tethering for selective synthesis of 2,2′-biphenols: the acetal method
TRANSCRIPT
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 Br�se *[b, d]
Introduction
2,2'-Biphenols form the centrepiece of a plethora of chemi-cal species,[1] for instance, phytochemicals, mycotoxins andother natural products, active pharmaceutical ingredientsand chiral ligands (e.g., 1–7; Scheme 1). Prominent membersof 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 derivativessince developed from it,[4] which include the vaulted biaryl2,2'-diphenyl-(4-biphenanthrol) [VAPOL, 2].[5] Others in-
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
Abstract: 2,2'-Biphenols are a largeand diverse group of compounds withexceptional properties both as ligandsand bioactive agents. Traditional meth-ods for their synthesis by oxidative di-merisation are often problematic andlead to mixtures of ortho- and para-connected regioisomers. To compoundthese issues, an intermolecular dimeri-sation strategy is often inappropriate
for the synthesis of heterodimers. The�acetal method� provides a solution forthese problems: stepwise tethering oftwo monomeric phenols enables hete-rodimer synthesis, enforces ortho regio-
selectivity and allows relatively facileand selective intramolecular reactionsto take place. The resulting dibenzo-ACHTUNGTRENNUNG[1,3]dioxepines have been analysed byquantum chemical calculations toobtain information about the activationbarrier 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
[a] Dr. K.-S. MastersSchool of Chemistry, Physics and Mechanical EngineeringFaculty of Science and EngineeringQueensland University of TechnologyGPO Box 2434, Brisbane, Queensland, 4001 (Australia)Fax: (+ 61) 7-3138-4207E-mail : [email protected]
[b] Dr. K.-S. Masters, Prof. Dr. S. Br�seInstitute of Organic Chemistry (IOC)Karlsruhe Institute of Technology (KIT)Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)Fax: (+ 49) 721-6084-8581E-mail : [email protected]
[c] Dr. A. Bihlmeier, Prof. Dr. W. KlopperTheoretical Chemistry GroupInstitute of Physical Chemistry (IPC)Karlsruhe Institute of Technology (KIT)Fritz-Haber-Weg 2, 76131 Karlsruhe (Germany)
[d] Prof. Dr. S. Br�seInstitute of Toxicology and Genetics (ITG)Karlsruhe Institute of Technology (KIT)Eggenstein-Leopoldshafen (Germany)
Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201301969.
Scheme 1. Representative ligands and natural products that exhibit the2,2'-biphenol core, and previously synthesised monomeric units related tothis core.
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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 beendescribed. By far the most commonly encountered methodfor 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 themonomeric phenol/hydroxyaryl derivative. This approachworks 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
substrate molecule are less well-suited, oxidative couplingresults in poor yields and undesirable regioselectivities.[16] Insome cases the resultant regioisomeric mixtures can be com-plex and difficult to separate, for example, dimerisation of1-naphthol (14),[15] 3-hydroxyphenol (18)[17] and methyl (2-hydroxy-4-methoxy-6-methyl)benzoate (21).[18]
Inspired by Bringmann�s lactone method,[19] we envisagedthat the undesirable predisposition of some substrates to un-dergo cyclisation at both the ortho- and para-positions couldbe 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 sucha strategy would result when the acetal intermediate couldbe constructed in a stepwise, modular fashion to providestrict enforcement of A+B reactivity between phenol/hy-droxyaryl substrates in a heterodimerisation process(Scheme 3). This is necessary for the synthesis of many non-
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 giveArO�CH2�OAr' substrates of the form 28 (Scheme 3) forcyclisation to dibenzo ACHTUNGTRENNUNG[1,3]dioxepines 29, which can becleaved under a variety of conditions[20] with either Brønstedor Lewis acid to yield the unmasked ortho,ortho-biphenoltargets 30. It is noteworthy that a related method has recent-ly been disclosed by Huang and Gevorgyan,[21] which utilisesa dialkyldioxysilane unit to link the two hydroxyarene com-ponents (one bromo-functionalised) and provide a route toobtain 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 associatedstudies.
Results and Discussion
Initial attempts to generate diaryloxy-substituted acetals oftype 28 (Scheme 3) from diiodomethane, bromoiodome-thane or chloroiodomethane failed: in each case, the puta-tive mono-substituted intermediate was not observed at anystage 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 thatthis 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 impartedby 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'-
Scheme 2. Examples of poor ortho/para selectivity in oxidative phenoliccoupling.
Scheme 3. The lactone concept of Bringmann et al, and the acetal con-cept, in which a molecular tether imparts ortho selectivity.
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 1for Pd catalyst, solvent, additive, reaction time, reaction temperature.
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biphenols by Stille–Kelly cou-pling[24] with hexamethylditin orby domino boronation–Suzukicoupling[25] with bis(pinacola-to)diboron. Both of these reac-tion sequences proceed viaa metallated intermediate; analternative PdII-catalysed methodwas also attempted, which uti-lised ethanol as the reduc-tant.[26] In these domino reac-tions, one of the two equivalent bromides of 32 undergoesan initial palladium-catalysed metallation with a trialkyl-stannyl or boronate ester to form 33 a (M =SnR3) or 33 b(M= B(OR)2), respectively, followed by the relevant Stille/Suzuki reaction under the same conditions. The addition ofsupplementary phosphine ligands prevented the formationof 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 yieldswere low, a result of the electron-rich nature of both arylbromides 32 and 33, which hinders oxidative insertion ofPd.[28]
We then reattempted the synthesis of these compounds bya new, sequential approach. Although few methods for theconstruction 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 desiredbiaryloxy acetals (e.g., 37) could be reliably accessed in highyields (Scheme 5).
As an extension of this protocol, 36 was reacted witha range of phenol derivatives, 4-methoxy- (38), 2,5-dimethyl-
(40), 4-fluoro- (42) and 2-hydroxy-6-methoxyben-zaldehyde (44), to furnish diphenoxy-substitutedacetals 39, 41, 43 and 45, respectively, in goodyields (75–82 %) [Scheme 6].
2-Bromophenol (31) was deprotonated witha slight excess of sodium hydride in dimethylforma-mide, then substituted with chloromethyl methylsulfide, which allowed methyl sulfide derivative 35(stable to hydrolysis and exposure to silica) to beisolated in excellent yield (95%). The thiol etherwas then reacted in a two-step, pseudo-one-pot pro-tocol. Firstly, treatment with sulfuryl dichloride
gave the aryloxymethylene chloride 36, then the volatilecompounds 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 thecourse of this study, the methyl sulfide required for chloridemetathesis was found to be consistently quantitative and thereaction can be carried on directly to the following step ina pseudo-one-pot manner without interruption for analyticalpurposes.
Commencing the sequence from the alternative partner,that is, the ortho-bromo-hydroxyarene, was also found to beappropriate for the construction of the diaryloxyacetal sub-strates. The general conditions, described above, were ap-plied to phenols substituted with an electron-releasing orelectron-withdrawing group (Scheme 7). 4-Methoxy-2-bro-mophenol (46) and 4-fluoro-2-bromophenol (50) were eachfacilely converted to the methylene methyl sulfide deriva-tives 47 (81 %) and 51 (97 %), respectively, then to themethylene 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. Thesynthetic 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 %).
With the ortho-bromo activated diaryloxyacetals sub-strates in hand, several methods to effect cyclisation todibenzo ACHTUNGTRENNUNG[1,3]-dioxepines were conceivable, which includeddirect arylation[30] or Heck-type cyclisation.[31] However, ourinterest was piqued by recent reports of a technique thatused alkali metal tert-butoxides in conjunction with a dia-mine as a radical initiator.[32] The combined effects of these
Table 1. Domino Stille–Kelly and boronation–Suzuki coupling to form dioexpine 34
Metal[a] Catalyst[b] Ligand, ([mol %]) Solvent T [8C] t [h] Yield [%]
1 Sn PdACHTUNGTRENNUNG(PPh3)4 – toluene 110 65 ND[b, c]
2 B PdACHTUNGTRENNUNG(dppf)Cl2[d] – DMSO 80 14 22[c]
3 B PdACHTUNGTRENNUNG(dppf)Cl2 dppf (5) DMSO 80 14 364 B PdACHTUNGTRENNUNG(PPh3)Cl2 PPh3 (10) DMSO 80 14 265 B PdACHTUNGTRENNUNG(OAc)2 GemPhos[e] (10) DMSO 80 14 106 B PdACHTUNGTRENNUNG(dppf)Cl2 EtOH (500) DMSO 80 14 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] .
Scheme 5. Modified synthesis of methylene chloride 36[28] and phenolicsubstitution. Conditions: a) NaH (1.2 equiv), ClCH2SCH3 (1.5 equiv),DMF, 0 8C to rt, 12 h, 95– quant (2.0–2 0 mmol scale); b) SO2Cl2
(1.25 equiv), CH2Cl2, 0 8C to rt, 1 h, quantitative; c) Phenol (1.1 equiv),K2CO3 (2.0 equiv), then 36, DMF, rt, 12 h, 77 %.
Scheme 6. Synthesis of diphenoxy acetals. Conditions: a) Phenol (1.1 equiv), K2CO3 (2.0 equiv), then 36, DMF,40 8C, 24 h, 75–82 %.
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FULL PAPERSelective Synthesis of 2,2'-Biphenols
reagents are to convert the bromo substituent to a highly re-active radical intermediate, which becomes arylated bya formal homolytic aromatic substitution (HAS) pathway;[33]
in some cases, as here, cyclisation is effected.[34]
When the reaction conditions for the test system of acti-vated dioxyacetal 37 (Scheme 8) were optimised (Table 2), itwas found that the best solvent was pyridine. Treatment of37 with potassium tert-butoxide (3 equiv) and 1,10-phenan-throline (40 mol %) in pyridine at 100 8C for 2 h provideda much larger conversion to 34 (68 %; Table 2, entry 3) thanwhen toluene (4 %; Table 2, entry 1), mesitylene (12 %;Table 2, entry 2) or collidine (44 %; Table 2, entry 4) wereused as the solvent. The temperature had some effect uponboth the conversion and selectivity of the reaction, althoughthe number of equivalents of butoxide apparently did not(Table 2, entry 5 versus 6 and 7). An interesting note is theapplication 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
alkali metal are in a non-planarconfiguration and possessa twist-angle other than thestandard 1808. This diamine ap-peared, by sight, to catalyse theformation of the deep-redwithin the reaction solution im-mediately upon addition atroom temperature. Also of noteis the unusual selectivity pro-moted between the dioxepineproduct 34 and byproduct 2-phenylphenol (63) when cata-lyst 65 was used (Table 2,entry 8; 34/63= 1:1). Formationof 63 is least prevalent underthe optimal conditions for theformation of dioxepine 34(Table 2, entry 5; 34/63=9:1).
In addition to the desiredortho substitution, achieved viathe radical intermediates 66
and 67 a (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 67 b,similar to observations of Charette (conversion of 68 to 70 aand 70 b ; Scheme 9)[34a] and are in agreement with the mech-anism postulated by Studer and Curran.[33c] Intermediate67 b could be converted by radical C!O transposition, de-scribed by Alabugin and co-workers.[35] Although sucha transformation of a carbon- to an oxygen-centred radicalmay be endothermic, the generation of 63 could, nonethe-less, be favoured by irreversible fragmentation of 67 c to rel-atively stable phenoxy radical 67 d and formaldehyde.
With optimal conditions for the cyclisation established onthe 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 homolyticcleavage was located on the phenyl ring of the substrate (37,
Scheme 8. Dibenzo ACHTUNGTRENNUNG[1,3]dioxepine and byproduct synthesised under theconditions described in Table 2.
Table 2. Optimisation of the HAS cyclisation.
Solvent[a] KOtBu[equiv]
Ligand([mol %])
T[b]
[8C]t[min]
37[c] 34[c] 63[c]
1 toluene 3.0 64 (40) 100 120 96 4 02 mesitylene 3.0 64 (40) 100 120 86 12 23 pyridine 3.0 64 (40) 100 120 15 68 174 collidine 3.0 64 (40) 100 120 47 44 95 pyridine 3.0 64 (40) 120 120 15 77 86 pyridine 3.0 64 (40) 80 240 60 33 77 pyridine 1.0 64 (40) 120 120 19 69 118 pyridine 3.0 65 (40) 120 120 0 51 49
[a] Dried solvent. [b] Heating was by microwave (MW) irradiation.[c] Values are conversions, determined by HPLC analysis of the reactionmixtures.
Scheme 7. Conditions: a) NaH (1.2 equiv), ClCH2SCH3 (1.5 equiv), DMF, 0 8C to rt, 12 h; b) SO2Cl2
(1.25 equiv), CH2Cl2, 0 8C to rt, 1 h; c) phenol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride,DMF, 40 8C, 24 h; d) 1-naphthol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride, DMF, 40 8C,24 h; e) 2-naphthol (1.1 equiv), K2CO3 (2.0 equiv), then aryloxymethylene chloride, DMF, 40 8C, 24 h.
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39, 41, 43 and 45 ; Scheme 10) the reaction progressed well,with good conversions and moderate yields of products 34and 71–75 (49–63 %). In contrast, when the radical-bearingsubstituted aryl group of 49 and 53 was the initial radical-bearing half of the molecule the yields of 71 and 73 weremuch 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 substrates39 and 43 when the reaction time was shortened to 6 min.Significant among these results is the ready cyclisation of 41to form the potentially-chal-lenging 1-oxy-2-methyl biarylmotif, a common feature insome of the end-target naturalproducts (e.g., 4–6, Scheme 1).
The generation of a 1:1 mix-ture of the regioisomeric defor-mylated dibenzo ACHTUNGTRENNUNG[1,3]dioxepineproducts 74 and 75 is intriguing;cyclisations of this type typical-ly exhibit a clear selectivity forthe ortho-substituted product,in this case 74. There are sever-al potential explanations (forexample, deformylation andcyclisation as discrete events)and there is always the possibil-ity that the regioisomeric ratioof 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-cal cyclisation of 32 to 34, albeit
in lower yield (28 %) than the model system. It appears thateither 1) the brominated carbon atom can also function asa valid point of attack for the radical anion, followed by theloss of a bromonium species rather than a proton, or
2) the cyclisation occurs at an unsubstituted ortho positionof the aryloxy unit and bromide is reduced under the radicalconditions either before or after this cyclisation.
Cyclisation of the dinaphthyloxy acetals delivered the de-sired dioxepine-centred products 76–79 (Scheme 11), albeitwith slightly lower yields (38–46 %) than for the diphenoxyacetals, and after extended reaction times (120 rather than60 min as standard). In the case of the 2,2'-dioxy-substitutedsubstrate 61, cyclisation occurred at the two available ortho
Scheme 10. Cyclisation of diphenoxy acetals. Conditions: KOtBu (3.0 equiv), 1,10-phenanthroline (40 mol %),pyridine and MW at 120 8C for a) 120 min, b) 6 min, c) 240 min.
Scheme 9. Competing ortho-7-exo and ipso-6-exo cyclisation pathways.
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positions and led to a mixture of BINOL precursor 77 andasymmetric dioxepine 78. A consistent ratio of 77/78= 2:1was obtained across a variety of reaction times; a doublingof 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 intheir structures), which is surprising given the axially-rotatednature of 77.
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 NMRspectra.[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 thetwo resonances. One case in which neither of these explana-tions seems probable is with 1,4-dimethyldibenzo ACHTUNGTRENNUNG[d,f]-ACHTUNGTRENNUNG[1,3]dioxepine (72) [Scheme 10], which has a significantasymmetric nature and the added steric interaction of themethyl substituent neighbouring the biaryl axis. Much to oursurprise, the 1H NMR spectrum (500 MHz, CDCl3) of thiscompound also exhibits a singlet resonance at d=
5.54 ppm.[37] To ascertain if the protons were equivalent dueto 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 theunsubstituted case, 34 (bridged biphenyl), the barrier is verysmall and rotation about the central phenyl–phenyl bondoccurs at low temperatures. For dioxepine 72, a higher barri-
er of around 50 kJ mol�1 was found. Comparison with recentinvestigations on the atropisomerisation of bridged biphen-yls[38] suggests that the interconversion of this compound canbe monitored by dynamic NMR spectroscopic measure-ments, which means that the rotation of the phenyl rings isstill fast. The activation barrier can be further enlarged bysymmetric substitution with methyl groups (e.g., in 80) toyield a barrier of around 150 kJ mol�1 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 derivedfrom cyclisation in ethanolic hydrochloric acid solutions de-livered the corresponding ortho,ortho-dihydroxy biaryls (1and 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, 120 8C,120 min, b) KOtBu (3 equiv), 1,10-phenanthroline (40 mol %), pyridine,MW, 120 8C, 240 min, c) KOtBu (3 equiv), 65 (40 mol %), pyridine, MW,120 8C, 240 min< .
Table 3. Computed activation barriers [kJ mol�1] for rotation about thebiaryl bond.
Compound TPSS/TZVP B3LYP/TZVP
34 2 6
72 46 54
80 152 167
Figure 1. B3LYP-optimised geometries of the equilibrium (left) and tran-sition states (right) of the investigated dioxepine compounds.
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donating, -withdrawing or sterically demanding). One note-worthy observation was that the time required for hydrolysisvaried somewhat, from 3 to 36 h: the most rapid reactionwas for the intrinsically strained BINOL acetal 77. The useof methanolic acid solutions, at slightly increased concentra-tion due to solubility issues, was equally valid. This pointmay become pertinent in future studies with xanthonedimers (e.g., 4–10, Scheme 1), the majority of which possesspotentially hydrolytically unstable methyl ester groups.
Conclusion
We have established a reliable method for the ortho-selec-tive formation of heterodimeric 2,2'-biphenols. Future workto investigate the acetal concept will involve application tothe synthesis of natural products, use of novel ligands basedon the ortho,ortho-dihydroxy biaryl motif, and attempts toapply transition-metal catalysis to improve the yield of theinitial dibenzo ACHTUNGTRENNUNG[1,3]dioexpine products. The development ofa coupling without the need for an activating group (in thiscase, a bromo substituent) would also be advantageous.Most exciting of all would be application of one of the lattertwo methodologies in conjunction with chiral ligands toinvoke axial chirality, which is found in many of the naturalproducts with a central ortho,ortho-biphenol motif.
Experimental Section
Computational Details : All quantum chemical calculations presented inthis 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 quadraturegrids (m5)[43] were employed. In the case of TPSS, the efficient resolutionof the identity approximation for two-electron Coulomb integrals wasused. The nature of the stationary points (minima and transition states)was confirmed through the calculation of vibrational frequencies. Thegiven activation barriers are computed from the zero-point vibrationalenergy corrected electronic energies and thus correspond to DH� ACHTUNGTRENNUNG(0 K).
General procedure for the synthesis of 2-bromoaryloxymethyl methyl sul-fides : Sodium hydride (1.20 equiv, 60 % dispersion in mineral oil) wasadded to a stirred solution of bromophenol (1.00 equiv) in anhydrousDMF (7.5 mL/mmol) at 0 8C (ice bath) under an inert atmosphere. After
the mixture was stirred at 0 8C for 30 min, chloromethyl methyl sulfide(neat, 1.50 equiv) was added dropwise. The reaction mixture was allowedto 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). Thecombined organic layers were washed with brine, dried over anhydrousNa2SO4, 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 0 8C (ice bath), then the cooling bath was removed. After the mixturehad been stirred at rt for 1 h, the volatile compounds were removedunder reduced pressure on a rotary evaporator located in a fume cup-board to give the corresponding methylene chloride as a pale-yellow ororange oil in quantitative yield and of sufficient purity to be used directlyin the next step. When storage was necessary, the compounds were foundto be stable for 6+ months under an inert atmosphere at �20 8C.
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) inDMF (5 mL/mmol phenol) at rt under an inert atmosphere. The reactionmixture was warmed to 40 8C and stirred for 24 h. The crude mixture wasthen loaded onto a long column of silica gel and eluted with cyclohexane,then a mixture of cyclohexane/ethyl acetate to deliver the pure biaryloxyacetal.
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 removedby vacuum, with stirring. The atmosphere was then replaced with argonand purged after evacuation (� 3). The reaction mixture was heated to120 8C by microwave irradiation for 120 min. After this time, the blood-red reaction mixture was allowed to cool to rt, then filtered througha short column of silica gel with ethyl acetate (50 mL). The volatile com-pounds were removed under reduced pressure then the crude productwas purified by column chromatography on silica gel with a mixture ofcyclohexane/dichloromethane.
General procedure b for the synthesis of dibenzo-[1,3]-dioxepines : As forgeneral 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 forgeneral procedure a, except with 240 min of heating by microwave irradi-ation.
General procedure d for the synthesis of dibenzo-[1,3]-dioxepines : As forgeneral 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.
General procedure for the hydrolysis of dibenzo-[1,3]-dioxepines to or-tho,ortho-biphenols : Concentrated HCl (aq) [0.20 mL/mL ethanol] wasadded dropwise a stirred solution of the dioxepine in ethanol (0.10 m).The cloudy reaction mixture was heated to 50 8C in an oil bath, thensealed with a septum. The reactions were monitored by TLC to detectconsumption of the starting material, and it was noted that once the sub-strate is consumed the reaction mixtures became optically clear. Reactiontimes varied greatly, depending on the nature of the substrate. When thereaction was complete, silica gel was added to the flask and the volatilecompounds were removed under reduced pressure. The crude productwas purified by column chromatography on silica gel with mixtures of cy-clohexane/ethyl acetate.
Scheme 12. Hydrolysis of selected dibenzo ACHTUNGTRENNUNG[1,3]dioxepines to delivertarget ortho,ortho-dihydroxyarenes. Conditions: HCl(aq)/EtOH (1:5) orHCl(aq)/MeOH (1:7), 50 8C, 4–36 h.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaftthrough theCenter for Functional Nanostructures (CFN, project no. C3.3). K.-S.M.would like to acknowledge the generous funding and support providedby the Alexander von Humboldt Foundation and Ms. Karolin Niessnerfor providing valuable analytic data.
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Received: May 22, 2013Published online: November 21, 2013
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FULL PAPERSelective Synthesis of 2,2'-Biphenols