsilyl dienol ethers. Although the
selective formation of the unwanted isomer 6 is possible
under various conditions, the best ratio in favor of the dienol
derivative 5 was 68:32. The enone 4 was also subjected to
modified Kharasch conditions [(a) MeMgBr, FeCl3; (b)
TMSCl, Et3N, HMPA, 23 °C, 2 h] resulting in the exclusive
formation of the trimethylsilyl dienol ether corresponding
In the context of the synthesis of functionalized decalin
derivatives, we became interested in the arylation of enone
(1) For a review, see: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234-245.
(2) For a review about coupling reactions of aryl chlorides, see: Littke,
A. F.; Fu, G. C. Angew. Chem. 2002, 114, 4350-4386; Angew. Chem.,
Int. Ed. 2002, 41, 4176-4211.
(3) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370.
(4) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182-5191.
(5) Wenkert, D.; Ferguson, S. B.; Porter, B.; Qvarnstrom, A.; McPhail,
A. T. J. Org. Chem. 1985, 50, 4114-4119.
Figure 1. Issues of regio- and stereochemistry in the potential
palladium-catalyzed arylation of 3,4,4a,5,6,7-hexahydro-1(2H)-
naphthalenone derivatives A.
(6) Bal, S. A.; Marfat, A.; Helquist, P. J. Org. Chem. 1982, 47, 5045-
5050.
(7) Tsantali, G. G.; Takakis, I. M. J. Org. Chem. 2003, 68, 6455-6458.
10.1021/ol051290x CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/02/2005

arylated derivatives in a Buchwald-Hartwig arylation. Thus,
dienol 6 ether was subjected to a palladium-catalyzed
arylation reaction with bromobenzene in the presence of
Pd(OAc)2, Ph3P, and Cs2CO3 as additive (Scheme 2).
Scheme 1. Synthesis of Enone 4
Scheme 2. Arylation of Silyl Dienol Ether 6 and a Mixture of
5 and 6
to 6. These conditions are known to produce the thermody-
namic dienol ether from a cyclic enone.8 However, the
trimethylsilyl derivative was not obtained very pure and
proved to be somewhat unstable. Although the mixture of
the two dienol ethers 5 and 6 could not be separated by
chromatography, their structures could be assigned by
comparison of the chemical shifts of the vinylic protons with
corresponding signals of similar compounds.9 Thus, the
vinylic protons of 6 appear at δ ) 4.92 and 5.96 ppm,
whereas the two vinylic protons of 5 resonate at δ ) 5.53
and 6.50 ppm. The latter is a doublet (J ) 9.8 Hz), which
clearly supports the assignment.
Suprisingly, the only product that we could isolate was the
7-phenyltetralone 7a. There were no Heck-type products10,11
and no R-arylated products detectable in the reaction mixture.
If the reaction was run on a mixture of 5 and 6 (5:6 ) 68:
32), the same compound 7a was isolated as the only product.
Since it was described earlier that R,â-unsaturated ketones
could be directly arylated in the γ-position with bromoarenes
and Pd(OAc)2/PPh3 in DMF/Cs2CO3 at 60-120 °C,12 we
applied these conditions directly to enone 4. Treatment of
enone 4 with bromobenzene under these conditions afforded
as well the unexpected biaryl derivative 7a in 32-45% yield
(eq 1). The normal γ-arylation product could not be detected
by LC-MS after reaction workup.
Table 1. Regioselectivity in the Formation of the Silyl Dienol
Ethers 5 and 6
Next, we tried to optimize this reaction by varying
additives, solvent, and phosphine ligands. As described in
the literature, certain tetraalkylammonium salts can positively
affect palladium-catalyzed Heck-type reactions.13 It was
found that addition of 1 equiv of tetrabutylammonium
bromide (TBAB) to the reaction mixture dramatically
increased the yield of the reaction, resulting in 71% yield of
7-phenyltetralone (Table 2, entry 3). In addition, heating of
the mixture was not necessary. These optimization studies
were followed by LC-MS using 10 mol % of biphenyl as an
internal standard. Regarding the solvent, DMF gave the best
yield (entry 3), followed by NMP (70%, entry 6). Among
various ligands that were tried, triphenylphosphine was found
ratio
yield of
entry
conditions
5: 6a 5 + 6 (%)
1
2
2,6-lutidine, CH2Cl2, -20 °C, 1 h
2,6-diisopropyl-N,N-dimethylaniline,
CH2Cl2, -20 °C, 24 h
Cy2NEt, CH2Cl2, -78 °C, 2 h
KN(SiMe3)2, THF/DMF (1:1),
-78 °C, 24 h
0:100
0:100
95
96
3
4
30:70
50:50
89
82
5
6
i-Pr2EtN, CH2Cl2, -20 °C, 24 h
i-Pr2EtN, CH2Cl2, -78 °C, 24 h
58:42
68:32
95
98
a The ratio 5/6 was determined by H NMR spectroscopy.
1
We then asked ourselves whether the regiochemistry of
the dienol ethers would be transformed to the corresponding
(10) For the Heck reaction of dienol ethers, see: Deagostino, A.; Prandi,
C.; Venturello, P. Org. Lett. 2003, 5, 3815-3817.
(8) Krafft, M. E.; Holton, R. A. J. Am. Chem. Soc. 1984, 106, 7619-
(11) For a recent review about the Heck reaction, see: Beletskaya, I. P.;
Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-3066.
(12) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998,
39, 6203-6206.
7621.
(9) (a) Munslow, W. D.; Reusch, W. J. Org. Chem. 1982, 47, 5096-
5099. (b) Kato, M.; Watanabe, M.; Awen, B. Z. J. Org. Chem. 1993, 58,
5145-5152.
(13) Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
3882
Org. Lett., Vol. 7, No. 18, 2005

Table 2. Effect of Trialkylammonium Salts, Solvents, and
Phosphine Ligands on the Reaction of Enone 4 with
Bromobenzene
Table 3. Synthesis of 7-Aryltetralones 7a-g
entry
key variables
yield of 7a [%]d
1a
2a
3a
4a
5a
6b
7b
8c
no PTC, 120 °C
Bu4NBr, 60 °C
Bu4NBr, 23 °C
Bu4NOAc, 23 °C
Bu4NClO4, 23 °C
NMP
dimethylacetamide
tBu3P
(o-tolyl)3P
45
20
71
7
48
70
67
tr
9c
27
0
10
10c
11c
(furyl)3P
dppf
a Reaction conditions: DMF, Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
PhBr (5 equiv), Cs2CO3 (2.5 equiv), additive (1 equiv). b Reaction condi-
tions: solvent, Pd(OAc)2 (5 mol %), PPh3 (10 mol %), PhBr (5 equiv),
Cs2CO3 (2.5 equiv), TBAB (1 equiv), 3 d, 23 °C. c Reaction conditions:
DMF, Pd(OAc)2 (5 mol %), phosphine (10 mol %), PhBr (5 equiv), Cs2CO3
(2.5 equiv), TBAB (1 equiv), 3 d, 23 °C. d Isolated yields.
to be the best one (entry 3). In the absence of a phosphine
ligand the reaction does not take place at all. Electron-
donating and hindered phosphines (t-Bu3P, entry 8; furyl3P,
entry 10) seemingly decrease the rate of the aromatization
step. With these ligands, mixtures of bi- and triarylated
products were detected by LC-MS.
Again, the reaction is highly γ-selective, and no R-arylated
products were detected. Actually, the putative product of the
normal γ-arylation was detected by LC-MS {[M]+(7a) +
4} at the beginning of the reaction. Furthermore, in some
cases intermediates with {[M]+(7a) + 2} were detected. The
rate of the dehydrogenation-aromatization is very high, and
only the aromatic product was detected at the end of the
reaction. With 1 equiv of bromobenzene, the reaction does
give 7a as well, but conversion and yield were lower.
We assume that the reaction proceeds via γ-arylation of
the dienolate anion, followed by a fast dehydrogenation/
aromatization of the intermediate in a tandem process. Most
likely the aromatization is initiated by insertion of a PdL2
species into an activated C-H bond, followed by the
elimination of PdL2H2. In essence, a reversal of classical
hydrogenation steps must take place. Addition of some
electron donors or hydrogen donors (HCO2H, cyclohexa-
diene, CuBr) that could be sacrificed did not allow us to
isolate nonaromatized intermediates. Addition of other
reagents (styrene, methyl acrylate, benzoquinone) that might
speed the aromatization step only decreased the yield of 7a.
In the absence of bromobenzene or in the presence of
chlorobenzene only products of self-condensation of enone
4 were detected.
a Reaction conditions: DMF, Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
PhBr (5 equiv), Cs2CO3 (2.5 equiv), TBAB (1 equiv), 23 °C.
8.33 ppm, which can be attributed to the isolated proton at
C-8.
7-Aryltetralones have been used, for example, in the
synthesis of CCR5 antagonists as anti-HIV-1 agents.14 These
aryltetralones were prepared in a multistep sequence consist-
ing of an intramolecular Friedel-Crafts cyclization of the
corresponding phenylbutyric acids followed by palladium-
catalyzed Suzuki coupling with arylboronic acids. As a whole
only a few examples of 7-aryltetralones 7 are described in
the literature.15
In a control experiment we applied the optimized condi-
tions to the coupling of 1-cyclohexene-1-carbaldehyde and
1-bromo-4-tert-butylbenzene (eq 2). Somewhat surprisingly,
Using the optimized conditions we coupled a number of
haloarenes with the enone 4. As it turned out, the reaction
has broad scope, at least for enone 4, and both aryl bromides
and iodides could be coupled in moderate to good yields
(Table 3). The 7-aryltetralones show a characteristic peak
we isolated not the expected biphenyl-3-carbaldehyde but
rather the normal γ-arylation product (41% yield). Charac-
1
in the H NMR spectrum in the range between δ ) 8.16-
Org. Lett., Vol. 7, No. 18, 2005
3883

teristic for this compound is a signal at δ ) 6.79 ppm for
the terminal enal H. The γ-H resonates at δ ) 3.62 ppm.
Related compounds are prepared by multistep sequences.16
withdrawing group might be a valuable option for accessing
certain biaryl compounds. Further studies that are underway
in our laboratory should help to elucidate the structural
requirements and the experimental ancillary conditions.
To summarize, we developed a new convenient synthesis
of 7-aryltetralones by a novel room-temperature palladium-
catalyzed arylation dehydroaromatization sequence. This
strategy of applying the arylation/aromatization to a cyclic
precursor containing one double bond and an electron-
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. In addition, we ac-
knowledge partial support by COST D28.
(14) Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishikawa, Y.;
Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura, O.; Baba, M.; Fujino,
M. J. Med. Chem. 2000, 43, 2049-2063.
(15) (a) Bergmann, E. D.; Blumberg, S.; Bracha, P.; Epstein, S.
Tetrahedron 1964, 20, 195-209. (b) Buckle, D. R.; Cantello, B. C. C.;
Smith, H.; Smith, R. J.; Spicer, B. A. J. Med. Chem. 1977, 20, 1059-
1064. (c) Smalley, T. L., Jr. Synth. Commun. 2004, 34, 1973-1980.
(16) (a) Mariano, P. S.; Ko, J. J. Am. Chem. Soc. 1973, 95, 8670-8678.
(b) Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.;
Mechoulam, R. Org. Biomol. Chem. 2005, 3, 1116-1123.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051290X
3884
Org. Lett., Vol. 7, No. 18, 2005