An alternative approach to para-C-H arylation of phenol: Palladium-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives

Article abstract of DOI:10.1021/ol300145g

An efficient approach to prepare para-aryl phenols has been developed by using a Pd-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives with aryl bromides. This approach provides various p-aryl phenols from the phenol surrogates, 2-cyclohexen-1-one derivatives, in a single reaction step on the basis of C-H arylation.

Full text of DOI:10.1021/ol300145g

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1172–1175
An Alternative Approach to para-CꢀH
Arylation of Phenol: Palladium-Catalyzed
Tandem γ-Arylation/Aromatization of
2-Cyclohexen-1-one Derivatives
Tatsushi Imahori,*,† Toru Tokuda,† Tatsuya Taguchi,‡ and Hiroki Takahata‡
Priority Organization for Innovation and Excellence, Kumamoto University,
2-39-1 Kurokami, Kumamoto 860-8555, Japan, and Faculty of Pharmaceutical Sciences,
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
imahori@kumamoto-u.ac.jp
Received January 19, 2012
ABSTRACT
An efficient approach to prepare para-aryl phenols has been developed by using a Pd-catalyzed tandem γ-arylation/aromatization of
2-cyclohexen-1-one derivatives with aryl bromides. This approach provides various p-aryl phenols from the phenol surrogates, 2-cyclohexen-
1-one derivatives, in a single reaction step on the basis of CꢀH arylation.
Biaryl compounds have attracted considerable synthetic
interest1 owing to their importance in various fields; they
are ubiquitous in natural products, pharmaceuticals, and
functional materials as structural motifs, as well as in metal
catalysis as ligands.2 Strategies for the efficient and selec-
tive construction of biaryls have been extensively explored.3,4
The significant progress in metal-catalyzed cross-coupling
reactions has greatly contributed to the development of
these strategies. The coupling between an arylmetal and
an aryl halide or pseudohalide is a representative method
for synthesizing biaryls.1 In recent years, highly efficient
and atom-economical cross-coupling approaches to bia-
ryls based on CꢀH arylation of arenes have been deve-
loped.4 The newer transformations do not require com-
plex prior preparation of arylmetals and/or aryl halides or
pseudohalides as a coupling partner; hence, these trans-
formations provide rapid and environmentally benign
access to biaryls while reducing the consumption of chem-
ical resources. Although the CꢀH arylations of arenes
are highly efficient and ideal routes to biaryls, their scope is
still limited.4,5 In particular, the regiochemistry of these
arylations remains a major concern. The CꢀH functiona-
lizations of arenes generally proceed at the ortho-position
† Kumamoto University.
‡ Tohoku Pharmaceutical University.
ꢀ
(1) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schultz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359–1469. (b) Cepanec, I., Ed. Synthesis of
Biaryls; Elsevier Ltd.: Oxford, 2004. (c) de Meijere, A., Diederich, F.,
Eds. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH:
New York, 2004.
(2) (a) Baudoin, O.; Gueritte, F. Stud. Nat. Prod. Chem., Part J 2003,
29, 355–417. (b) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W.
J. Med. Chem. 2000, 43, 3443–3447. (c) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893–930. (d) Demus, D., Goodby,
J. W., Gray, G. W., Spiess, H.-W., Vill, V., Eds. Handbook of Liquid
Crystals; Wiley-VCH: Weinheim, 1998. (e) Kraft, A.; Grimsdale, A. C.;
Holmes, A. B. Angew. Chem., Int. Ed. 1998, 37, 402–428. (f) Bringmann,
G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427.
(3) For selected examples of innovative synthetic approaches to
biaryls, see: (a) Achburn, B. O.; Carter, R. G.; Zakharov, L. N.
J. Am. Chem. Soc. 2007, 129, 9109–9116. (b) Yoshida, K.; Imamoto,
T. J. Am. Chem. Soc. 2005, 127, 10470–10471. (c) Nishida, G.; Noguchi,
K.; Hirano, M.; Tanaka, K. Angew. Chem., Int. Ed. 2007, 46, 3951–3954.
(4) For reviewson CꢀH arylation of arenes, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. (b) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447–2464. (c) Ackermann, L.;
Vicene, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(5) The CꢀH arylation of electron-deficient heterocycles is still a
limited reaction. See: Seiple, L. B.; Rodrigues, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
13194–13196 and references therein.
r
10.1021/ol300145g
Published on Web 02/01/2012
2012 American Chemical Society

of a directing group on the arene, and other regioselectiv-
ities are quite rare.4,6ꢀ8 Recently, a few pioneering studies
have been reported on the meta-9 and para-10 selective
CꢀH arylations of arenes. However, there is scope for
further development with regard to the efficient construc-
tion of biaryls in the desired linkages.
To effect such development, we envisaged an alterna-
tiveapproach toCꢀH arylation of arenesbymodifying the
conventional stepwise strategy of biaryl construction. The
stepwise approach to biaryls;introduction of an aryl unit
to a precursor of arene and subsequent arene formation of
the arylated precursor;is a reliable method for construct-
ing diverse biaryls; however, in this approach, the effi-
ciency is compromised.3 An alternative approach to CꢀH
reaction step while introducing an aryl unit at the
p-position by CꢀH arylation. That is, an alternative
approach to p-CꢀH arylation of phenol, which is a rare
reaction (Scheme 1),12 has been developed.
Pd-catalyzed γ-arylation of R,β-unsaturated ketones13
and Pd-catalyzed dehydrogenation of 2-cyclohexen-1-one
derivatives14 and related compounds15 to afford corre-
sponding arenes have been previously reported. On the
basis of these transformations, we investigated the Pd-
catalyzed tandem γ-arylation/aromatization of 2-cyclo-
hexen-1-one derivatives (Scheme 1). By partially employ-
ing the conditions used for γ-arylation of R,β-unsatura-
ted ketones,13 2-cyclohexen-1-one (1, 1.0 mmol) was trea-
tedwith4-bromotoluene (2a, 2.0 mmol) inthe presence of5
mol % Pd(OAc)2, 10 mol % PPh3, and Cs2CO3 (1.15 mmol)
with molecular sieves 4A (MS4A, 100 mg) in N,N-
dimethylformamide (DMF, 5 mL) at 80 °C for 15 h;
consequently, the desired 4-(p-tolyl)-phenol (3aa) was
obtained in 33% yields. Side products 4aa (0.28 mmol)16
and 4,40-bistoluene (5a, 0.55 mmol) were also obtained
(Table 1, entry 1). Interestingly, the γ-arylation product,
4-(p-tolyl)-2-cyclohexen-1-one (6aa), was not isolated un-
der the above-mentioned conditions. The desired product
was directly obtained during the reaction. We speculated
that both the γ-arylation13 and subsequent aromatization
of 2-cyclohexen-1-one14 proceeded sequentially to produce
biaryl 3aa in a single reaction step. The additional self-
Michael condensation of 2-cyclohexen-1-one appears to
have proceeded for 4aa during the reaction.
Scheme 1. para-CꢀH Arylation of Phenol and the Alternative
Approach
arylation of arenes could be the tandem stepwise approach
in a single reaction step with the regioselective introduc-
tion of an aryl unit by CꢀH arylation; this approach
could directly provide biaryls in the desired linkage from
an arene surrogate on the basis of CꢀH arylation. Herein,
we report on such an approach, namely, Pd-catalyzed
tandem γ-arylation/aromatization of 2-cyclohexen-1-one
derivatives with aryl bromides (Scheme 1).11 This trans-
formation provides p-arylated phenols from the phenol
surrogates, 2-cyclohexen-1-one derivatives, in a single
Table 1. Optimization of Reaction Conditions
(6) For reviews on metal-catalyzed CꢀH functionalization of arenes,
see: (a) Colby, D. A; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624–655. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147–1169. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094–5115. See also ref 4.
(7) Some meta- or para CꢀH functionalizations of arenes have been
developed. However, most of the reactions display unclear regioselec-
tivity and provide some regioisomers. See: (a) Cho, J.-Y.; Iverson, C. N.;
Smith, M. R., III. J. Am. Chem. Soc. 2000, 122, 12868–12869. (b)
Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390–391. (c) Boebel, T. A.;
Hartwig, J. F. Organometallics 2008, 27, 6013–6019. (c) Zhang, Y.-H.;
Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–5074.
(8) We have developed uniquely regioselective or regiocontrolled
CꢀH functionalizations of arenes. See: (a) Imahori, T.; Kondo, Y.
J. Am. Chem. Soc. 2003, 125, 8082–8083. (b) Imahori, T.; Suzawa, K.;
Kondo, Y. Heterocycles 2008, 76, 1057–1060. (c) Imahori, T.; Uchiyama,
M.; Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450–2451.
(9) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597.
(10) Recently, para-selective CꢀH arylations of arenes have been
reported. See: (a) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer,
F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458–462. (b) Wang,
X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 13864–13867.
(11) A related biaryl construction, which provides 4-aryltetralones,
has been developed. See: Varseev, G. N.; Maier, M. E. Org. Lett. 2005, 7,
3881–3884.
a Isolated yields. b Figures in parentheses are yields of side product
4aa. c DMF was used as solvent instead of NMP. d The reaction was per-
formed with 1.15 equiv of Cs2CO3 and 2.0 equiv of 2a for 12 h. e Maier’s
conditions; 2.5 equiv of Cs2CO3 were utilized in the presence of 1.0 equiv
of TBAB for 5 days. TBAB: tetrabutyl ammonium bromide. ND: Not
detected. NMP: N-methylpyrrolidinone. DMF: N,N-dimethylformamide.
(12) Only one example of the selective para-CꢀH arylation of phenol
has been reported in ref 10a (Scheme 1).
Org. Lett., Vol. 14, No. 4, 2012
1173

Next, the conditions were varied tooptimize the reaction
efficiency(Table1).17 Treating the substrate with10mol %
Pd(OAc)2 and 20 mol % PPh3 provided 3aa in 53% yield
(entry 2). An evaluation of various solvents indicated
that N-methylpyrrolidone (NMP) was also suitable for
the tandem reaction. When the reaction was performed
in NMP at 80 °C, slightly better results were obtained.
With 20 mol % Pd(OAc)2, the yield of 3aa increased up
to 57% (entry 5). Other combinations of the Pd cata-
lyst and phosphine ligand did not provide good yields
(entries 6ꢀ9); Pd(OAc)2 and PPh3 gave the best results.17
Additionally, we investigated the effect of additives. Tetra-
butyl ammonium bromide (TBAB) was found to be
the critical additive in the related tandem γ-arylation and
aromatization reaction developed by Maier.11 However,
the addition of TBAB did not improve our results (entries
10,11). Other additives also gave poor results.17 The reac-
tion temperature also affected the results (entries 4,5,
12ꢀ15). The best result was obtained when 20 mol %
Pd(OAc)2 and 40 mol % PPh3 were used at 70 °C in NMP,
producing 3aa in 66% yield (entry 14).
Table 2. Pd-Catalyzed Tandem γ-Arylation/Aromatization of
2-Cyclohexen-1-one Derivatives
We selected the reaction conditions listed as entry 13 in
Table 1 (90 °C inNMP, 20mol % Pd(OAc)2, and40mol %
PPh3) to investigate the scope of our new approach to
biaryls (Table 2).18 The reaction of 2-aryl-2-cyclohexen-1-
ones (1bꢀ1f)19 with 2a proceeded in moderate to good
yields to afford various terphenyls20 (45%ꢀ73%, entries
2ꢀ6,11,14). Various aryl groups such as phenyl (1b),
4-methoxyphenyl (1c), 4-fluorophenyl (1d), para-tolyl (1e),
and 2-naphthyl (1f) were found to be compatible. The
substituents on the aryl groups affected the results.
An electron-donating methoxy group reduced the yield
slightly (45%, entry 3).21 The reaction was also compatible
(13) (a) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1998, 39, 6203–6206. (b) Hyde, A. M.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 177–180.
(14) (a) Wilds, A. L.; Djerassi, C. J. Am. Chem. Soc. 1946, 68, 1715–
1719. (b) Horning, E. C; Horning, M. G. J. Am. Chem. Soc. 1947, 69,
1359–1361. (c) Wilds, A. L.; Werth, R. G. J. Org. Chem. 1952, 17, 1154–
1161. Quite recently, a Pd(II)-catalyzed aromatization of 2-cyclohexen-
1-one under mild reaction conditions has been reported. See: (d) Izawa,
Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209–213.
(15) Pd(II)-catalyzed aromatization of 2-cyclohexan-1-one-based en-
€
amine has been reported. See: (a) de Meijere, A.; Brase, S. J. Organomet.
Chem. 1999, 576, 88–110. (b) Ishikawa, T.; Uedo, E.; Tani, R.; Saito, S.
J. Org. Chem. 2001, 66, 186–191.
(16) The structure of 4aa was determined by comparing analytical
data with that of an analog. For the analogous compound, see: Cacchi,
S.; Misiti, D.; Palmieri, G. J. Org. Chem. 1982, 47, 2995–2999.
(17) Selected examples are listed in Table 1. A detailed optimization
of reaction conditions is described in the Supporting Information.
(18) We tentatively carried out the reaction at higher temperature
(90 °C). When uncontrollable side reactions occurred, the reactions were
investigated at lower temperature.
a Isolated yield. b The reaction was performed at 70 °C. c NMR yield
using internal standard (ClCH2CH2Cl). d The reaction was performed at
80 °C. e DMF was utilized as solvent.
(19) 2-Aryl-2-cyclohexen-1-one were synthesized as reported. See:
Felpin, F.-X. J. Org. Chem. 2005, 70, 8575–8578.
(20) For utilities of terphenyls, see: Miguez, J. M. A.; Adrio, L. A.;
Sousa-Pedrares, A.; Vila, J. M.; Hii, K. K. J. Org. Chem. 2007, 72, 7771–
7774 and references therein.
(21) An inseparable side product was produced in the reaction. Thus,
the yield of the desired product 3ca was estimated from 1H NMR of the
mixture using an internal standard (1,2-dichloroethane). See Table 2.
The authentic sample of 3ca was obtained by purification with HPLC
(InertSustain C18, H2O/CH3CN = 35/65).
with an alkyl group on the 2-cyclohexene-1-one nucleus.
The reaction of 6-methyl-2-cyclohexen-1-one (1g)22 with
2a afforded 2-methyl-4-(para-tolyl)phenol (3ga) in 47%
yield (entry 7). When 5-bromo-meta-xylene (2b) was used
as an aryl bromide, the corresponding biaryl was obtained
in 60% yield (entry 8). Next, the scope of aryl bromides
as a coupling partner was investigated (entries 8ꢀ15).
(22) 6-Methyl-2-cyclohexen-1-one was synthesized using a reported
method. See: Marques, F. A.; Lenz, C. A.; Simonelli, F.; Maia, B. H. L.
N. S.; Vellasco, A. P.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 1939–1941.
1174
Org. Lett., Vol. 14, No. 4, 2012

The use of various aryl bromides, 5-bromo-meta-xylene (2b),
bromobenzene (2c), 2-bromoanisole (2d), 3-bromo-N,
N-dimethylaniline (2e), ethyl 4-bromobenzoate (2f), and
2-bromonaphthalene (2g), affordedthedesired products in
moderate to good yields (52%ꢀ64%).23 The position of
the substituents on the aryl bromides did not seem to
hinder the reactions. In spite of its steric bulk, 2-bromoa-
nisole had good reactivity (61%, entry 12). m-Substituted
aryl bromides also provided good results (entries 13,15).
Various 2-cyclohexene-1-one derivatives and aryl bro-
mides provided acceptable results.
After straight tautomerization, 4-aryl-phenol (3ax) is
obtained. Reentry of Pd(0) into the next catalytic cycle could
be accomplished via the reductive homocoupling reaction of
aryl bromides. Oxidative addition of another aryl bromide
(2x) to the anionic Pd(0) followed by reductive elimination
regenerates Pd(0), providing the homocoupling side product
5x.24 An alternative plausible mechanism is the generation of
a Pd(IV) species after the palladation at the 6- or 4-position
of 4-aryl-2-cyclohexen-1-one with another aryl bromide fol-
lowed by β-elimination of ArPd(II)Ar to produce the corre-
sponding dienone.24b
Although the detailed mechanism of the proposed tan-
dem γ-arylation/aromatization reaction remains unclear
at this stage of our investigations, some mechanistic in-
sights have been obtained. The reaction of 1c with 1.0 equiv
of 2a mainly provided the γ-arylation product 6ca in 46%
yield with only a small amount of 3ca (<17%, including
impurity) and a trace amount of 5a (eq 1), whereas the
use of 3.0 equiv of 2a yielded 3ca as the main product
(45%, Table 2, entry 3). This result suggests that an excess
amount of aryl bromide is necessary to promote aromati-
zation. Generation of homocoupling side products of aryl
bromides (5a) seems to be involved in the aromatization
process. Moreover, the expected reaction intermediate
(6ca) was detected, which supports the proposed sequence
of γ-arylation/aromatization.
Figure 1. Proposed mechanism of the tandem γ-arylation/aro-
matization of 2-cyclohexen-1-one derivatives.
In summary, we have developed a Pd-catalyzed tandem
γ-arylation/aromatization of 2-cyclohexen-1-one derivatives
with aryl bromides, which is an alternative approach to the
p-CꢀH arylation of phenol with a phenol surrogate. In this
approach, widely accessible 2-cyclohexen-1-one deriva-
tives14d,19,22 function as the phenol surrogate. Although this
transformation gives moderate to good yields, a wide range
of p-aryl phenols could be efficiently synthesized in a single
reaction step on the basis of CꢀH arylation. Further opti-
mization and expansion of the scope of this reaction as well
as mechanistic studies are currently underway.
On the basis of these mechanistic insights and related
reports,13ꢀ15,24,25 a mechanism of the tandem γ-arylation/
aromatization reaction is proposed, as shown in Figure 1.
The γ-arylation of 2-cyclohexen-1-one (1a) initially pro-
ceeds via palladation at the γ-position with ArPdBr, which
is generated from the oxidative addition of the aryl bro-
mide (2x) to Pd(0), and subsequent reductive elimination
of Pd(0).13 Next, the aromatization of a 2-cyclohexen-1-
one unit occurs.14,15 On the basis of the result of tandem
γ-arylation/aromatization of 1c with 1.0 equiv of 2a (eq 1),
we speculate that the aromatization could be a result of
the palladium-catalyzed reductive coupling of aryl bro-
mides.24 Palladation of the generated 4-aryl-2-cyclohexen-
1-one (6ax) at the 6- or 4-position with ArPdBr proceeds in
the presence of a Cs base. Subsequent β-elimination of
anionic Pd(0), which is the key intermediate in Pd-catalyzed
reductive homocoupling of aryl halides,24 provides 4-aryl-
cyclohexa-2,5-dienone or 4-aryl-cyclohexa-2,4-dienone.14,15,25
Acknowledgment. This work was supported by
Kumamoto University and a Grant-in-Aid for Young
Scientists from JSPS. This work was performed under the
Cooperative Research Program of the “Network Joint Re-
search Center for Materials and Devices (Institute for Mate-
rials Chemistry and Engineering, Kyushu University).” We
thank Profs. Seiji Kurihara and Ryo Irie (Kumamoto
University) for their kind support.
(23) When 2d or 2g was utilized as an aryl bromide, the reaction in
DMF provided better results.
(24) (a) Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261–274. (b)
Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1, 1205–1208.
(c) Kurobashi, M.; Waki, Y.; Tanaka, H. J. Org. Chem. 2003, 68, 3938–
3942. See also ref 15a.
(25) For palladium-catalyzed dehydrogenation of ketones to pro-
duce R,β unsaturated ketones, see: (a) Muzart, J. Eur. J. Org. Chem.
2010, 3779–3790. (b) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,
14566–14569.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1175