Aerobic oxidative heck/dehydrogenation reactions of cyclohexenones: Efficient access to meta-substituted phenols

Article abstract of DOI:10.1002/anie.201209457

Jockeying for the (meta)position: A new dicationic palladium(II) catalyst, employing a 6,6′-dimethyl-2,2′-bipyridine ligand, promotes both the aerobic oxidative Heck coupling and dehydrogenation reactions of cyclohexenones. These reactions may be combined in a one-pot sequence to enable the straightforward synthesis of meta-substituted phenols (see scheme). Copyright

Full text of DOI:10.1002/anie.201209457

Angewandte
Chemie
DOI: 10.1002/anie.201209457
Synthetic Methods
Aerobic Oxidative Heck/Dehydrogenation Reactions of
Cyclohexenones: Efficient Access to meta-Substituted Phenols**
Yusuke Izawa, Changwu Zheng, and Shannon S. Stahl*
Phenol derivatives are common and important structural
motifs in bioactive natural products and pharmaceuticals,[1]
and the selective synthesis of substituted phenols is facilated
by the strong ortho/para-directing effect of the hydroxy group.
The same directing effect, however, limits access to analogous
meta-substituted derivatives. In recent years, considerable
the dehydrogenation step to avoid direct conversion of the
cyclohexenone starting material into an unsubstituted phenol.
Furthermore, while aerobic oxidative Heck reactions have
extensive precedent with terminal alkenes,[9,10] analogous
reactions with cyclohexenone tend to be more difficult.[11,12]
With this substrate, the palladium(II) enolate must isomerize
to place the palladium atom on the opposite side of the ring to
undergo b-hydride elimination (Scheme 2).[13] Finally, the
catalyst and reaction conditions must be compatible with both
reactions in the sequence. The only general method for
dehydrogenation of cyclohexenones to phenols employs
a strong acid additive (p-TsOH; Scheme 3),[5a] which inter-
feres with oxidative Heck reactions.[14]
À
efforts have targeted C H functionalization reactions which
enable preparation of meta-substituted arenes by steric[2] or
directing-group[3] control over the site selectivity. The overall
efficiency of these methods is often limited by functional-
group interconversions or installation and removal of direct-
ing groups needed to access the final product.[4] Moreover, in
molecules with more than one electronically or sterically
active substituent, competition between the directing groups
can lead to product mixtures. Following our recent develop-
ment of palladium-catalyzed aerobic dehydrogenation reac-
tions of ketones,[5–7] we envisioned that meta-substituted
phenols could be accessed efficiently by an aerobic oxidative
Heck/dehydrogenation sequence with cyclohexenone
(Scheme 1).[8] Cyclohexenone is a convenient and inexpensive
Scheme 2. Mechanistic steps highlighting the requirement for isomer-
ization of the palladium(II) enolate intermediate in Heck reactions of
cyclohexenone.
Scheme 1. Strategy for the synthesis of meta-substituted phenols.
Scheme 3. Previously reported aerobic dehydrogenation conditions for
the synthesis of phenols. DMSO=dimethylsulfoxide, TFA=trifluoro-
acetate, Ts=4-toluenesulfonyl.
phenol precursor, and the proposed strategy exploits the
intrinsic regioselectivity of additions to electron-deficient
À
alkenes to enable functionalization of the meta C H bond.
Herein, we describe a new palladium catalyst and reaction
conditions compatible with this sequence, and we showcase
their utility in the synthesis of a pharmaceutically active
phenol derivative.
Our initial studies targeted the identification of non-acidic
reaction conditions for aerobic dehydrogenation of 3-methyl-
cyclohexenone. Upon screening diverse PdX2 sources, ligands,
additives, and solvents (see the Supporting Information for
full screening data), we found that the dicationic palladi-
um(II) complex [Pd(CH3CN)4](BF4)2 was particularly effec-
tive as a catalyst (Table 1). Formation of palladium black and
gradual loss of catalytic activity during the reaction prompted
us to test ancillary ligands to stabilize the catalyst. Most of the
ligands tested inhibited the reaction (Table 1 and the Sup-
porting Information). However, 4,5-diazafluorenone (L4)[15]
and 6,6’-dimethyl-2,2’-bipyridine (L5) enabled good product
yields to be obtained. While screening of numerous additives,
including Brønsted bases, copper(II) and silver(I) salts, and
quinones showed little beneficial effect, nearly quantitative
yield of the phenol product (95%) was obtained when
9 mol% AMS (anthraquinone-2-sulfonic acid sodium salt)
was included in the reaction with the ligand L5.[16] The
The proposed sequence in Scheme 1 faces several chal-
lenges. The oxidative Heck reaction must be more facile than
[*] Y. Izawa,[+] Dr. C. W. Zheng,[+] Prof. S. S. Stahl
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: stahl@chem.wisc.edu
[+] These authors contributed equally to this work.
[**] We thank Dr. Doris Pun for assistance in product purification.
Financial support was provided by the NIH (R01 GM100143),
Mitsubishi Chemical Corporation, and the Shanghai Institute of
Organic Chemistry (postdoctoral fellowship for C.W.Z.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209457.
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Table 1: Dehydrogenation of 3-cyclohexenones: Screening results.[a,b]
Table 2: Dehydrogenation of substituted cyclohexenones.[a]
Entry
1
Cyclohexenone
Phenol
t [h]
Yield [%][b]
90[c]
10
2
3
4
R=Ph
10
36
6.5
96[c]
46
63
[a] Reactions were performed on a 1.0 mmol scale in DMSO (0.2 mL),
1 atm O2. [b] Product yield determined by GC analysis. [c] H2O (0.05 mL)
and AMS (0.09 mmol) were added. Reaction time: 6.5 h. See the
Supporting Information for details.
R=CH2(N-pip)[d]
R=CH2CO2Me
5
10
87
optimal result was obtained upon addition of water (20 vol%)
to enhance the solubility of AMS.
The optimized reaction conditions proved to be effective
with a number other substituted cyclohexenones, including
those with heteroatom substituents (Table 2). These neutral
reaction conditions revealed some advantages over the
previously reported reaction conditions in Scheme 3. For
example, 6-phenylcyclohexanone underwent dehydrogena-
tion to o-phenyl phenol in only 33% yield under the previous
reaction conditions, but this product is obtained in excellent
yields under the present reaction conditions (entries 1 and 2).
The successful reaction of 3-arylcyclohexenones, prepared by
oxidative Heck reactions with cyclohexenone (entries 9–11),
provided a useful starting point for the investigation of
oxidative Heck and tandem oxidative Heck/dehydrogenation
reactions.
Preliminary experiments showed that this catalyst was
quite effective for the oxidative Heck coupling of 4-methoxy-
phenylboronic acid and cyclohexenone. Moreover, the reac-
tion could take place at 508C, a temperature at which no
conversion of cyclohexenone into phenol was observed. In
DMSO, the oxidative Heck reaction proceeded in 65% yield.
Upon heating of this reaction mixture to 808C, nearly
complete in situ conversion into the 3-aryl phenol was
observed (i.e., 64% yield of the phenol; Table 3, entry 1).
Several other solvents, including N,N-dimethylformamide
(DMF), N-methylpyrrolidone (NMP) and 1,4-dioxane,
proved to be better for the oxidative Heck reaction
(entries 2–7). However, they proved less effective for the
tandem sequence (e.g., entry 2). Further studies revealed that
an effective one-pot sequence could be achieved by perform-
ing the oxidative Heck reaction in NMP at 508C with
subsequent addition of DMSO and heating to 808C for the
dehydrogenation step. This protocol enabled a good yield of
the phenol to be obtained (84%, entry 12).
6
7
8
R=Ac
R=CO2Me
R=CF3
24
24
12
77
73
68
9
10
11
R=H
R=CHO
R=OH
10
10
10
89
52[c]
83
[a] Reactions were performed on a 1.0 mmol scale in DMSO/H2O (v/v
0.2/0.05 mL). [b] Yield of isolated product. [c] PdII/L5/AMS=5%/5%/
15%. [d] pip = piperidyl.
led to higher yields than those obtained with electron-
deficient substrates, as the latter substrates were more
susceptible to the formation of homocoupling products.
Halogenated arylboronic acids (X = F, Cl, Br) were tolerated
in the oxidative Heck reaction, with yields ranging from 68 to
86% (entries 4–6 and 18). The same arylboronic acids were
then employed in the one-pot oxidative Heck/dehydrogen-
ation to afford the 3-substituted phenol derivatives. In most
cases, the phenol yields correlate closely with the yields of the
3-aryl cyclohexenones in the independent oxidative Heck
reaction.
To demonstrate the potential utility of the aerobic
oxidative Heck/dehydrogenation sequence and further test
its functional-group compatibility, we investigated the syn-
thesis of URB597 from cyclohexenone and the commercially
available benzamide-derived boronic acid 1 (Scheme 4).
URB597 is a potent inhibitor of fatty acid amide hydrolase
(FAAH) and an important focus of efforts to treat pain,
anxiety, and depression.[17,18] The phenol intermediate 3 was
prepared by a stepwise oxidative Heck coupling of 1 and
[Pd(CH3CN)4](BF4)2/L5 proved to be very effective as
a stand-alone catalyst for the oxidative Heck reactions with
cyclohexenone. Good yields of the 3-arylcyclohexenones
were obtained with a variety of arylboronic acids (Table 4).
Reactions with the electron-rich arylboronic acids typically
2
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Table 3: Optimization of the reaction conditions for the oxidative Heck
Table 4: Oxidative Heck and one-pot oxidative Heck/dehydrogenation
reactions to prepare substituted cyclohexenones and phenols.[a]
and one-pot oxidative Heck/dehydrogenation reactions.[a]
Entry
Oxidative Heck
Solvent
Oxidative Heck/
dehydrogenation
Conc.
t1
[h]
Yield
[%][c]
Solvent
t2
Yield
[%][d]
Entry
R
Oxidative Heck
Oxidative Heck/
dehydrogenation
t2 [h] Yield [%][c]
[m][b]
[h]
t1 [h] Yield [%][b]
1
2
3
4
5
6
7
8
DMSO
DMF
NMP
1,4-dioxane
CH3CN
DMF
DMF
DMF
NMP
NMP
1.3
1.3
1.3
1.3
1.3
2.5
5.0
2.5
2.5
3.1
3.1
3.1
8
3
3
3
3
3
3
3
3
3
3
4
65
95
90
93
73
96
80
–
–
–
–
95
–
–
–
–
–
–
–
24
24
–
–
–
64
25[e]
–
–
–
1
2
3
4
5
6
7
8
p-Me
p-tBu
p-MeO
p-Cl
p-Br
p-F
p-OH
p-Ph
p-COOMe
p-CF3
p-CN
p-H
4
4
4
4
4
4
4
13
4
4
97
98
94
85
65
86
85
62
86
56
41
76
32
36
32
32
32
32
32
36
32
32
36
32
91
85
80
68
41
87
64
63
74
40
35
75
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
24
24
24
32
32
54
72
82
82
84
9
10
11[f]
12[f,g]
9
NMP
NMP
10
11
12
13
4
[a] Reaction conditions: Heck reactions [cyclohexenone (0.75 mmol),
boronic acid (0.25 mmol), PdII =[Pd(CH3CN)4](BF4)2, 508C, 3-8 h];
dehydrogenation: T increased to 808C, 24–32 h (for entries 8–12, 0.2 mL
DMSO added). [b] Concentration of boronic acid. [c] Yield determined by
GC analysis. [d] Yield determined by 1H NMR spectroscopy. [e] Recov-
ered 65% of Heck product. [f] Used 10% AMS. [g] Used 0.5 mmol
cyclohexenone.
13
14
15
16
m-MeO
m-Me
m-NO2
m-CF3
13
13
13
4
83
89
48
68
36
36
36
32
47
76
42
60
17
18
o-Me
o-F
13
13
73
75
36
36
58
66
[a] Reactions conditions: cyclohexenone (0.5 mmol), arylboronic acid
(0.25 mmol) in NMP (0.2 mL for Heck and 0.08 mL for one-pot) at 508C
for Heck reactions. For the one-pot reactions, DMSO was then added
and the reactions were continued at 808C for 32 or 36 h. See the
Supporting Information for details. [b] Yields of the isolated 3-substi-
tuted cyclohexenones. [c] Yields of the isolated phenols.
hexenone and aerobic dehydrogenation of cyclohexenones.
The one-pot sequence developed for these reactions repre-
sents an efficient strategy for the preparation of meta-
substituted of phenols, which should be advantageous or
À
highly competitive with other approaches based on C H
functionalization of an aromatic ring.
Received: November 27, 2012
Published online: && &&, &&&&
Scheme 4. Application of one-pot oxidative Heck/dehydrogenation
reactions in the synthesis of URB597.
Keywords: dehydrogenation · Heck reaction · oxidation ·
palladium · synthetic methods
.
cyclohexenone, followed by catalytic dehydrogenation of the
isolated intermediate 2, and in a direct, one-pot process. The
[Pd(CH3CN)4](BF4)2/L5 catalyst was employed for each of
these steps, and both pathways led to the phenol product 3 in
good yield (ca. 72%, in each case).
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Synthetic Methods
Y. Izawa, C. W. Zheng,
S. S. Stahl*
&&&& — &&&&
Aerobic Oxidative Heck/
Dehydrogenation Reactions of
Cyclohexenones: Efficient Access to
meta-Substituted Phenols
Jockeying for the (meta)position: A new
dicationic palladium(II) catalyst, employ-
ing a 6,6’-dimethyl-2,2’-bipyridine ligand,
promotes both the aerobic oxidative Heck
coupling and dehydrogenation reactions
of cyclohexenones. These reactions may
be combined in a one-pot sequence to
enable the straightforward synthesis of
meta-substituted phenols (see scheme).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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