Significant enhancement in the efficiency and selectivity of iron-catalyzed oxidative cross-coupling of phenols by fluoroalcohols

Article abstract of DOI:10.1002/anie.201409694

Significant enhancement of both the rate and the chemoselectivity of iron-catalyzed oxidative coupling of phenols can be achieved in fluorinated solvents, such as 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 2,2,2-trifluoroethanol (TFE), and 1-phenyl-2,2,2-trifluoroethanol. The generality of this effect was examined for the cross-coupling of phenols with arenes and polycyclic aromatic hydrocarbons (PAHs) and of phenol with β-dicarbonyl compounds. The new conditions were utilized in the synthesis of 2-dehydroxycalodenin B in only four synthetic steps. Not just a solvent: The use of fluorinated solvents leads to a significant rate acceleration and enhancement of the chemoselectivity of the iron-catalyzed oxidative coupling of phenols. This method was used for the synthesis of 2-dehydroxycalodenin B.

Full text of DOI:10.1002/anie.201409694

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Chemie
DOI: 10.1002/anie.201409694
Oxidative Cross-Coupling
Significant Enhancement in the Efficiency and Selectivity of Iron-
Catalyzed Oxidative Cross-Coupling of Phenols by Fluoroalcohols**
Eden Gaster, Yulia Vainer, Almog Regev, Sachin Narute, Kavitha Sudheendran, Aviya Werbeloff,
Hadas Shalit, and Doron Pappo*
Abstract: Significant enhancement of both the rate and the
chemoselectivity of iron-catalyzed oxidative coupling of phe-
nols can be achieved in fluorinated solvents, such as 1,1,1,3,3,3-
hexafluoropropan-2-ol (HFIP), 2,2,2-trifluoroethanol (TFE),
and 1-phenyl-2,2,2-trifluoroethanol. The generality of this
effect was examined for the cross-coupling of phenols with
arenes and polycyclic aromatic hydrocarbons (PAHs) and of
phenol with b-dicarbonyl compounds. The new conditions
were utilized in the synthesis of 2’’’-dehydroxycalodenin B in
only four synthetic steps.
salts (5–20 mol%) and a terminal oxidant. The most widely
used solvents for such reactions are 1,2-dichloroethane
(DCE) and toluene. Prolonged heating at an elevated
temperature (60–1008C) is typically required to initiate the
oxidation process and to ensure satisfactory conversions.
Under these conditions, by-products resulting from over-
oxidation,[6d] Friedel–Crafts alkylation,[6b,g] and various homo-
coupling processes (Scheme 1)[6e] may affect the selectivity
and efficiency of the reaction.
S
ynthetic methods based on iron chemistry have gained
considerable attention in recent years,[1] partially as a result of
the implementation of green chemistry concepts in organic
chemistry.[2] Of particular interest is the iron-catalyzed
oxidative cross-coupling reaction,[3] also known as cross-
dehydrogenative coupling (CDC),[4] which offers a practical
and sustainable strategy for the formation of a new carbon–
Scheme 1. Chemoselectivity of the iron-catalyzed oxidative cross-cou-
pling of phenols.
À
carbon bond directly from two C H bonds. In these methods,
iron complexes with high oxidation states are generated
following the oxygen–oxygen bond scission of organic per-
oxides or molecular oxygen.[5] These high-valent iron species
are capable of inducing a single electron transfer (SET)
process, generating an active radical cation species that reacts
with a nucleophile.
The iron oxidative cross-coupling of phenols is an
extremely important synthetic tool for the production of
advanced phenol-based materials from readily available
building blocks.[6] The development of this chemistry relies
on the ability of phenols to stabilize a positive charge either
a) during an electrophilic aromatic substitution with an
oxidized coupling partner, such as a b-ketoester,[6b,g] an a-
hydroxy ketone,[6f] or a cyclic ether,[6a] or b) following the
single-electron oxidation of the phenol to an electrophilic
phenoxyl radical cation that, in turn, reacts with various
carbon–hydrogen nucleophiles, such as a second phenol,[5b,c]
an a-substituted b-ketoester,[6e] a nitroalkane,[5a] or a conju-
gated alkene.[6c,d] The general catalytic system relies on FeIII
1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) and 2,2,2-tri-
fluoroethanol (TFE)[7] are polar solvents with low boiling
points, high dielectric constants and high ionization power
that have a significant stabilizing effect on radical cation
intermediates.[8] HFIP was effectively applied by the Kita
group as a solvent in the hypervalent iodine oxidative
coupling reactions of arenes[8a,9] and by the Waldvogel
group in electrochemical oxidative coupling reactions.[10] As
part of our group’s interest to study the role of additives in the
iron-catalyzed oxidative cross-coupling of phenols,[6e] we
examined the role of fluorinated alcohols in this chemistry.
Here, we report the significant effect of fluoroalcohols on
the iron-catalyzed oxidative coupling of phenols. The use of
fluorinated solvents reduces the oxidation potential of the
phenols, thereby facilitating coupling reactions under mild
conditions. Moreover, we demonstrated that under common
CDC conditions, dimerization processes are preferred,
whereas under the modified conditions phenols react with
high chemoselectivity with arenes and polycyclic aromatic
hydrocarbons (PAHs) or b-diketones. The applicability of this
chemistry in drug discovery is demonstrated for the synthesis
of 2’’’-dehydroxycalodenin B.
[*] E. Gaster,[+] Y. Vainer,[+] A. Regev, Dr. S. Narute, Dr. K. Sudheendran,
A. Werbeloff, H. Shalit, Dr. D. Pappo
Department of Chemistry, Ben-Gurion University of the Negev
Beer-Sheva 84105 (Israel)
E-mail: pappod@bgu.ac.il
We first examined the effect of fluorinated alcohols on the
iron-mediated oxidative dimerization of 2-naphthol (1a). For
purposes of comparison, 1a was self-coupled in DCE at room
temperature with FeCl3 (5 mol%), as the catalyst, and
tBuOOtBu (2.5 equiv), as the terminal oxidant (Figure 1).
Under these conditions, only 9% conversion was obtained
after 24 h. A high accelerating effect was observed when the
[+] These authors contributed equally to this work.
[**] This work was supported by the Israel Science Foundation (Grant
No. 1406/11).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409694.
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Table 1: Oxidation potentials of phenols in different solvents and their
cross-coupling with compound 2.[a]
entry
R
Eox (V)[b]
CH3CN TFE
Product, yield [%][c]
HFIP DCE[d]
HFIP
1
2-Nf (1a)
3,5-Me2 (1c) 0.68
H (1d)
4-Br (1e)
3-Cl (1 f)
0.61
0.52 0.48
95
27
ND[e]
3, 63
4, 49
5, 64
6, 38
2[f]
3
0.66 0.62
0.68 0.63
0.73 0.67
0.84 0.76
0.73
0.83
0.90
NR[g]
NR[g]
NR[g]
4
5
[a] Conditions: phenol 1 (1 equiv), ethyl 2-oxocyclopentane-carboxylate
(2, 1.5 equiv), Fe(ClO4)3 hydrate (10 mol%), 1,10-phenanthroline
(10 mol%), tBuOOH (solution in decane, 2 equiv), HFIP (0.5m), 08C.
[b] Cyclic voltammetry conditions: phenol (3 mm), supporting electro-
lyte: tetrabutylammonium hexafluorophosphate (50 mm) in solvent
(5 mL) versus Ag/0.01m AgNO3 in 0.1m TBAP/CH3CN, 50 mVsÀ1
.
[c] Yield of the isolated product. [d] Conditions: FeCl3 (10 mol%), 1,10-
phenanthroline (5 mol%), tBuOOtBu, DCE, 708C.[6e] [e] ND=not
determined. [f] tBuOOtBu (2.5 equiv), HFIP (1m), room temperature.
[g] NR=no reaction.
Figure 1. Effect of the solvent on the oxidative coupling of 2-naphthol
(1a).[a] [a] Conditions: 1a (1 mmol), FeCl3 (0.05 mmol), tBuOOtBu
(2.5 mmol), solvent (1m), room temperature. The following solvents
Next, the effect HFIP has on cross-coupling reactions was
studied. The coupling of phenoxyl radicals to a-substituted b-
ketoesters was chosen as the benchmark reaction, because it
was suitable only for naphthols and electron-rich phenols,
while being ineffective for phenols with higher oxidation
potentials.[6e] Indeed, when 3,5-dimethylphenol (1c) and ethyl
2-oxocyclopentanecarboxylate (2) were reacted under our
previously reported conditions [FeX3 (10 mol%), 1,10-phe-
nanthroline (5 mol%), tBuOOtBu (2.5 equiv), DCE,
708C],[6e] the polycyclic hemiacetal 3 was isolated in 27%
yield for X = Cl and 34% yield for X = ClO4. In contrast,
when this transformation was performed in HFIP at reduced
temperatures under modified conditions [Fe(ClO4)3 hydrate
(10 mol%), 1,10-phenanthroline (10 mol%),[13] and tBuOOH
(5m solution in decane, 2 equiv)] the coupling product 3 was
isolated with an improved yield of 63%. The novel catalytic
system possesses superior oxidizing power and for the first
time phenols with higher oxidation potentials, such as 1d (R =
H, 0.63 V), 1e (R = 4-Br, 0.67 V), and 1 f (R = 3-Cl, 0.76 V),
were coupled at temperature as low as 08C with partner 2 to
afford 3–6 in moderates yields.
Oxidative cross-coupling of phenols with electron-rich
arenes is a powerful strategy for synthesizing nonsymmetrical
biaryls.[5b,9b,10a,b,14] The development of a successful process
relies on the ability to selectively oxidize a phenol in the
presence of an arene coupling partner. This is a challenging
task, because undesired homocoupling pathways must be
avoided.[14b] Indeed, when 6-methoxycarbonyl-2-naphthol
(1b, 1 equiv) and 2-methoxynaphthalene (7, 1.3 equiv) were
reacted under the common CDC conditions [FeCl3 (5 mol%),
tBuOOtBu (1.5 equiv), DCE at 708C], BINOL [1b]2 was
formed exclusively in 96% yield (Scheme 2). However, when
the reaction was performed in HFIP at room temperature, the
cross-coupling process dominated, and biaryl 8 was isolated in
^
were used: ( ) 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP); (~) 2,2,2-
trifluoroethanol (TFE); (*) 2,2,2-trichloroethanol; (&) 1-phenyl-2,2,2-
trifluoroethanol; (&) 1,1,1-trifluoropropan-2-ol; (*) 1,2-dichloro-
ethane. The reaction progress was monitored by HPLC.
reaction was performed in TFE or 2,2,2-trichloroethanol,
affording BINOL 2a with 75% and 97% conversion,
respectively, after 24 h. Remarkably, when the reaction was
performed in HFIP, almost complete consumption of 2-
naphthol was observed within 1 h. 1,1,1-Trifluoropropan-2-ol
and 1-phenyl-2,2,2-trifluoroethanol had no impact on the
reaction rate, and ethanol and acetic acid were not efficient
solvents for this transformation.
To further investigate this accelerating effect, the oxida-
tion potentials of various phenols in three different solvents
were measured (Table 1). The cyclic voltammetry experi-
ments demonstrate the effect of fluorinated alcohols on the
oxidation potentials of the phenols. For example, the Eox of 2-
naphthol (1a) in HFIP (0.48 V, entry 1) was lower than the
oxidation potentials measured in TFE (0.51 V) or in aceto-
nitrile (0.61 V). These results support the notion that HFIP
stabilizes the aromatic radical cation intermediates generated
during the SET process.[5b,8a,9b] This rate accelerating effect
may be accounted for in at least two additional ways:
1) Based on the study of Berkessel and others,[7b–f] it is
suggested that fluoroalcohols weaken the peroxide bonds by
forming multiple H-bond network thereby reducing the
activation energy of the peroxide oxygen–oxygen bond
cleavage in what is considered to be the rate-determining
step of the process[5b] and 2) HFIP may coordinate to the
metal, forming iron complexes[11] with improved oxidizing
capabilities.[12]
2
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reported example of an iron-catalyzed Csp2 OH)–Csp2
À
(Ar
À
(Ar H)
CDC reaction.
The efficiency of the iron catalyst and the power of this
chemistry in designing multistep processes that rely on
a single catalytic system were examined. The coupling of
3,5-dimethoxyphenol (1g) with arene 9 in TFE afforded the
isolated biaryl 15 in 51% yield (Table 2). In a different
experiment b-ketoester 2 was introduced into the reaction
mixture after the formation of 15, and the living iron catalyst
mediated a second oxidative coupling reaction, affording
hemiacetal 20 in 43% yield. This example emphasizes the
generality of the new set of conditions and stresses the
versatility of iron catalysis.
Scheme 2. Oxidative cross-coupling of phenols with arenes.
Our final set of experiments was designed to study the
effect fluoroalcohols have on different types of iron-catalyzed
oxidative cross-coupling of phenols. Despite their structural
similarity to b-ketoesters, b-diketones failed to react with
phenols under common CDC conditions.[6g] For example,
when 1,3-bis(4-methoxyphenyl)-1,3-propanedione (21) and p-
cresol (1h) were reacted using FeCl3(H2O)6 (10 mol%) as the
catalyst and tBuOOtBu (2.5 equiv) as the terminal oxidant in
DCE at 708C (Scheme 3), only dimer [21]2 was isolated in
50% yield. The formation of this dimer provides evidence for
the tendency of 21 to transform to electrophilic radical
species.
56% yield. The coupling of different phenols with 1,3,5-
trimethoxybenzene (9) in HFIP afforded nonsymmetrical
biaryl products 10–14 in good yields (Table 2). PAHs such as
anthracene, pyrene,[15] and benzopyrene are excellent cou-
pling partners, and their coupling with naphthol derivatives
was highly selective, affording PAH biaryl products 16–19 in
excellent yields. To the best of our knowledge, this is the first
Table 2: Scope of the phenol–arene oxidative cross-coupling.[a]
Scheme 3. Oxidative cross-coupling of p-cresol 1h with 21.
A comprehensive optimization study (see Table 2S in the
Supporting Information, SI) was performed to identify
improved catalytic conditions. It was found that a high
degree of chemoselectivity was obtained when the reaction
was carried out in a HFIP/TFE mixture (1:1), affording the
cross-coupling product 22 in 87% yield (Scheme 3). Cyclic
voltammetry measurements of b-diketone 21, performed in
acetonitrile (Eox = 0.995 V), TFE (1.08 V), and HFIP (1.20 V)
displayed an opposite trend to the one recorded for phenols
(Table 1). These oxidation potentials imply that the oxidation
of b-diketone 21 is much slower in protic fluorinated solvents
and as a result, the chemoselectivity of the cross-coupling
reaction improves.
A study of the reaction scope (Table 3) revealed that 2-
naphthol derivatives and electron-rich phenols react under
catalytic conditions with good to excellent yields (compounds
22–26, 29, and 32). However coupling of phenols that are less
nucleophilic than the b-diketone coupling partner are better
coupled using a stoichiometric amount of iron salts (com-
[a] Conditions: phenol (1 equiv), arene (1–3 equiv), FeCl3 (5–15 mol%),
tBuOOtBu (1.5–2 equiv), HFIP. [b] FeCl3(H2O)6 (5 mol%), tBuOOtBu
(2 equiv), HFIP. [c] TFE was used as solvent. [d] 1-Phenyl-2,2,2-tri-
fluoroethanol was used as the solvent at 408C. [e] For the exact coupling
conditions see the SI.
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Table 3: Scope of the b-diketone–phenol oxidative coupling.[a]
pling reactions of phenols by introducing fluorinated
alcohols as solvents. The reduction in the oxidation
potentials of the phenols in these solvents affects
both the efficiency and the selectivity of the
processes, promoting the coupling of phenols with
various nucleophiles under mild catalytic conditions
(even at 08C rather than 708C). Under our modified
conditions, arenes, including PAHs, and b-diketones,
which failed to react with phenols under catalytic
conditions in common organic solvents, have
become legitimate coupling partners for phenols.
The new conditions were utilized, for the first time,
for the synthesis of 2’’’-dehydroxycalodenin B.
Received: October 2, 2014
Revised: November 18, 2014
Published online: && &&, &&&&
[a] Conditions: Fe(ClO4)3 hydrate (10 mol%), 1,10-phenanthroline (10 mol%),
tBuOOtBu (2 equiv), HFIP/TFE (1:1). For the exact coupling conditions see the SI.
[b] Fe(ClO4)3 hydrate (30 mol%). [c] FeCl3(H2O)6 (100 mol%) in DCE. [d] Fe(ClO4)3
(100 mol%) in HFIP/TFE (1:1). Phen=1,10-phenanthroline.
Keywords: cross-dehydrogenative coupling ·
.
fluorinated solvents · iron catalysis ·
oxidative cross-coupling · phenols
pounds 27, 28, 30, and 31). The reactions of nonsymmetrical b-
diketones with phenols produced either a single product
(benzofurans 30 and 31) or a mixture of two constitutional
isomers (as in 32a and 32b).
Iron-catalyzed phenol oxidative cross-coupling is a power-
ful synthetic tool for assembling bioactive phenolic natural
products in a minimum number of synthetic steps.[6b,e]
Calodenin B (33, Scheme 4) and 2,3-dihydrocalodenin B
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4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
Communications
Communications
Oxidative Cross-Coupling
Not just a solvent: The use of fluorinated
solvents leads to a significant rate accel-
eration and enhancement of the chemo-
selectivity of the iron-catalyzed oxidative
coupling of phenols. This method was
used for the synthesis of 2’’’-dehydroxy-
calodenin B.
E. Gaster, Y. Vainer, A. Regev, S. Narute,
K. Sudheendran, A. Werbeloff, H. Shalit,
D. Pappo*
&&&& — &&&&
Significant Enhancement in the Efficiency
and Selectivity of Iron-Catalyzed
Oxidative Cross-Coupling of Phenols by
Fluoroalcohols
6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!