Tethering for selective synthesis of 2,2′-biphenols: The acetal method

Article abstract of DOI:10.1002/chem.201301969

2,2'-Biphenols are a large and diverse group of compounds with exceptional properties both as ligands and bioactive agents. Traditional methods for their synthesis by oxidative dimerisation are often problematic and lead to mixtures of ortho- and para-connected regioisomers. To compound these issues, an intermolecular dimerisation strategy is often inappropriate for the synthesis of heterodimers. The 'acetal method' provides a solution for these problems: stepwise tethering of two monomeric phenols enables heterodimer synthesis, enforces ortho regioselectivity and allows relatively facile and selective intramolecular reactions to take place. The resulting dibenzo[1,3]dioxepines have been analysed by quantum chemical calculations to obtain information about the activation barrier for ring flip between the enantiomers. Hydrolytic removal of the dioxepine acetal unit revealed the 2,2′-biphenol target. All tied up! Oxidative dimerisation of phenols often results in regioisomeric mixtures. One solution is the use of an acetal tether to impart ortho reactivity to the hydroxyarenes in a 1:1 ratio. Cyclisation forms dibenzo[1,3]dioxepine intermediates, then cleavage of the acetal linker delivers the unmasked biphenol (see scheme). Copyright

Full text of DOI:10.1002/chem.201301969

FULL PAPER
DOI: 10.1002/chem.201301969
Tethering for Selective Synthesis of 2,2’-Biphenols: The Acetal Method
Kye-Simeon Masters,*[a, b] Angela Bihlmeier,[c] Wim Klopper,[c] and Stefan Brꢀse*[b, d]
Abstract: 2,2'-Biphenols are a large
and diverse group of compounds with
exceptional properties both as ligands
and bioactive agents. Traditional meth-
ods for their synthesis by oxidative di-
merisation are often problematic and
lead to mixtures of ortho- and para-
connected regioisomers. To compound
these issues, an intermolecular dimeri-
sation strategy is often inappropriate
for the synthesis of heterodimers. The
ꢀacetal methodꢁ provides a solution for
these problems: stepwise tethering of
two monomeric phenols enables hete-
rodimer synthesis, enforces ortho regio-
selectivity and allows relatively facile
and selective intramolecular reactions
to take place. The resulting dibenzo-
AHCTUNGTRENN[GUN 1,3]dioxepines have been analysed by
quantum chemical calculations to
obtain information about the activation
barrier for ring flip between the enan-
tiomers. Hydrolytic removal of the di-
oxepine acetal unit revealed the 2,2’-bi-
phenol target.
Keywords: acetals · aromatic sub-
stitution · biaryls · dioxepines · teth-
ers
Introduction
clude natural products, for instance, plant-derived polyphe-
nolics, such as skyrin (3),[6] and the super-antibiotic vanco-
mycin.[7] Further examples include xanthone dimer mycotox-
ins, for example, xanthonol (4),[8] hirtusneanoside A (5),[9]
rugulotrosin A (6),[10] and secalonic acids A–G (generic for-
mula 7).[11] Previous work from our group[12] and others[13]
has culminated in the synthesis of some monomeric units of
2,2'-Biphenols form the centrepiece of a plethora of chemi-
cal species,[1] for instance, phytochemicals, mycotoxins and
other natural products, active pharmaceutical ingredients
and chiral ligands (e.g., 1–7; Scheme 1). Prominent members
of this extensive family of compounds[2] possess axial chirali-
ty.[3] These include the very first axially chiral ligand 1,1'-bi-
naphthalene-2,2'-diol (BINOL, 1) and the many derivatives
since developed from it,[4] which include the vaulted biaryl
2,2'-diphenyl-(4-biphenanthrol) [VAPOL, 2].[5] Others in-
[a] Dr. K.-S. Masters
School of Chemistry, Physics and Mechanical Engineering
Faculty of Science and Engineering
Queensland University of Technology
GPO Box 2434, Brisbane, Queensland, 4001 (Australia)
Fax: (+61)7-3138-4207
E-mail: kye.masters@qut.edu
[b] Dr. K.-S. Masters, Prof. Dr. S. Brꢂse
Institute of Organic Chemistry (IOC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-6084-8581
E-mail: kye.masters@kit.edu
stefan.braese@kit.edu
[c] Dr. A. Bihlmeier, Prof. Dr. W. Klopper
Theoretical Chemistry Group
Institute of Physical Chemistry (IPC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 2, 76131 Karlsruhe (Germany)
[d] Prof. Dr. S. Brꢂse
Institute of Toxicology and Genetics (ITG)
Karlsruhe Institute of Technology (KIT)
Eggenstein-Leopoldshafen (Germany)
Scheme 1. Representative ligands and natural products that exhibit the
2,2'-biphenol core, and previously synthesised monomeric units related to
this core.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301969.
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these widely occurring species, for example, blennolide C
(8),[14] diversonol (9) and 4-dehydroxydiversonol (10).
Despite the vast number of valuable and interesting com-
pounds that contain this common structural motif, no uni-
versally applicable methodology for their synthesis has been
described. By far the most commonly encountered method
for construction of compounds that feature an ortho,ortho-
biphenolic unit, at least in the case of the homodimeric com-
pounds, is the oxidative coupling of two molecules of the
monomeric phenol/hydroxyaryl derivative. This approach
works superbly in the specific cases for which it is well-
known; a good example is the facile oxidative coupling of 2-
naphthol (11) in the synthesis of 1 (Scheme 2).[15] Nonethe-
less, in other cases, in which the inherent properties of the
Scheme 3. The lactone concept of Bringmann et al, and the acetal con-
cept, in which a molecular tether imparts ortho selectivity.
symmetrical ortho,ortho-biphenolic natural products, for ex-
ample 4, 5 and 7 (Scheme 1). It seemed that a simple meth-
ylene unit would be an appropriate molecular tether to give
ꢀ
ꢀ
ArO CH2 OAr' substrates of the form 28 (Scheme 3) for
cyclisation to dibenzo[1,3]dioxepines 29, which can be
AHCTUNGTRENNUNG
cleaved under a variety of conditions[20] with either Brønsted
or Lewis acid to yield the unmasked ortho,ortho-biphenol
targets 30. It is noteworthy that a related method has recent-
ly been disclosed by Huang and Gevorgyan,[21] which utilises
a dialkyldioxysilane unit to link the two hydroxyarene com-
ponents (one bromo-functionalised) and provide a route to
obtain challenging seven-membered rings.[22] We have re-
cently communicated the key reactions in this synthetic sce-
nario,[23] and now disclose full details, which include forma-
tion of the substrates and the results of some associated
studies.
Results and Discussion
Initial attempts to generate diaryloxy-substituted acetals of
type 28 (Scheme 3) from diiodomethane, bromoiodome-
thane or chloroiodomethane failed: in each case, the puta-
tive mono-substituted intermediate was not observed at any
stage and the di-ortho-bromoaryloxy acetal 32 (Scheme 4)
was isolated in near-quantitative yield. The enhanced reac-
tivity of the mono-substituted intermediate was such that
this species reacted more rapidly than the initial dihalome-
thane. This observation can be explained by the enhanced s-
bond polarisation on the methylene carbon atom imparted
Scheme 2. Examples of poor ortho/para selectivity in oxidative phenolic
coupling.
substrate molecule are less well-suited, oxidative coupling
results in poor yields and undesirable regioselectivities.[16] In
some cases the resultant regioisomeric mixtures can be com-
plex and difficult to separate, for example, dimerisation of
1-naphthol (14),[15] 3-hydroxyphenol (18)[17] and methyl (2-
hydroxy-4-methoxy-6-methyl)benzoate (21).[18]
ꢀ
ꢀ
by the ArO CH2X bond relative to the X CH2X bond.
Although these homo-dimeric acetal-linked diaryloxyar-
enes were not the originally intended targets, nonetheless,
we attempted to establish if they could be converted to 2,2'-
Inspired by Bringmannꢁs lactone method,[19] we envisaged
that the undesirable predisposition of some substrates to un-
dergo cyclisation at both the ortho- and para-positions could
be circumvented by application of an intramolecular tether.
The tether, attached at the aryloxy moieties, would limit re-
activity to the ortho sites. A further advantage of such
a strategy would result when the acetal intermediate could
be constructed in a stepwise, modular fashion to provide
strict enforcement of A+B reactivity between phenol/hy-
Scheme 4. General scheme for domino Stille–Kelly and boronation–
Suzuki coupling. Conditions: a) CH2ICl (5.0 equiv), K2CO3 (4.0 equiv),
DMF, rt, 2.5 h, 84%; b) [M]2 ([CH3]3Sn)2 or (C6H12BO2)2); see Table 1
for Pd catalyst, solvent, additive, reaction time, reaction temperature.
droxyaryl substrates in
a
heterodimerisation process
(Scheme 3). This is necessary for the synthesis of many non-
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Chem. Eur. J. 2013, 19, 17827 – 17835

Selective Synthesis of 2,2'-Biphenols
FULL PAPER
Table 1. Domino Stille–Kelly and boronation–Suzuki coupling to form dioexpine 34
(40), 4-fluoro- (42) and 2-hydroxy-6-methoxyben-
zaldehyde (44), to furnish diphenoxy-substituted
acetals 39, 41, 43 and 45, respectively, in good
yields (75–82%) [Scheme 6].
2-Bromophenol (31) was deprotonated with
a slight excess of sodium hydride in dimethylforma-
mide, then substituted with chloromethyl methyl
sulfide, which allowed methyl sulfide derivative 35
(stable to hydrolysis and exposure to silica) to be
isolated in excellent yield (95%). The thiol ether
was then reacted in a two-step, pseudo-one-pot pro-
tocol. Firstly, treatment with sulfuryl dichloride
Metal[a] Catalyst[b]
Ligand, ([mol%]) Solvent T [8C] t [h] Yield [%]
c]
1
2
3
4
5
6
Sn
B
B
B
B
B
Pd
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)Cl2
Pd(OAc)2
Pd(dppf)Cl2
G
–
–
toluene 110
65
14
14
14
14
14
ND[b,
22[c]
36
26
10
[d]
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
dppf (5)
PPh3 (10)
GemPhos[e] (10)
EtOH (500)
8
[a] Reactions were run on a 0.50 mmol scale with bis(organometal) reagent [A=hex-
methylditin (1.2 equiv), B=bis(pinacolato)diboron (1.0 equiv)] and catalyst
(10 mol%). In reactions 2–6, K2CO3 (3.0 equiv) was used as base. Heating was per-
formed in sealed vials inserted in an aluminium block. [b] ND=none detected. [c] For-
mation of Pd black observed. [d] dppf=1,1'-(bisdiphenylphosphino)ferrocene.
[e] GemPhos=[2.2]paracyclophanediyldiphosphane[28]
.
biphenols by Stille–Kelly cou-
pling[24] with hexamethylditin or
by domino boronation–Suzuki
coupling[25] with bis(pinacola-
to)diboron. Both of these reac-
tion sequences proceed via
a metallated intermediate; an
alternative PdII-catalysed method
Scheme 6. Synthesis of diphenoxy acetals. Conditions: a) Phenol (1.1 equiv), K2CO3 (2.0 equiv), then 36, DMF,
408C, 24 h, 75–82%.
was also attempted, which uti-
lised ethanol as the reduc-
tant.[26] In these domino reac-
gave the aryloxymethylene chloride 36, then the volatile
tions, one of the two equivalent bromides of 32 undergoes
an initial palladium-catalysed metallation with a trialkyl-
stannyl or boronate ester to form 33a (M=SnR3) or 33b
(M=B(OR)2), respectively, followed by the relevant Stille/
Suzuki reaction under the same conditions. The addition of
supplementary phosphine ligands prevented the formation
of Pd black, as described by Nising et al.[25d,e] Although sev-
eral sets of conditions for each transformation were investi-
gated (see Table 1), the conversions and subsequent yields
were low, a result of the electron-rich nature of both aryl
bromides 32 and 33, which hinders oxidative insertion of
Pd.[28]
We then reattempted the synthesis of these compounds by
a new, sequential approach. Although few methods for the
construction of asymmetric diaryloxy acetals, such as 28,
exist in the literature, a useful procedure reported by Guil-
laumet and co-workers[29] provided facile access to 2-bromo-
phenoxymethylene chloride (36), from which the desired
biaryloxy acetals (e.g., 37) could be reliably accessed in high
yields (Scheme 5).
compounds were removed under reduced pressure (caution!
stench) and the chloride was substituted with a second hy-
droxyaryl component. Although the aryloxymethylene chlor-
ides reported here were each characterised during the
course of this study, the methyl sulfide required for chloride
metathesis was found to be consistently quantitative and the
reaction can be carried on directly to the following step in
a pseudo-one-pot manner without interruption for analytical
purposes.
Commencing the sequence from the alternative partner,
that is, the ortho-bromo-hydroxyarene, was also found to be
appropriate for the construction of the diaryloxyacetal sub-
strates. The general conditions, described above, were ap-
plied to phenols substituted with an electron-releasing or
electron-withdrawing group (Scheme 7). 4-Methoxy-2-bro-
mophenol (46) and 4-fluoro-2-bromophenol (50) were each
facilely converted to the methylene methyl sulfide deriva-
tives 47 (81%) and 51 (97%), respectively, then to the
methylene chloride derivatives 48 and 52, respectively. Re-
action of these species with phenol delivered the heterodiar-
yl acetals 49 and 53 in 54 and 71% yield, respectively. The
synthetic protocol also proved readily amenable to the syn-
thesis of homo- and hetero-dimeric dinaphthyloxy deriva-
tives, to deliver acetal-linked species 57, 61 and 62
(Scheme 7) in good yields (74–88%).
As an extension of this protocol, 36 was reacted with
a range of phenol derivatives, 4-methoxy- (38), 2,5-dimethyl-
With the ortho-bromo activated diaryloxyacetals sub-
strates in hand, several methods to effect cyclisation to
dibenzoACHTNUTRGNE[UNG 1,3]-dioxepines were conceivable, which included
Scheme 5. Modified synthesis of methylene chloride 36[28] and phenolic
substitution. Conditions: a) NaH (1.2 equiv), ClCH2SCH3 (1.5 equiv),
DMF, 08C to rt, 12 h, 95– quant (2.0–2 0 mmol scale); b) SO2Cl2
(1.25 equiv), CH2Cl2, 08C to rt, 1 h, quantitative; c) Phenol (1.1 equiv),
K2CO3 (2.0 equiv), then 36, DMF, rt, 12 h, 77%.
direct arylation[30] or Heck-type cyclisation.[31] However, our
interest was piqued by recent reports of a technique that
used alkali metal tert-butoxides in conjunction with a dia-
mine as a radical initiator.[32] The combined effects of these
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K.-S. Masters, S. Brꢂse et al.
alkali metal are in a non-planar
configuration
and
possess
a
twist-angle other than the
standard 1808. This diamine ap-
peared, by sight, to catalyse the
formation of the deep-red
within the reaction solution im-
mediately upon addition at
room temperature. Also of note
is the unusual selectivity pro-
moted between the dioxepine
product 34 and byproduct 2-
phenylphenol (63) when cata-
lyst 65 was used (Table 2,
entry 8; 34/63=1:1). Formation
of 63 is least prevalent under
the optimal conditions for the
formation of dioxepine 34
(Table 2, entry 5; 34/63=9:1).
In addition to the desired
ortho substitution, achieved via
the radical intermediates 66
Scheme 7. Conditions: a) NaH (1.2 equiv), ClCH2SCH3 (1.5 equiv), DMF, 08C to rt, 12 h; b) SO2Cl2
(1.25 equiv), CH2Cl2, 08C to rt, 1 h; c) phenol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride,
DMF, 408C, 24 h; d) 1-naphthol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride, DMF, 408C,
24 h; e) 2-naphthol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride, DMF, 408C, 24 h.
reagents are to convert the bromo substituent to a highly re-
active radical intermediate, which becomes arylated by
a formal homolytic aromatic substitution (HAS) pathway;[33]
in some cases, as here, cyclisation is effected.[34]
Table 2. Optimisation of the HAS cyclisation.
Solvent[a]
KOtBu
Ligand
T[b]
t
37[c] 34[c] 63[c]
[equiv]
([mol%])
[8C]
[min]
1
2
3
4
5
6
7
8
toluene
mesitylene 3.0
3.0
64 (40)
64 (40)
64 (40)
64 (40)
64 (40)
64 (40)
64 (40)
65 (40)
100
100
100
100
120
80
120
120
120
120
120
240
120
120
96
86
15
47
15
60
19
0
4
12
68
44
77
33
69
51
0
2
17
9
8
7
When the reaction conditions for the test system of acti-
vated dioxyacetal 37 (Scheme 8) were optimised (Table 2), it
was found that the best solvent was pyridine. Treatment of
37 with potassium tert-butoxide (3 equiv) and 1,10-phenan-
throline (40 mol%) in pyridine at 1008C for 2 h provided
a much larger conversion to 34 (68%; Table 2, entry 3) than
when toluene (4%; Table 2, entry 1), mesitylene (12%;
Table 2, entry 2) or collidine (44%; Table 2, entry 4) were
used as the solvent. The temperature had some effect upon
both the conversion and selectivity of the reaction, although
the number of equivalents of butoxide apparently did not
(Table 2, entry 5 versus 6 and 7). An interesting note is the
application of an atypical, axially-chiral diamine catalyst,
(R)-[1,1'-binaphthalene]-2,2'-diamine (65), to effect this re-
action. In 65 the two nitrogen atoms that coordinate to the
pyridine
collidine
pyridine
pyridine
pyridine
pyridine
3.0
3.0
3.0
3.0
1.0
3.0
120
120
11
49
[a] Dried solvent. [b] Heating was by microwave (MW) irradiation.
[c] Values are conversions, determined by HPLC analysis of the reaction
mixtures.
and 67a (Scheme 9), 63 was consistently observed as a by-
product under the optimised reaction conditions. These con-
ditions appear to also promote a competitive ipso-substitu-
tive cyclisation of the aryl radical to give intermediate 67b,
similar to observations of Charette (conversion of 68 to 70a
and 70b; Scheme 9)[34a] and are in agreement with the mech-
anism postulated by Studer and Curran.[33c] Intermediate
67b could be converted by radical C!O transposition, de-
scribed by Alabugin and co-workers.[35] Although such
a transformation of a carbon- to an oxygen-centred radical
may be endothermic, the generation of 63 could, nonethe-
less, be favoured by irreversible fragmentation of 67c to rel-
atively stable phenoxy radical 67d and formaldehyde.
With optimal conditions for the cyclisation established on
the test substrate, we proceeded to apply the same condi-
tions to a variety of substituted diphenoxy acetal substrates.
In cases when the bromide-activated group for homolytic
cleavage was located on the phenyl ring of the substrate (37,
Scheme 8. Dibenzo
conditions described in Table 2.
ACHTUNGTRENNUNG[1,3]dioxepine and byproduct synthesised under the
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Selective Synthesis of 2,2'-Biphenols
FULL PAPER
Scheme 9. Competing ortho-7-exo and ipso-6-exo cyclisation pathways.
39, 41, 43 and 45; Scheme 10) the reaction progressed well,
with good conversions and moderate yields of products 34
and 71–75 (49–63%). In contrast, when the radical-bearing
substituted aryl group of 49 and 53 was the initial radical-
bearing half of the molecule the yields of 71 and 73 were
much diminished, to 8 and 13%, respectively, and the re-
mainder of the mass balance was not isolated from either re-
action mixture after chromatography. Under these condi-
tions it appears preferable to functionalise the less-substitut-
ed arene for radical cyclisation. Also noteworthy is the re-
markably small difference in yield obtained with substrates
39 and 43 when the reaction time was shortened to 6 min.
Significant among these results is the ready cyclisation of 41
to form the potentially-chal-
in lower yield (28%) than the model system. It appears that
either 1) the brominated carbon atom can also function as
a valid point of attack for the radical anion, followed by the
loss of a bromonium species rather than a proton, or
2) the cyclisation occurs at an unsubstituted ortho position
of the aryloxy unit and bromide is reduced under the radical
conditions either before or after this cyclisation.
Cyclisation of the dinaphthyloxy acetals delivered the de-
sired dioxepine-centred products 76–79 (Scheme 11), albeit
with slightly lower yields (38–46%) than for the diphenoxy
acetals, and after extended reaction times (120 rather than
60 min as standard). In the case of the 2,2'-dioxy-substituted
substrate 61, cyclisation occurred at the two available ortho
lenging 1-oxy-2-methyl biaryl
motif,
a common feature in
some of the end-target natural
products (e.g., 4–6, Scheme 1).
The generation of a 1:1 mix-
ture of the regioisomeric defor-
mylated dibenzoACHTUNGTRENNUNG[1,3]dioxepine
products 74 and 75 is intriguing;
cyclisations of this type typical-
ly exhibit a clear selectivity for
the ortho-substituted product,
in this case 74. There are sever-
al potential explanations (for
example, deformylation and
cyclisation as discrete events)
and there is always the possibil-
ity that the regioisomeric ratio
of 1:1 obtained here is a coinci-
dence that results from a combi-
nation of several competing fac-
tors. Also of interest is the radi-
Scheme 10. Cyclisation of diphenoxy acetals. Conditions: KOtBu (3.0 equiv), 1,10-phenanthroline (40 mol%),
cal cyclisation of 32 to 34, albeit pyridine and MW at 1208C for a) 120 min, b) 6 min, c) 240 min.
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K.-S. Masters, S. Brꢂse et al.
er of around 50 kJmolꢀ1 was found. Comparison with recent
investigations on the atropisomerisation of bridged biphen-
yls[38] suggests that the interconversion of this compound can
be monitored by dynamic NMR spectroscopic measure-
ments, which means that the rotation of the phenyl rings is
still fast. The activation barrier can be further enlarged by
symmetric substitution with methyl groups (e.g., in 80) to
yield a barrier of around 150 kJmolꢀ1 and, thus, a conforma-
tionally stable isomer (Table 3, Figure 1).
The final transformation in the synthetic sequence in-
volved excision of the methylene acetal to unmask the or-
tho,ortho-dihydroxy functionality of the biaryl compound.
Although it is well-known that the methylene-linked 1,1-
dioxy moiety is among the most kinetically stable of acetals,
we found that mild heating of the 1,3-dioxepines derived
from cyclisation in ethanolic hydrochloric acid solutions de-
livered the corresponding ortho,ortho-dihydroxy biaryls (1
and 81–83, Scheme 12) in good to excellent yields (68–
92%), regardless of the nature of the substituents (electron-
Scheme 11. Cyclisation of dinaphthyloxy acetals. Conditions: a) KOtBu
(3 equiv), 1,10-phenanthroline (40 mol%), pyridine, MW, 1208C,
120 min, b) KOtBu (3 equiv), 1,10-phenanthroline (40 mol%), pyridine,
MW, 1208C, 240 min, c) KOtBu (3 equiv), 65 (40 mol%), pyridine, MW,
1208C, 240 min<.
Table 3. Computed activation barriers [kJmolꢀ1] for rotation about the
biaryl bond.
Compound
TPSS/TZVP
B3LYP/TZVP
34
72
2
6
positions and led to a mixture of BINOL precursor 77 and
asymmetric dioxepine 78. A consistent ratio of 77/78=2:1
was obtained across a variety of reaction times; a doubling
of reaction time from 2 to 4 h resulted in a greater-than-
commensurate increase in yield (11 to 46%). The dioxe-
pine-centred dinaphthyls were fluorescent under UV light,
which suggested a degree of electronic communication be-
tween the p systems (i.e. some conformational planarity in
their structures), which is surprising given the axially-rotated
nature of 77.
46
54
80
152
167
During characterisation of the dioxepines, we were sur-
prised to note that the two methylene protons in the dioex-
pine ring were consistently detected as a singlet in the NMR
spectra.[36] This may be explained either by rapid intercon-
version through ring-flipping between the two conforma-
tions, in which the methylene protons exchange their chemi-
cal environment, or by a coincidental isochronicity of the
two resonances. One case in which neither of these explana-
tions seems probable is with 1,4-dimethyldibenzo
ACHTUNGTRNE[NUNG d,f]-
ACHTUNGTRENNUNG[1,3]dioxepine (72) [Scheme 10], which has a significant
asymmetric nature and the added steric interaction of the
methyl substituent neighbouring the biaryl axis. Much to our
1
surprise, the H NMR spectrum (500 MHz, CDCl3) of this
compound also exhibits
a singlet resonance at d=
5.54 ppm.[37] To ascertain if the protons were equivalent due
to a facile ring-flip at ambient temperature, quantum chemi-
cal calculations were carried out. We computed the activa-
tion barrier for the interconversion between the two possi-
ble conformations for various substituted dioxepines. In the
unsubstituted case, 34 (bridged biphenyl), the barrier is very
small and rotation about the central phenyl–phenyl bond
occurs at low temperatures. For dioxepine 72, a higher barri-
Figure 1. B3LYP-optimised geometries of the equilibrium (left) and tran-
sition states (right) of the investigated dioxepine compounds.
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Selective Synthesis of 2,2'-Biphenols
FULL PAPER
the mixture was stirred at 08C for 30 min, chloromethyl methyl sulfide
(neat, 1.50 equiv) was added dropwise. The reaction mixture was allowed
to warm to rt and stirred for 12 h. The reaction was quenched with water
(20 mL/mmol bromophenol) and extracted with hexanes or cyclohexane
(10 mL/mmol bromophenol), then dichloromethane (5 mL/mmol). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and the volatile compounds were removed under re-
duced pressure. The crude residue was purified by SiO2 column chroma-
tography (cyclohexane/dichloromethane mixtures) to give the pure phe-
noxymethyl methyl sulfide.
General procedure for the synthesis of 2-bromoaryloxymethylene chlor-
ides (caution! stench): SO2Cl2 (1.25 equiv) was added to a stirred solu-
tion of the methyl sulfide (1.00 equiv) in dichloromethane (10 mL/mmol)
at 08C (ice bath), then the cooling bath was removed. After the mixture
had been stirred at rt for 1 h, the volatile compounds were removed
under reduced pressure on a rotary evaporator located in a fume cup-
board to give the corresponding methylene chloride as a pale-yellow or
orange oil in quantitative yield and of sufficient purity to be used directly
in the next step. When storage was necessary, the compounds were found
to be stable for 6+ months under an inert atmosphere at ꢀ208C.
General procedure for the synthesis of biaryloxy acetals: Aryloxymethy-
lene chloride (neat oil, 1.00 equiv) was added dropwise to a stirred sus-
pension of phenol (1.10 equiv) and potassium carbonate (2.00 equiv) in
DMF (5 mL/mmol phenol) at rt under an inert atmosphere. The reaction
mixture was warmed to 408C and stirred for 24 h. The crude mixture was
then loaded onto a long column of silica gel and eluted with cyclohexane,
then a mixture of cyclohexane/ethyl acetate to deliver the pure biaryloxy
acetal.
Scheme 12. Hydrolysis of selected dibenzoACTHNUTRGNE[NUG 1,3]dioxepines to deliver
target ortho,ortho-dihydroxyarenes. Conditions: HCl(aq)/EtOH (1:5) or
HCl(aq)/MeOH (1:7), 508C, 4–36 h.
donating, -withdrawing or sterically demanding). One note-
worthy observation was that the time required for hydrolysis
varied somewhat, from 3 to 36 h: the most rapid reaction
was for the intrinsically strained BINOL acetal 77. The use
of methanolic acid solutions, at slightly increased concentra-
tion due to solubility issues, was equally valid. This point
may become pertinent in future studies with xanthone
dimers (e.g., 4–10, Scheme 1), the majority of which possess
potentially hydrolytically unstable methyl ester groups.
General procedure a for the synthesis of dibenzo-[1,3]-dioxepines:
Bromo-substituted substrate (0.25 mmol) and anhydrous pyridine
(1.5 mL) were added to a 10 mL microwave vial, followed by 1,10-phe-
nanthroline (18 mg, 0.10 mmol) and potassium tert-butoxide (84 mg,
0.75 mmol). The vial was capped and the atmosphere cautiously removed
by vacuum, with stirring. The atmosphere was then replaced with argon
and purged after evacuation (ꢄ3). The reaction mixture was heated to
1208C by microwave irradiation for 120 min. After this time, the blood-
red reaction mixture was allowed to cool to rt, then filtered through
a short column of silica gel with ethyl acetate (50 mL). The volatile com-
pounds were removed under reduced pressure then the crude product
was purified by column chromatography on silica gel with a mixture of
cyclohexane/dichloromethane.
Conclusion
We have established a reliable method for the ortho-selec-
tive formation of heterodimeric 2,2'-biphenols. Future work
to investigate the acetal concept will involve application to
the synthesis of natural products, use of novel ligands based
on the ortho,ortho-dihydroxy biaryl motif, and attempts to
apply transition-metal catalysis to improve the yield of the
initial dibenzoACHTUNGTRENNUNG[1,3]dioexpine products. The development of
a coupling without the need for an activating group (in this
case, a bromo substituent) would also be advantageous.
Most exciting of all would be application of one of the latter
two methodologies in conjunction with chiral ligands to
invoke axial chirality, which is found in many of the natural
products with a central ortho,ortho-biphenol motif.
General procedure b for the synthesis of dibenzo-[1,3]-dioxepines: As for
general procedure a above, except with 6 min of heating by microwave ir-
radiation.
General procedure c for the synthesis of dibenzo-[1,3]-dioxepines: As for
general procedure a, except with 240 min of heating by microwave irradi-
ation.
General procedure d for the synthesis of dibenzo-[1,3]-dioxepines: As for
general procedure a, except with the substitution of (R)-[1,1'-binaphtha-
lene]-2,2'-diamine (28.4 mg, 0.10 mmol) for 1,10-phenanthroline.
Experimental Section
General procedure for the hydrolysis of dibenzo-[1,3]-dioxepines to or-
tho,ortho-biphenols: Concentrated HCl (aq) [0.20 mL/mL ethanol] was
added dropwise a stirred solution of the dioxepine in ethanol (0.10m).
The cloudy reaction mixture was heated to 508C in an oil bath, then
sealed with a septum. The reactions were monitored by TLC to detect
consumption of the starting material, and it was noted that once the sub-
strate is consumed the reaction mixtures became 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 volatile
compounds were removed under reduced pressure. The crude product
was purified by column chromatography on silica gel with mixtures of cy-
clohexane/ethyl acetate.
Computational Details: All quantum chemical calculations presented in
this work have been performed with the TURBOMOLE program pack-
age.[39] Geometries of the equilibrium and transition states of the dioxe-
pines were optimised within the framework of density functional theory.
TPSS[40] and B3LYP[41] functionals were used in combination with a def2-
TZVP basis set,[42] and tight convergence criteria and fine quadrature
grids (m5)[43] were employed. In the case of TPSS, the efficient resolution
of the identity approximation for two-electron Coulomb integrals was
used. The nature of the stationary points (minima and transition states)
was confirmed through the calculation of vibrational frequencies. The
given activation barriers are computed from the zero-point vibrational
°A
energy corrected electronic energies and thus correspond to DH CTHNUGTENR(NUG 0 K).
General procedure for the synthesis of 2-bromoaryloxymethyl methyl sul-
fides: Sodium hydride (1.20 equiv, 60% dispersion in mineral oil) was
added to a stirred solution of bromophenol (1.00 equiv) in anhydrous
DMF (7.5 mL/mmol) at 08C (ice bath) under an inert atmosphere. After
Chem. Eur. J. 2013, 19, 17827 – 17835
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17833

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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
through the
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Chem. Eur. J. 2013, 19, 17827 – 17835

Selective Synthesis of 2,2'-Biphenols
FULL PAPER
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Received: May 22, 2013
Published online: November 21, 2013
Chem. Eur. J. 2013, 19, 17827 – 17835
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17835