The acetal concept: Regioselective access to ortho,ortho-diphenols via dibenzo-1,3-dioxepines

Article abstract of DOI:10.1002/anie.201207485

Traditional methods are ill-suited for the synthesis of ortho,ortho-biphenols, a structural motif found in many polyphenolic natural products, as well as synthetically useful compounds such as the chiral ligands binol, vapol, and vanol. The new route consists of a radical-based reaction of an acetal-tethered biphenyl ether substrate and subsequent hydrolytic cleavage of the dibenzo-1,3-dioxepine intermediate. Copyright

Full text of DOI:10.1002/anie.201207485

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DOI: 10.1002/anie.201207485
Diphenol Synthesis
The Acetal Concept: Regioselective Access to ortho,ortho-Diphenols
via Dibenzo-1,3-dioxepines**
Kye-Simeon Masters* and Stefan Brꢀse*
À
The biaryl C C linkage is one of the most significant in
bioactive and widespread ergochrome family of mycotoxins,
including the secalonic acids (5).[11] Despite the vast number
of compounds known to contain this motif (see 8, Scheme 1;
over 18500 compounds identified recently in a Scifinder
chemistry, and has long[1] been a point of synthetic focus.[2]
À
Nonetheless, some biaryl C C linkages remain difficult to
synthesize, usually for electronic reasons. One of these is the
ortho,ortho-diphenol system (Figure 1), since transition-
metal-catalyzed cross-coupling disfavors oxidative insertion
Scheme 1. Comparison of the dimerization of 1- and 2-naphthol.
Scholar search), a general, reliable, regioselective method for
their synthesis remains elusive. Herein, we describe a strategy
providing access to a potentially wide range of synthetic
targets of this type.
Figure 1. Representative ortho,ortho-diphenols.
ortho to a hydroxy or protected hydroxy group.[3] In eliminat-
ing the requirement for oxidative insertion into a carbon–
Existing transformations of phenolic substrates to form
biaryls have generally been accomplished with oxidative
coupling.[12] A drawback of this method is that it fails utterly
with substrates that are not suited in terms of sterics or
electronics, and results instead in either lack of reactivity or
poor regioselectivity profiles. For example, 2-naphthol (6,
Scheme 1) consistently forms binol (1) in dimerization
reactions,[13] whereas 1-naphthol (9) with its greater radical
stabilization reacts to form mixtures of 2,2’-, 2,4’-, and 4,4’-
linked dimers (10, 11, and 12, respectively).[13]
The lack of a general method for the regioselective
formation of dimeric and heterodimeric ortho,ortho-diphe-
nols (and derivatives thereof) is therefore a shortcoming in
the range of existing synthetic methodologies. One possibility
to address the poor selectivity is the application of an
intramolecular tether, which would limit the reactivity to
physically accessible sites of the substrate. Inspired by elegant
methods for biaryl coupling relying on temporary intra-
molecular tethers, including Bringmannꢀs “lactone concept”
(Scheme 2),[14] and the work of Lipshutz,[15] we envisioned
that the use of a tether to impose ortho regioselectivity upon
the reaction of phenolic substrates would provide access to
target molecules with a 1,1’-dihydroxy-2,2’-biaryl motif. The
method would involve the acetal linkage of the two phenolic
À
(pseudo)halide bond, C H activation has begun to show great
promise as a more direct alternative,[4] particularly with the
use of protected hydroxy groups as directing groups.[5]
We have an ongoing interest in the synthesis of the
ortho,ortho-dihydroxybiaryl motif,[6] which is found in numer-
ous structurally fascinating and biologically active natural
products, drugs, and useful ligands for asymmetric catalysis.
Examples of these include binol[7] (1, Figure 1) and vanol
(2),[8] and the natural products skyrin (3)[9] and gossypol (4).[10]
In particular, key synthetic targets of our group are the highly
[*] Dr. K.-S. Masters, Prof. Dr. S. Brꢀse
Institute of Organic Chemistry (IOC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76133 Karlsruhe (Germany)
E-mail: kye.masters@kit.edu
stefan.braese@kit.edu
Prof. Dr. S. Brꢀse
Institute of Toxicology and Genetics (ITG)
Karlsruhe Institute of Technology (KIT)
Eggenstein-Leopoldshafen (Germany)
[**] K.-S.M. would like to thank the Alexander von Humboldt Founda-
tion for generous funding and support, and the Brꢀse group for the
fond memories.
À
moieties, followed by C C bond formation, and finally
removal of the linker.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207485.
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subsequently converted to the chloride with sulfuryl dichlor-
ide and reacted with a second phenol, 22, in a pseudo-one-pot
reaction, yielding a range of acetal-linked compounds 16.
Yields were consistently good to excellent.
À
We then optimized the C C bond formation with the
simple bromo-functionalized biphenyl acetal 25 (Scheme 4),
which gave 1,3-dioxepine 26 as the product, alongside 2-
Scheme 2. The lactone concept and the acetal concept. TM cat. =tran-
sition-metal catalyst.
Owing to the ready accessibility of the substrates[16] and
the simplicity of the reaction reagents and conditions, we felt
we had ample time to attempt construction of the biaryl
connection by a newly described alternative to transition-
Scheme 4. Competing cyclizations to dioxepine 26 and phenol 27.
À
metal-catalyzed coupling and C H functionalization. The
phenylphenol (27) as a byproduct. Testing several solvents for
this reaction under microwave irradiation, we found that
pyridine was superior to mesitylene, toluene, and collidine
(Table 1, entries 1–4).[17e] An increase in temperature to
1208C gave a better conversion (77% by HPLC analysis,
49% yield of isolated product, entry 5). Reaction for a longer
time at a reduced temperature (808C for 240 min, entry 6)
resulted low conversion. A decrease in the number of
equivalents of base gave a lower conversion (69%, entry 7).
Lastly, application of a novel ligand, (R)-(1,1’-binaphthyl)-
2,2’-diamine (24) (entry 8), proved to also promote the
reaction, although with an undesirable selectivity profile.
The isolation of 2-phenylphenol (27) is noteworthy, in that
it not only supports the mechanistic hypothesis of Studer and
Curran,[18] but provides insight into the formation of the
seven-membered ring, which can be entropically disfavored.
In light of the previous observations of competing ipso
cyclizations under these same conditions,[17e] it seems reason-
able that, rather than the desired 7-ortho cyclization to 26 via
intermediate B (Scheme 4), a competing 6-ipso cyclization
can progress to 27 through intermediate C; the oxidation of
the cyclohexadienyl radicals (rearomatization) can occur
stepwise by either electron transfer then proton transfer
(B)/deformylation (C), or by the alternative sequence of
recent discovery of a biaryl-coupling methodology involving
radical anion intermediates and utilizing diamine ligands and
tert-butoxide base, with no need for metal-containing sub-
strates or catalysts, has aroused considerable interest
(Scheme 3).[17] The methodology involves coupling of aryl
iodides or bromides with pyridine and pyrazine,[17a] ben-
zene,[17b] or substituted arenes.[17c–e] The mechanism appears to
follow a homolytic radical aromatic substitution (HAS)
pathway.[18]
The ortho-bromo-substituted methylene diphenyl ether
substrates were readily synthesized from commercially avail-
able phenols and their ortho-brominated derivatives, exploit-
ing a facile and high-yielding two-step protocol previously
reported by Guillaumet and co-workers:[16] The bromo-
substituted phenol 19 was reacted under basic conditions
with chloromethyl methyl sulfide to yield 20, which was
Table 1: Reaction optimization.[a]
Entry Solv.[b] KOtBu
[equiv] (mol%) [8C] [min]
Ligand
T
t
Conversion [%][c]
25
26
27
1
2
3
4
5
6
7
8
Tol.
Mes.
Pyr.
Coll.
Pyr.
Pyr.
Pyr.
Pyr.
3.0
3.0
3.0
3.0
3.0
3.0
1.0
3.0
23 (40) 100
23 (40) 100
23 (40) 100
23 (40) 100
23 (40) 120
120
120
120
120
120
240
120
120
96
86
15
47
15
60
19
0
4
0
2
17
9
8
7
12
68
44
77
33
69
51
23 (40)
80
23 (40) 120
24 (40) 120
11
49
Scheme 3. Synthesis of substrates; Ligands tested; Optimization. Con-
ditions for the conversions at the top: a) NaH, DMF, chloromethyl
methyl sulfide; b,c) SO2Cl2, CH2Cl2, solvent removal; then 22, K2CO3,
DMF. Reaction conditions for the conversion at the bottom are given
in Table 1.
[a] Heating by means of microwave irradiation. [b] Solvents: Tol. =to-
luene, Mes.=mesitylene, Pyr.=pyridine, Coll.=collidine. [c] Conversion
values, determined by HPLC analysis of the reaction mixtures.
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events.[18] The scission of the O C bond under radical
conditions is known and can be employed for synthetic
purposes.[19]
tively, a bromine radical, may also be an alternative final step
in the mechanism.
Reaction of the binaphthyl acetals (40, 43, and 45,
Scheme 6) proceeded much more slowly under the reaction
conditions. Acetal 40, derived from 1-bromo-2-naphthol and
2-naphthol, cyclized to form a mixture of symmetrical and
À
We next investigated the scope of the reaction with
substituted diphenyl acetal derivatives, utilizing the optimized
conditions (Scheme 5). Reaction of acetals with either
Scheme 6. Scope of the reaction with dinaphthyl acetals. Reaction
conditions: KOtBu (3 equiv), 1,10-phenanthroline (40 mol%), pyridine,
microwave irradiation at 1208C for a) 120 min, c) 240 min, d) as in (c),
but with (R)-(1,1’-binaphthalene)-2,2’-diamine (40 mol%) as catalyst.
Scheme 5. Scope of the reaction with diphenyl acetals. Reaction
conditions: KOtBu (3 equiv), 1,10-phenanthroline (40 mol%), pyridine,
and microwave irradiation at 1208C for a) 120 min, b) 6 min,
c) 240 min.
unsymmetrical 1,3-dioexpines, 41 and 42, in moderate yield
and a consistent 2:1 ratio. Acetal 43, a derivative of 2-bromo-
1-naphthol and 1-naphthol, likewise cyclized slowly, giving
the unusual 1,3-dioxepine 44. The unsymmetrical dinaphthyl
acetal 45, from 1-bromo-2-naphthol and 1-naphthol, gave
access to the unsymmetrical dioxepine 46. Interestingly, this
was the only dioxepine in which the methylene protons were
electron-donating or electron-withdrawing substituents on
the arene not bearing the bromide proved favorable, forming
the desired dibenzo-1,3-dioxepines (examples 28 and 30) with
complete regioselectivity. For the para-methoxy-substituted
acetal 28, reaction times of 6 and 120 min gave the same
results. Even the reaction of the sterically demanding 3,5-
dimethylphenyl acetal 32 proved facile. Substitution on the
bromo-functionalized ring of the diphenyl acetal (examples
34 and 35) was less well-tolerated; the substrates were
completely consumed, complex mixtures formed, and the
1,3-dioexpines were obtained in poor yields. The aldehyde
functionality was not tolerated under the reaction condi-
tions,[20] and products 37 and 38 were formed in a 1:1 ratio.
This outcome may have resulted from either initial radical
deformylation and nonselective cyclization of the resulting m-
methoxylated intermediate, although the ratio of products is
not in accord with the ortho selectivities normally observed
for HAS reactions.[18] An alternative explanation is 6-exo
cyclization of the type leading to intermediate of type C
(Scheme 4), followed by a nonselective rearomatizing C-
migration. Lastly, the reaction also proceeded with the
symmetrical bis-bromophenyl acetal 39, although in a much
less satisfactory yield (28%). This result indicates that the loss
of either bromonium ion and electron transfer, or alterna-
1
observed to give a JA,A system in the H NMR spectrum. It
was furthermore found that the use of the chiral diamine 24 as
the catalyst did not impart enantioselectivity in the formation
of 41 (binol acetal), supporting the suggestion of Studer and
Curran that the diamine functions as a radical initiator and is
[18]
À
not directly involved in the C C bond-forming step.
The hydrolysis of methylene acetals is known to require
relatively harsh conditions.[21] We nonetheless found that
heating the 1,3-dioxepines in ethanolic hydrochloric acid
solutions gave the desired 2,2’-diphenolic products in good to
excellent yields (Scheme 7). Diphenol-derived dioxepine 26
hydrolyzed to 2,2’-diphenol 47 in excellent yield (92%), and
the methoxy and fluoro derivatives, 29 and 31, reacted to give
their respective diphenol products, 48 and 49. The hydrolysis
of binol-acetal (dioxepine 41) to binol (2, identical with
commercially available rac-binol) was notably rapid (3 h),
most probably due to the steric strain intrinsic to this system.
One exception was bis(1-naphthyl) acetal 44, which appears
to possess an unusual degree of stability to Brønsted acid, and
did not react under these conditions.
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Scheme 7. Hydrolysis of selected dibenzo-1,3-dioxepines. Reaction
conditions: aq. HCl/EtOH (1:5), 508C, 4–36 h.
Further studies into the scope and application of this
reaction are underway in our laboratories, and will be
reported shortly. We believe that the “acetal concept” will
prove to be a generally applicable solution to the regioselec-
tive synthesis of ortho,ortho-diphenols.
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Experimental Section
General procedure for the synthesis of dibenzo-1,3-dioxepines: A
10 mL microwave vial was charged with the bromo-substituted
substrate (0.25 mmol) and anhydrous pyridine (1.5 mL), followed
by 1,10-phenanthroline (18 mg, 0.10 mmol) and potassium tert-
butoxide (84 mg, 0.75 mmol). The vial was capped and the atmos-
phere cautiously removed with stirring under vacuum, then replaced
with argon (repeated three times). The reaction mixture was then
heated to the stated temperature for the stated time by means of
microwave irradiation for 120 min. After this time, the blood-red
reaction mixture was allowed to cool to room temperature, then
filtered/washed through a short column of silica gel with ethyl acetate
(50 mL) as eluent. The volatiles were removed under reduced
pressure; the resulting crude was purified by column chromatography
on silica gel with cyclohexane/dichloromethane mixtures, yielding the
dibenzo-1,3-dioxepine.
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General procedure for the hydrolysis of dibenzo-1,3-dioxepines
to ortho,ortho-biphenols: To a stirred solution of the dioxepine in
ethanol (0.10m) was added dropwise concentrated HCl(aq.) (0.20 mL
per mL ethanol). The cloudy reaction mixture was then heated to
508C in an oil bath, then the flask was sealed with a septum. The
reactions were monitored by thin-layer chromatography for con-
sumption of starting material; it was noted that when the substrate
had been consumed the reaction mixtures was optically clear.
Reaction times varied greatly, depending on the nature of the
substrate. When the reaction was complete, silica gel was added to the
flask and the volatiles were removed under reduced pressure, then the
crude was purified by column chromatography on silica gel with
cyclohexane/ethyl acetate mixtures, yielding the 2,2’-diphenol.
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[20] Radical deformylation is a facile and well-documented process:
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Received: September 16, 2012
Published online: November 23, 2012
Keywords: acetal tethers · biphenols · dioxepines · diphenols ·
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radical cyclization
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