Patent Application
20050165185
The present invention relates to a method for preparing a conjugated molecule such as a conjugated polymer or oligomer (in particular a polyaryl, polyheterocycle (e.g. polyheteroaryl) or oligoheterocycle including a block oligoheterocycle) comprising an improved coupling step.
Electroactive materials such as polyheteroaryls and oligoheteroaryls are gaining widespread academic and commercial interest due to their optical and electronic properties which may allow exploitation in electronic devices such as transistors (e.g. field effect transistors FETs useable in mobile phones, calculators, smart cards, etc) and LED's. For example, organic semiconductors have the potential advantage over inorganic semiconductors of low cost fabrication and patterning, large area fabrication and greater scope for tuning. Alternatively, synthesis from acyclic precursors can lead to high purity compounds but can be highly convoluted and significant material losses must be tolerated.
Successful organic semiconductors are likely to have a significant degree of control in regioregularity so as to allow efficient alignment and ordering in the solid state. As electrical performance of such materials improve, their manufacture is set to become one of the major speciality chemical opportunities of this century.
Although solution phase chemistry may be used to target polyheterocycles and oligoheterocycles using repetitive coupling reactions, the purification strategies required to meet the requisite levels of purity are inefficient rendering the methods of questionable commercial applicability. Moreover conventional methods for preparing oligoheterocycles (such as oligothiophenes) using solution phase cross-coupling (e.g. Suzuki, Kharasch, Stille or Negishi type processes) are plagued by undesirable side reactions such as homocoupling and loss of functional groups making purification arduous and inefficient.
It is desirable therefore to provide a process which allows control over the number of monomer units incorporated into the oligomer chains and/or the sequence of monomer units if more than one type of monomer unit is present.
The advantages of solid phase chemistry, i.e. chemistry using solid supports, over solution phase chemistry include ease of purification, amenability to automation, the ability to use excess reagents to drive reactions to completion without the penalty of making purification tedious and dilution effects (site isolation) which prevent homocoupling. For these reasons, solid phase synthesis is seen as an attractive alternative for preparing polyheterocycles and oligoheterocycles on a large scale but as yet has undergone little investigation. Synthesis on a solid polymer support necessitates two additional steps to solution phase synthesis, namely covalent attachment of the first monomer to the support via a linker and cleavage of the polymer from the support.
It is desirable that on cleavage the linker group be eliminated from the conjugated molecule and optionally replaced by a functional group for use in a further reaction.
One drawback of the application of solid phase synthesis is that on cleavage from the resin/linker an undesirable functional group may be left on the molecule that may be deleterious to the performance of the polymer material. Attachment in known processes is typically via “protecting group” based linkers meaning that a functional group (e.g. OH, COOH) incorporated in the first monomer is regenerated on polymer cleavage. Such functionality may be undesirable for the envisaged applications. For example, Malenfant and Fr{dot over (e)}chet, Chem. Commun, 1998, 2657-2658 disclose the synthesis of asymmetric oligothiophenes bound by an ester linkage to a chlormethylated macroporous resin using alternating bromination and Stille coupling reactions. Malenfant utilizes a Wang resin (1 in
Thus viewed from one aspect the present invention provides a method for preparing a conjugated molecule comprising a first monomer coupled to a second monomer, said method comprising:
By ipso-degermylation is meant replacing the germyl group by a proton or other group which may be a functional group permitting further reaction.
The product may be a homopolymer or copolymer.
Preferably the solid phase synthesis of the conjugated molecules such as polyaryls or polyheterocycles is improved by using a “double coupling strategy” which permits multiple coupling reactions for a single coupling step such that the level of coupling may be driven to high levels to increase purity of the final product. The present invention also provides a solid phase synthesis of conjugated molecules in which a first monomer linked to a solid support by a germyl linking group is coupled to a protected second monomer whose protecting group renders the coupled product inert to subsequent coupling.
Thus, in such solid phase chemistry a solid support which comprises bound germyl linking groups is coupled with the first monomer optionally in at least two successive stages to maximise the proportion of the germyl groups so coupled with the first monomer and coupling of each monomer (or subsequent oligomer) linked to the support to subsequent protected monomers may be carried out in at least two successive stages to maximise the proportion of the linked monomer or oligomer which is reacted. Should a coupling group be lost before completion of the reaction with the second or subsequent monomer it is preferable, if possible, to reform the group and to react again with the said monomer until the desired product is obtained. By these means the uniformity of the product is maximised.
The term conjugated molecule is intended to cover high or low molecular weight polymers and co-polymers including oligomers and co-oligomers. Preferably the conjugated molecule is a conjugated oligomer. Typically the method may be used to synthesise a range of conjugated molecules from simple dimers to more complex block co-polymers (such as block co-oligomers).
The term monomer is intended to cover single monomer units or a block of monomer units.
In an embodiment of the invention, each of the first, second and nth monomers are capable of contributing to the-system of the conjugated molecule. For example, the first, second and nth monomer may be independently selected from the group of monomer units consisting of an unsaturated monocyclic or polycyclic (e.g. fused polycyclic) hydrocarbon (e.g. a carboaromatic) monomer unit which is optionally ring substituted, an unsaturated monocyclic or polycyclic (e.g. a fused polycyclic) heterocyclic (e.g. heteroaromatic) monomer unit which is optionally ring substituted, an unsaturated acyclic hydrocarbon bridging monomer unit and a heteroatomic (or polyheteroatomic) bridging monomer unit. The first, second and nth monomer may be the same or different. Optional ring substituents may be chosen to enhance the electronic (or other) properties of the conjugated molecule (e.g. a substituent which has an electron withdrawing or donating effect).
Preferably the conjugated polymer is a polyheterocycle, wherein at least one of the first, second and nth monomers (preferably at least the first monomer) is an optionally ring substituted heterocyclic monomer unit. Preferably more than one of (e.g. all of) the first, second and nth monomers is an optionally ring substituted heterocyclic monomer unit. Preferably at least one of the first, second and nth monomers is a 5- or 6-membered optionally ring substituted heterocyclic monomer unit. The optionally ring substituted heterocyclic monomer unit may contain one, two or three heterocyclic atoms which may be the same or different. Preferably the (or each) heterocyclic atom is selected from the group consisting of nitrogen, sulphur, oxygen, phosphorous and selenium, preferably the group consisting of nitrogen, oxygen and sulphur, particularly preferably the group consisting of nitrogen and sulphur.
The term polyheterocycle is intended to cover high or low molecular weight polymers and co-polymers including oligomers and co-oligomers. Preferably the polyheterocycle is an oligoheterocycle. Typically the method may be used to synthesise a range of polyheterocycles from simple dimers to more complex block co-polymers (including block co-oligomers).
Preferably at least one of the first, second and nth monomers (preferably at least the first monomer) is an optionally ring substituted unsaturated monocyclic or polycyclic (e.g. fused polycyclic) hydrocarbon (e.g. a carboaromatic) monomer unit. For example, the conjugated molecule may be a polyaryl. Particularly preferably at least one of the first, second and nth monomers is an optionally ring substituted phenylene, styryl or anilino monomer unit suitably of formula —Ar′NAr ′″Ar″— is present, the groups Ar′, Ar′″ and Ar″ being aryl groups, in which the aryl groups may be phenyl groups. Ar′″ may be substituted (e.g. o- or p-substituted) with a group which has an electron withdrawing or donating effect.
Preferably at least one of the first, second and nth monomers is an unsaturated acyclic hydrocarbon bridging monomer unit selected from the group consisting of alkeno and alkyno bridging monomer units. Preferably the unsaturated acyclic hydrocarbon bridging monomer unit is of formula [CR═CR]n (where n is 1 to 5, preferably 1 to 3 and R is hydrogen or a C1-6-alkyl group) or [C≡C]m (where m is 1 to 3). Preferred examples are etheno, ethyno and buta[1,3]dieno bridging monomer units.
By way of example, at least one of the first, second and nth monomers, i.e. any of the monomers, is selected from the group of monomer units consisting of optionally ring substituted thiophene, furan, pyridine, imidazole, isothiazole, isooxazole, pyran, pyrazine, pyridazine, pyrazole, pyridine, pyrimidine, triazole, oxadiazole, pyrrole, indazole, indole, indolizine, pyrrolizine, quinazoline, quinoline and phenyl. Preferably at least one of (preferably more than one of) the first, second and nth monomer units is selected from the group consisting of optionally ring substituted thiophene and pyridine and particularly preferably is thiophene which may be substituted at the 3- or 4-position with an alkyl group (e.g. a C1-12-alkyl such as a hexyl or octyl) or an aryl (e.g. a phenyl) group.
If desired at least one of the first, second and nth monomers (preferably the first and second monomer) may be a block of monomer units, each monomer unit being as hereinbefore defined.
The conjugated molecule typically comprises up to 20, preferably up to 10 monomer units.
Two directional synthesis may be possible if the first monomer has two reactive positions. For example, where the first monomer is thiophene linked to germanium at the 3-position, it may be possible to simultaneously couple at positions 2- and 5-without separate synthetic steps.
Although any suitable protecting group may be used to protect the non-coupling position of the second monomer, silyl based protecting groups are preferred to exploit favourable differences in reactivity between germanium and silicon. Examples include Me3Si (TMS), Et3Si, iPr3Si, Me2tBuSi, Me2PhSi. A particularly preferred example is TMS (trimethyl silane) or tert. butyl dimethyl silane. Corresponding silyloxy groups may also be used.
Step (D) may be carried out before, after or simultaneously with step (E) leading to symmetrically end functionalised or—telechelic molecules with useful end functionality. A silyl protecting group may be removed in step (C) nudeophilically with basic sources (e.g. K3PO4 or Cs2CO3) and/or fluoride sources (e.g. CsF or nBu4NF) or electrophilically (e.g. using electrophiles described below).
The ipso-degermylation of step (D) may be ipso-protodegermylation or electrophilic ipso-degermylation (e.g. ipso-halodegermylation).
By way of example, ipso-protodegermylation may be carried out using a strong organic acid (for example trifluoroacetic acid (TFA), HCO2H, ACOH, ClCH2CO2H or Cl2CHCO2H), a mineral acid (for example HCl, H2SO4 or HF) or a source of fluoride ions (for example CsF or Bu4NF) with conditions generally milder than those used for removal of the protecting group for example a silyl group.
Electrophilic ipso-degermylation may be carried out using a source of halonium ions (F+, Cl+, Br+ or I+), NO+, NO2+, SO3+, RCO+, RSO2+, BHal2+(e.g. BCl2+) or B(OH)2+. Where conditions are mild, the protecting group may be left intact to release a protected conjugated molecule. Subsequent removal of the protecting group in step (C) using a different electrophile leads advantageously to an unsymmetrical conjugated molecule. Under more forcing conditions, the protecting group may be removed simultaneously (e.g. electrophilic ipso-desilylation) advantageously releasing a symmetrically end functionalised conjugated molecule.
ipso-halodgermylation may be carried out using a source of halonium ions (X+). For example, ipso-bromodegermylation may be carried out using a source of bromonium ions (Br+) such as bromine or N-bromosuccinimide (NBS), ipso-iododegermylation using a source of iodonium ions (I+) such as iodine, ICI or N-iodosuccinimide (NIS) and ipso chlorodegermylation using a source of chloronium ions (Cl+) such as N-chlorosuccinimide (NCS), dichloramine-T or chlorine. In the case of polymers and oligomers which are not adversely affected by oxidising conditions an advantageously cheap and therefore preferred step for preparing halonium ions is to use a group I metal halide together with an oxidant. For example, NaBr may be used with an oxidant such as H2O2 or (preferably) dichloramine-T to produce bromonium ions.
In a preferred embodiment, step (E) comprises:
This embodiment advantageously releases block co-oligomers with varying (but precisely defined) topology. Preferably compound AY is a functionalised block conjugated polymer (or a functionalised block conjugated oligomer) wherein the block conjugated polymeric group Y is preferably a block of monomeric units as hereinbefore defined. For example, group Y may be a dimeric, trimeric, tetrameric, pentameric or hexameric thiophene or pyridine block. Functionality A is typically bromine or iodine preferably bromine.
New C—C bonds may be advantageously formed by ipso-degermylative cleavage to leave an end capping group which may be tailored to introduce desirable electronic properties to the conjugated molecule. For example, ipso-degermylation may be carried out using a source of acylium ions such as a Freidel-Crafts reagent (e.g. carboxylic acid chloride and Lewis acid) to leave a ketone end group. For example, ipso-degermylation may be carried out using germyl-Stille type cleavage with an aryl, heteroaryl, vinyl, benzyl, allyl, alkynyl or propargyl halide (I, Br or Cl), sulphonate ester (triflate, nosylate, mesylate or tosylate) or diazonium salt (N2+) in the presence of a catalytic amount of Pd(0) having suitable ligands (e.g. phosphine ligands) and a reagent capable of rendering germanium hypervalent (e.g. a source of fluoride ions such as CsF or Bu4NF) to leave an aryl, heteroaryl, vinyl, benzyl, allyl, alkynyl or propargyl end group respectively. Generally ipso degermylative cleavage may be carried under conditions suitable to leave the protecting group intact. This may be followed by electrophilic removal of the protecting group (step (D)) with an electrophilic group as described above or nucleophilic removal of the protecting group with a base (e.g. CsF or K3PO4) to give unsymmetrical conjugated molecules.
Electrophilic ipso-degermylation advantageously leaves end functionality on the conjugated molecule which subsequently may be displaced by groups chosen to enhance the properties (e.g. electroactive properties) of the conjugated molecule. For example, the end functionality may be tailored to facilitate solution phase synthesis of block co-oligoheterocycles thereby giving greater versatility in preparing potentially useful electroactive materials.
Thus in a preferred embodiment, step (E) comprises:
Preferably end functionality E is other than an end carboxyl (or a derivative (e.g. ester)) thereof. Particularly preferably the end functionality E is bromine, iodine or a boronic group such as boronic acid groups or derivatives thereof (e.g. ester derivatives thereof). Preferred are boronic acid groups of formula —B(OR)n (as defined hereinafter), particularly preferably B(OH)2.
Group Y′ may be an end capping group such as a linear or branched alkyl (e.g. C1-6-alkyl), aryl, benzyl, vinyl, propargyl, allyl or alkynyl group or a conjugated molecule such as an oligoheterocydic group.
Preferably compound A′Y′ is a functionalised block conjugated polymer (or a functionalised block conjugated oligomer) wherein the block conjugated polymeric group Y′ is preferably a block of a conjugated molecule as hereinbefore defined. For example, group Y′ may be a dimeric, trimeric, tetrameric, pentameric or hexameric thiophene or pyridine block. Functionality A′ is typically bromine, iodine or a metallic for example a organometallic functionality such as an organoboron, organomagnesium, organozinc or organotin functionality. Preferred is a boronic functionality (e.g. an organoboron functionality —B(OR)n as defined hereinafter), particularly preferably B(OH)2. In this embodiment, step (D) may be carried out in the presence of a catalyst such as palladium or nickel.
It will be appreciated that this embodiment permits the synthesis of block conjugated molecules with a variety of precisely defined topologies. For example, it would be possible to synthesise a range of block conjugated co-oligomers such as PY′, PY′P, PY′P′(wherein P and Y′ are as hereinbefore defined and P′ which is different to P is a block of monomer units as hereinbefore defined).
The precise conditions for the ipso-degermylation of step (E) may be optimised by the skilled person to reflect its sensitivity to the electronic nature of the conjugated (e.g. heterocyclic) system. For example, electron rich heterocycles such as thiophene generally cleave most readily whereas electron deficient heterocycles such as pyridine require more forcing conditions. Moreover the conditions can be tailored to carry out step (D) before, after or simultaneous with step (E).
Step (B) may be carried out using a suitable coupling protocol. Many such protocols are established in the art and will be familiar to the skilled person (see inter alia Loewe at al, Adv. Mater. 1999, 11, 250-257). These include Suzuki, Kharasch (e.g. McCullough), Stille and Negishi type reactions, preferably Suzuki or Kharasch type reactions. Step (B) is typically carried out in the presence of a transition metal catalyst such as nickel or (preferably) palladium.
In a preferred embodiment, step (B) further comprises:
This embodiment relies on the fact that the immobilised first monomer may be selectively halogenated in the coupling position without ipso-degermylative cleavage.
Prior to step (B1), the method may further comprise: (B0) lithiating the first monomer for example using nBuLi or lithium disopropylamide (LDA) in the coupling position.
Step (B1) may be carried out using bromine, iodine (e.g. in the presence of a mercury salt such as acetate or hexanoate) or (preferably) a milder source of iodonium ions. The source of iodinium ions is preferably 1,2-diiodoethane. Particularly preferably halogenation with 1,2-diiodoethane is carried out in reduced ambient light (e.g. in darkness). Particularly preferably halogenation is carried out with 1,2-diiodoethane in an amount at least one fold excess of the amount of lithiating agent (preferably LDA) used in step (B0).
In an alternative embodiment, step (B) comprises:
The alternative embodiment relies on the fact that the immobilised first monomer may be selectively metallated (or transmetallated) in the coupling position without ipso degermylative cleavage. For example, the immobilised first monomer may be transmetallated using nBuLi and an organometallic transmetallating compound.
In a preferred alternative embodiment, step (B1′) comprises: (B1′a) lithiating the first monomer at the coupling position (for example in the presence of nBuLi) and (B1′b) transmetallating the first monomer at the coupling position. The first monomer is advantageously stable to strong bases such as nBuLi. For pyridine and thiophene, this generally leads to lithiation and transmetallation at the coupling position adjacent the heterocyclic atom.
The first or second monomer may be metallated (or transmetallated) at its coupling position with a metallic group e.g. an organometallic group. For example, the metallic group may be selected from organoboron, organomagnesium, organotin and organozinc groups. Preferred are organoboron groups such as boronic acid groups or derivatives thereof (e.g. ester derivatives thereof). Particularly preferably the organoboron group is of formula:
—B(OR)n
(wherein: n is 2 or 3; and each R is independently hydrogen or an optionally substituted linear or branched C1-6-alkyl group or two groups R represent an optionally substituted alkano bridging group between two oxygen atoms).
For the purposes of this specification we define boron as being a metal.
For example, two groups R may represent an optionally substituted ethano or propano bridging group between two oxygen atoms. Preferred is an ethano bridging group between two oxygen atoms which is preferably dialkyl (e.g. dimethyl) substituted at each carbon.
Preferred is a hypervalent boronate complex or a boronic ester group (or a hypervalent complex thereof). It is advantageous to use a weak base (e.g. NaHCO3). Particularly preferred is a hypervalent boronate complex which advantageously does not require the addition of base (and therefore essentially does not remove any silyl protecting group). The hypervalent boronate complex may be a hypervalent alkyl boronate complex with a suitable metal counterion (e.g. Na or (preferably) Li). Preferred is the hypervalent ethyl boronate complex, particularly preferably in the absence of a base.
Certain of the hypervalent organoboron intermediates useful as first and/or second monomers in the method of the invention may lead to improved coupling and being novel are therefore patentably significant per se.
Viewed from a further aspect the present invention provides a compound of formula:
[X—B(OR)3]M
wherein:
The group B(OR)3 may include a pinacolato group. For example, two groups R may represent an optionally substituted ethano or propano bridging group between two oxygen atoms. Preferred is an ethano bridging group between two oxygen atoms which is preferably dialkyl (e.g. dimethyl) substituted at each carbon.
In a preferred embodiment, each R is the same and is a C1-6-alkyl group. The hypervalent boronate complex of this embodiment advantageously does not require the addition of base (and therefore is not susceptible to removal of any silyl protecting group). Particularly preferred is the hypervalent ethyl boronate complex (ie R is ethyl).
Group X may be an optionally ring substituted heterocyclic moiety. The heterocyclic moiety may contain one, two or three heterocyclic atoms which may be the same or different. Preferably the (or each) heterocyclic atom is selected from the group consisting of nitrogen, sulphur, oxygen, phosphorous and selenium, preferably the group consisting of nitrogen, oxygen and sulphur, particularly preferably the group consisting of nitrogen and sulphur. Preferably the heterocyclic moiety may be a 5- or 6-membered optionally ring substituted heterocyclic moiety.
By way of example, the heterocyclic moiety may be selected from the group consisting of optionally ring substituted thiophene, furan, pyridine, imidazole, isothiazole, isooxazole, pyran, pyrazine, pyridazine, pyrazole, pyridine, pyrimidine, triazole, oxadiazole, pyrrole, indazole, indole, indolizine, pyrrolizine, quinazoline, quinoline and phenyl. Preferably the heterocyclic moiety is selected from the group consisting of optionally ring substituted thiophene and pyridine and particularly preferably is thiophene which may be substituted at the 3-position with an alkyl group (e.g. a C1-8-alkyl such as a hexyl or octyl) or an aryl (e.g. a phenyl) group.
The counterion M may be a suitable metal counterion (e.g. Na or (preferably) Li).
The solid support may be any support compatible with the chosen parameters (e.g. solvent, temperature, reagents) and with chosen methods for monitoring the progress of the coupling reaction (e.g. IR or MAS NMR). Suitable solid supports may be surfaces, beads or fibres and will typically be polymeric including resins (preferably macroporous resins), tentagels or polystyrenes. The resins may be hydroxy functionalised (e.g. polyethyleneglycol based resins such as ARGOGEL™) or chloromethylated (e.g. chloromethylated polystyrene) to facilitate linking step (A).
In a preferred embodiment, step (A) comprises:
The immobilised germyl linking group may be pre-prepared on the solid support or prepared in situ as desired. For example, an immobilised germyl linking group may be prepared from a solid support (e.g. resin) pre-functionalised with germanium. By way of example, a pre-prepared germane-containing styrenyl monomer may be copolymerised with styrene using a cross linker to give germanium functionalised polystyrene which may be straightforwardly activated for carrying out step (A2).
For step (A2), suitable reagents and conditions will be familiar to the skilled person and guidance may be found inter alia in Denat et al, Synthesis, 1992, 954-956 and Lukevics et al, J. Organomet. Chem., 1988, 20, 69-210.
The first monomer may be metallated (preferably lithiated) and reacted with the immobilised germyl linking grouping in step (A2). For this purpose, the immobilised germyl linking group has a suitable leaving group which is preferably chloride. The first monomer may be metallated in the chosen position (e.g. 2-, 3- or 2- and 5-positions of thiophene, pyrrole and furan and 2- or 3-positions of pyridine) whilst optionally protecting other positions. The chosen position may (for example) be metallated directly (e.g. lithiated directly using LDA) or by halogen-metal exchange of a halogen-substituted (e.g. bromo-substituted) first monomer (e.g. using n-BuLi). The germanium of the immobilised germyl linking group may be bound to an electronegative group to assist linking step (A2).
Alternatively the first monomer may be linked in step (A2) by cross-coupling. For this purpose, the first monomer may be halogenated. The first monomer may be halogenated in the chosen position (e.g. 2-, 3- or 2- and 5-positions; of thiophene, pyrrole and furan and 2- or 3-positions of pyridine) whilst optionally protecting other positions. Such a cross-coupling reaction is typically mediated by a Pd(0) catalyst in the presence of a mild base.
Step (A1) may comprise:
Suitable immobilisable germyl linkers and methods for carrying out steps (A1), (A1′) and (A2) will generally be familiar to the skilled person and guidance may be found in inter alia Spivey et al, Chem Commun., 1999, 835-836 and Spivey et al, J. Org. Chem., 2000, 65, 5253-5263.
Typically the immobilisable germyl linker is derivable from GeCI4 and may be of formula:
ZGeR2X
wherein:
each group R which may be the same or different is an alkyl (such as methyl, ethyl, butyl or isopropyl), aryl, CF3 or an electronegative group or precursor thereof;
Where X is H or a group MR′n, the first monomer may be linked in step (A2) via a cross-coupling reaction. For this purpose, the first monomer may be halogenated and reacted with the immobilised germyl linking group. Preferably M is silicon, germanium or boron.
Preferably one group R is an electronegative group which advantageously improves the efficiency of subsequent germanium cleavage (such as germyl-Stille type cleavage) during linking step (A2). The electronegative group may be a non-carbon bound group such as an oxygen or nitrogen bound group or a halide. Preferably the electronegative group is an alkoxy or amino group. A preferred alkoxy group R is OR1 (wherein R1 is a C1-6-alkyl). A preferred amino group R is NR22 (wherein R2 is a C1-6-alkyl).
Where one group R is a precursor to an electronegative group, step (A2) is preceded by:
This embodiment usefully permits a stable immobilisable germyl linker precursor to be converted into an immobilised germyl linking group which undergoes more efficient cleavage during step (A2). Step (A0) may be carried out oxidatively (e.g. by Germa-Polonovoski or Germa-Pummerer type reactions).
Immobilising group Z may be adapted to undergo Mitsunobu or Williamson type immobilisation to the solid support. Suitable immobilising groups Z include for example an etherifiable group such as a hydroxylated group (e.g. a terminal hydroxy containing group) for immobilisation on a suitably functionalised resin by etherification. For this purpose, the solid (e.g. polymeric) support is functionalised (e.g. hydroxyl or chloromethyl functionalised). The suitability of immobilising group Z and the immobilisation conditions may be conveniently predetermined in solution by a Mitsunobu reaction using for example ethoxyethanol or by a Williamson reaction using for example 2-chloroethylethanol.
A solid support particularly useful for carrying out a process according to the invention is of formula X(OR—GeR1R2 Hal)n in which X is a high molecular weight material of low solubility in water and organic solvents, suitably a hydrocarbon resin substituted by alkoxy chains, for example polystyrene substituted by alkoxy, preferably propoxy or more preferably ethoxy or propoxy/ethoxy chains, R is a hydrocarbon group suitably having 1 to 12 and more preferably 3 to 10 carbon atoms, for example an alkyl, aryl group or arylalkyl group, the aryl group suitably comprising a benzene ring optionally substituted by alkyl groups, the Ge being preferably linked to an alkyl group, R1 and R2 individually being alkyl groups preferably having 1 to 6 carbon atoms and Hal representing a halide for example a bromide, iodide or preferably chloride atom and n being a large integer.
Protection/deprotection of the first monomer may facilitate the linking step (A). For example, a protecting group may be used to prevent unwanted lithiation at a specific position (e.g. the α-position) prior to step (A2). Although any suitable protecting group may be used, a trimethylsilyl, TMS, or tert. butyl dimethylsilyl, TBDMS, group is preferred and may be removed with familiar reagents such as a base e.g. K3PO4 or CsF prior to coupling step (B).
The invention thus provides a method for preparing a conjugated molecule comprising a first monomer coupled to a second monomer, said method comprising:
The present invention will now be described in a non-limitative sense with reference to the following Examples and the Figures in which:
Example 1 relates to a solution phase model of the solid phase synthesis of a high purity thiophene oligomer having well-defined regiochemistry using a germyl linker. Assembly of the oligomer is a stepwise process in which each monomer unit is added sequentially through repetitive transition metal mediated coupling to obtain highly pure and well-defined structures.
In order to compare materials obtained by the present method with conventional methods, it was decided to investigate the solution phase synthesis of hexylthiophene oligomers using a germyl linker 3 (see
There are a number of options available for step 5 depending on the intended use of the cleaved oligomer. Protocols that result in the cleavage of both symmetrically end-functionalised and—telechelic oligomers with various useful end-functionality are possible.
Cleavage by an electrophile E+(e.g. H+, I+, Br+, Cl+, F+, NO+, NO2+, SO3+, RCO+, RSO2+, BHal2+(e.g. BCI2+) or B(OH)2+) results in electrophilic ipso-degermylation to introduce substituent YE leaving the TMS blocking group intact (Y=RMe2Ge to Y=YE; Z=TMS). Under more forcing conditions both electrophilic ipso-degermylation and ipso-desilylation occurs giving symmetrically end-functionalised oligomer (Y=RMe2Ge to Y=YE and Z=TMS to Z=ZE where YE=ZE). The use of two different electrophiles sequentially gives an—telechelic oligomer (8n+1, Y=YE and Z=ZE where YE ZE). The use of an electrophile RCO+ in a Friedel-Crafts type ipso-degermylation is particularly attractive as subsequent reduction of the resulting ketone carbonyl to a methylene group (using for example LiAlH4-AlCl3) leaves an alkyl end-functionalised conjugated molecule. These are known to have favourable electronic properties (see for example Katz, Acc. Chem. Res., 2001, 45, 11).
Cleavage by a germyl-Stille type cross-coupling protocol introduces a C—C bond in place of the C—Ge bond leaving the TMS blocking group intact (Y=RMe2Ge to Y=YCC; Z=TMS). Potential cross-coupling partners for this type of cleavage are substrates that can undergo oxidative insertion of Pd(0) to yield an active Pd(II) intermediate as in a standard Stille-type cross-coupling. These include aryl, heteroaryl1 benzyl, allyl, propargyl, and alkynyl halides (e.g. I, Br, Cl), sulfonate esters (e.g. OSO2CF3, OSO2CH3, OSO2p-Tol), and diazonium salts (N2+). Cleavage in this fashion could be followed by electrophilic ipso-desilylayion as described above (Z=TMS to Z=ZE) or by nucleophilic ipso-protodesilylation (cf step 2, e.g.
Treatment with a base (e.g. CsF, K3PO4) to effect nucleophilic ipso protodesilylation (Z=TMS to Z=H) could also be performed prior to cleavage. Such cleavage by an electrophile E+, or by sequential use of two electrophiles, as described above, could again result in—telechelic or symmetrical oligomers by electrophilic ipso-degermylation without or with subsequent electrophilic substitution at the other terminus [(Y=RMe2Ge to Y=YE; Z=H) or (Y=RMe2Ge to Y=YE and Z=H to Z=ZE where YE ZE or YE ZE]. Similarly, such cleavage by a Germyl-Stille type cross-coupling, as described above, could result in—telechelic oligomers (Y=RMe2Ge to Y=YCC; Z=H) which could undergo subsequent electrophilic substitution at the other terminus (Z=H to Z=ZE).
In this manner a wide range of usefully end-functionalised oligomers can be produced which may have useful electroactive properties in their own right and/or be valuable substrates for subsequent incorporation into more complex structures (e.g. block co-oligomers).
Preparation of Block Co-Oligomers (
An oligoheterocyclic block prepared as described above is in an advantageous form for incorporation into a block co-oligomeric structure. Block coupling could be achieved by a number of possible protocols:
All reactions were performed under anhydrous conditions and an atmosphere of nitrogen in flame-dried glassware. Yields refer to chromatographically and spectroscopically (1H NMR) homogenous materials, unless otherwise indicated.
Solvents and reagents: All solvents were distilled before use. ‘Petrol’ refers to the fraction of light petroleum-ether boiling between 40-60° C. Commercial grade solvents used for flash chromatography were distilled before use. Anhydrous solvents were obtained as follows: DMF: Stirred over MgSO4 under nitrogen for 24 h, distilled under reduced pressure, and stored over molecular sieves (4 Å) under nitrogen. MeNO2: Distilled from CaH2 under nitrogen immediately prior to use. THF and Et2O: Distilled from sodium/benzophenone ketyl under nitrogen immediately prior to use. ‘Degassed’ refers to solutions that have been subjected to three successive freeze-thaw cycles on a nitrogen/high-vacuum line. All chemicals were handled in accordance with COSHH regulations. All reagents were used as commercially supplied. Chromatography: Flash chromatography was carried out using Merck Kiesegel 60 F254 (230-400 mesh) silica gel. Only distilled solvents were used as eluents. Thin layer chromatography (TLC) was performed on Merck which were visualised either by quenching of ultraviolet fluorescence (λmax, =254 nm) or by charring with 10% KMnO4 in 1M H2SO4. Infra red spectra: These were recorded as thin films, nujol mulls, or as solutions in CHCl3, on a Perkin-Elmer Paragon 1000 Fourier transform spectrometer. Only selected absorbencies (λmax) are reported. 1H NMR spectra: These were recorded at 250 MHz on a Bruker AM-250 instrument, and at 300 MHz and 400 MHz on Varian Inova-300 and 400 instruments respectively. Chemical shifts (8H) are quoted in parts per million (δH), referenced to the appropriate residual solvent peak. Coupling constants (J) are reported to the nearest Hz. 13C NMR spectra: These were recorded at 63 MHz on a Bruker AM-250 instrument, and at 100 MHz on a Varian Inova-300. Chemical shifts (° C.) are quoted in ppm, referenced to the appropriate solvent peak. Mass spectra: Low resolution mass spectra (m/z) were recorded on either a VG platform or VG prospec spectrometers, with only molecular ions (M+ or MH+), and major peaks being reported with intensities quoted as percentages of the base peak. High Resolution Mass Spectrometry (HRMS) measurements are valid to ±5 ppm.
Tin(IV)chloride (1.50 mL, 12.8 mmol) was added drop-wise to a solution of {2-[4(2-ethoxy-ethoxy)phenyl]ethyl}-trimethyl-germane (421 mg, 1.4 mmol) in nitromethane (2 mL) at RT to give a pink solution. The reaction mixture was then heated at 50° C. for 16 h. Volatiles were then removed by distillation (90° C., 0.5 mmHg) to leave chlorodimethylgermane 3 as a brown oil (440 mg, 91%).); 1H NMR (CDCl3): δ 0.59 (s, 6H), 1.24 (t, J=7, 3H), 1.49 (t, J=8, 2H), 2.80 (t, J=8, 2H), 3.59 (q, J=7, 2H), 3.77 (t, J=5, 2H), 4.10 (t, J=6, 2H), 6.85 (d, J=8.5, 2H), 7.10 (d, J=8, 2H); MS (EI+) m/z 332 (M+). HRMS (EI+) calcd. for C14H23ClGe74O2 (M) 332.0598, found 332.0586.
A solution of n-BuLi (0.787 mL, 2.2M, 1.73 mmol) in hexanes was added drop-wise to a degassed solution of 2-bromo-3-hexylthiophene1 (387 mg, 1.57 mmol) in THF (3 mL) at −78° C. The mixture was stirred for 40 min at this temperature, and then trimethylchlorosilane (0.600 mL, 4.71 mmol) added drop-wise at −78° C. The resulting mixture was stirred for 1 hr at this temperature, warmed to RT and stirred for a further 1 hr. After quenching with sat. NH4Cl (aq) (100 mL), the mixture was extracted with Et2O (3×100 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography (pentane) gave silylthiophene 4 as a colourless oil (329 mg, 87%). Rf 0.85 (pentane); 1H NMR (CDCl3): δ 0.03 (s, 9H), 0.58 (t, J=6.5, 3H), 0.95-1.10 (m, 6H), 1.22-1.31 (m, 2H), 2.36 (t, J=8, 2H), 6.73 (d, J=4.5, 1H), 7.14 (d, J=4.5, 1H); MS (Cl+) m/z 240 (M+). HRMS (Cl+) calcd. for C13H24SiS (M) 240.1368, found 240.1361.
A solution of LDA (0.315 mL, 2.0M, 0.63 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a degassed solution of silylthiophene 4 (144 mg, 0.60 mmol) in THF (2 mL) at −78° C. This solution was stirred for 40 min at this temperature, and then transferred by cannula to a degassed solution of chlorodimethylgermane 3 (100 mg, 0.30 mmol) in THF (1 mL) at −78° C. The resulting mixture was stirred for 1 hr at this temperature, warned to RT and stirred for a further 1 hr. After quenching with sat. NH4Cl (aq) (50 mL), the mixture was extracted with Et2O (3×50 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography (petro/EtOAc, 9/1) gave silylthiophenedimethylgermane 51 as a yellow oil (86.0 mg, 53%). Rf 0.61 (9/1, petrol/EtOAc); 1H NMR (CDCl3) δ 0.33 (s, 9H), 0.39 (s, 6H), 0.86 (t, J=7.5, 3H), 1.24 (t, J=7, 3H), 1.24-1.42 (m, 8H), 1.54-1.62 (m, 2H), 2.63-2.72 (m, 4H), 3.59 (q, J=7, 2H), 3.77 (t, J=5.5, 2H), 4.09 (t, J=6, 2H), 6.83 (d, J=8.5, 2H), 7.06 (s, 1H), 7.07 (d, J=8, 2H); 13C NMR (CDCl3) δ-2.18 (2xq), 0.46 (3xq), 14.10 (q), 15.19 (q), 19.11 (t), 22.65 (t), 29.56 (t), 30.09 (t), 31.10 (t), 31.77 (t), 31.98 (t), 66.84 (t), 67.50 (t), 69.05 (t), 114.55 (2xd), 128.72 (2xd), 136.45 (d), 136.79 (s), 137.59 (s), 144.24 (s), 151.46 (s), 156.96 (s); IR (neat) 2928, 2858, 1688, 1611, 1584, 1511, 1246, 1125, 839 cm−1; MS (EI+) m/z 536 (M+). HRMS (EI+) calcd. for C27H46O2SiSGe74 (M) 536.2200, found 536.2214.
To TMS protected germylthiophene 51 (5.7 mg, 0.011 mmol) in DMF (1 mL) was added ceasium fluoride (8.1 mg, 0.053 mmol) and the mixture left to stir for 24 hrs at 60° C. The reaction mixture was partitioned between Et2O (40 mL) and water (75 ml) and the Et2O layer extracted with water (3×40 mL). The organic layer was dried (MgSO4), the solvent removed in vacuo and the residue purified by flash chromatography (petrol/EtOAc, 9/1) to give germyldithiophene 61 as a brown oil (4.8 mg, 97%). Rf 0.38 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.38 (s, 6H), 0.88 (t, J=7, 3H), 1.23 (t, J=7, 3H), 1.25-1.30 (m, 8H), 1.54-1.62 (m, 2H), 2.62 (t, J=8, 2H), 2.67 (t, J=8.5, 2H), 3.59 (q, J=7, 2H), 3.77 (t, J=5.5, 2H), 4.09 (t, J=5.5, 2H), 6.83 (d, J=8, 2H), 6.96 (s, 1H), 7.06 (s, 1H), 7.11 (d, J=8, 2H); 13C NMR (CDCl3) δ-2.29 (2xq), 14.12 (q), 15.19 (q), 19.10 (t), 22.63 (t), 29.16 (t), 30.09 (2xt), 30.67 (t), 31.71 (t), 66.84 (t), 67.52 (t), 69.05 (t), 114.57 (2xd), 124.51 (d), 128.72 (2xd), 134.51 (d), 136.75 (s), 139.57 (s), 144.48 (s), 156.96 (s); IR (neat) 2927, 2857, 1611, 1511, 1246, 1126 cm−1; MS (EI+) m/z 464 (M+); HRMS (EI+) calcd. for C24H38Ge74O2S (M) 464.1804, found 464.1798.
A solution of n-BuLi (2.21 mL, 1.5M, 3.30 mmol) in hexanes was added drop-wise to a degassed solution of germylthiophene 61 (512 mg, 1.10 mmol) in THF (3 mL) at −78° C. After stirring for 40 min at this temperature, a solution of degassed 1,2-diiodoethane (1.569, 5.52 mmol) in THF (2 mL) was added by cannula at −78° C. The resulting mixture was stirred in the dark for 1 hr at this temperature, warmed to RT and stirred for a further 1 hr. The reaction mixture was partitioned between sat. Na2S2O3 (aq) (200 mL) and Et2O (100 ml), extracted with Et2O (2×100 mL), the organics combined and then dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petrol/EtOAc, 9/1) to give germylthiopheneiodide 71 as a yellow oil (632 mg, 98%). Rf 0.41 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.37 (s, 6H), 0.88 (t, J=6.5, 3H), 1.23 (t, J=7, 3H), 1.25-1.31 (m, 8H), 1.53-1.56 (m, 2H), 2.53 (t, J=8, 2H), 2.66 (t, J=8, 2H), 3.59 (q, J=7, 2H), 3.77 (t, J=5.5, 2H), 4.09 (t, J=6, 2H), 6.75 (s, 1H), 6.83 (d, J=8.5, 2H), 7.07 (d, J=8, 2H); 13C NMR (CDCl3) δ-2.30 (2xq), 14.13 (q), 15.20 (q), 19.06 (t), 22.63 (t), 29.05 (t), 30.02 (t), 30.14 (t), 31.65 (t), 31.91 (t), 66.85 (t), 67.51 (t), 69.05 (t), 77.91 (s), 114.58 (2xd), 128.73 (2xd), 133.86 (d), 136.41 (s), 145.61 (s), 148.17 (s), 157.02 (s); IR (neat) 2928, 2856, 1611, 1584, 1510, 1455, 1246, 1125 cm−1; MS (EI+) m/z 590 (M+). HRMS (ES+) calcd. for C24H38O2SGe74 (MH) 591.0849, found 591.0870.
A solution of LDA (0.690 mL, 2.0M, 1.38 mmol) in hexanes/ethylbenzene/THF was added drop-wise to a degassed solution of TMS thiophene 4 (166 mg, 0.69 mmol) in THF (2 mL) at −50° C. After stirring for 40 min at this temperature, a degassed solution of 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (334 mg, 1.79 mmol) in THF (2 mL) was added by cannula at −78° C. The resulting mixture Was stirred for 30 min at this temperature, warmed to RT and stirred for a further 15 min. The reaction mixture was cooled to 0° C. and anhydrous HCl in Et2O (1.79 ml, 1.0M, 1.79 mmol) added. The mixture was left to stir at this temperature for 15 min and then allowed to warm to RT. The solvent was removed in vacuo and the residue taken up in dry Et2O. The solution was passed through a pad of dry celite, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (petro/EtOAc, 19/1) to give thiophene pinacolato boronic ester as a courless oil (131 mg, 52%). 1H NMR (CDCl3): δ 0.03 (s, 9H), 0.58 (t, J=7, 3H), 0.94-1.02 (m, 6H), 1.03 (s, 12H), 1.27 (m, 2H), 2.36 (t, J=8, 2H), 7.26 (s, 1H). 13C NMR (CDCl3) δ 0.23 (3xq), 14.07 (q), 22.58 (t), 24.74 (4xq), 29.43 (t), 31.00 (t), 31.76 (2xt), 83.97 (2xs), 140.01 (d), 141.46 (s), 151.64 (s) (absent: SCB); MS (EI+) m/z 367 (M+).
A solution of n-BuLi (0.298 mL, 1.5M, 0.45 mmol) in hexanes was added drop-wise to a solution of silylthiophene 4 (97.6 mg, 0.41 mmol) in THF (2 mL) at −50° C. and stirred for 40 min at this temperature. To this was added triethylborate (0.207 mL, 1.22 mmol) drop-wise at −50° C. The resulting mixture was stirred for 1 hr at this temperature, warmed to RT and stirred for a further 30 min. The solvent was then removed in vacuo to give the triethylborate lithium salt 9 as a white powder. mp 95-98° C.; 1H NMR (CDCl3): δ 0.33 (s, 9H), 0.88 (t, J=6.5, 3H), 1.17-1.58 (m, 17H), 2.66 (t, 2H), 4.14 (q, J=7, 6H), 7.46 (s, 1H).
To a degassed solution of triethylborate salt 9 (63.0 mg, 0.101 mmol) and germylthiopheneiodide 71 (30.0 mg, 0.051 mmol) in THF (1 mL) at −78° C. was added Pd(PPh3)4 (6.0 mg, 0.0051 mmol) and the resulting mixture stirred at 60° C. for 24 hr. The reaction mixture was partitioned between water (100 mL) and Et2O (50 ml), extracted with Et2O (2×50 mL) and the organics combined and dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petrol/EtOAc, 9/1) to give silyl protected germyldithiophene 52 as a yellow oil (29.0 mg, 90%). Rf 0.50 (petro/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.05 (s, 9H), 0.10 (s, 6H), 0.53-0.62 (m, 6H), 0.94 (t, J=7, 3H), 0.94-1.08 (m, 14H), 1.28-1.34 (m, 4H), 2.30-2.48 (m, 6H), 3.30 (q, J=7, 2H), 3.47 (t, J=4.5, 2H), 3.79 (t, J=4.5, 2H), 6.54 (d, J=8.5, 2H), 6.63 (s, 1H), 6.74 (s, 1H), 7.80 (d, J=8.5, 2H). 13C NMR (400 MHz, CDCl3) δ-2.34 (2xq), 0.43 (3xq), 14.08 (2xq), 15.16 (q), 19.08 (t), 22.62 (2xt), 29.20 (t), 29.31 (t) 29.39, (t), 30.07 (t), 30.70 (t), 31.48 (t), 31.64 (t), 31.70 (t), 31.77 (t), 66.82 (t), 67.53 (t), 69.03 (t), 114.58 (2xd), 128.73 (2xd), 128.79 (d), 132.61 (s), 135.63 (s), 136.11 (d), 136.67 (s), 137.97 (s), 140.19 (s), 140.34 (s), 150.68 (s), 156.97 (s); IR (neat) 2956, 2928, 2858, 1732, 1611, 1584, 1511, 1236 cm−1; MS (EI+) m/z 702 (M+). HRMS (ES+) calcd. for C37H61O2SiS2Ge74 (MH) 703.3094, found 703.3089.
To TMS protected germyldithiophene 52 (60.0 mg, 0.086 mmol) in DMF (1 mL) was added ceasium fluoride (63.4 mg, 0.42 mmol) and the mixture left to stir for 24 hrs at 60° C. The reaction mixture was partitioned between Et2O (50 mL) and water (100 ml) and the Et2O layer extracted with water (3×50 mL). The organic layer was dried (MgSO4), the solvent removed in vacuo and the residue purified by flash chromatography (petrol/EtOAc, 9/1) to give germyldithiophene 62 as a brown oil (54.0 mg, 99%). Rf 0.40 (9/1, petrol/EtOAc); 1H NMR (CDCl3): δ 0.40 (s, 6H), 0.85-0.90 (m, 6H), 1.23 (t, J=7H, 3H), 1.20-1.33 (m, 14H), 1.56-1.62 (m, 4H), 2.59 (t, J=7.5, 2H), 2.66-2.76 (m, 4H), 3.59 (q, J=7, 2H), 3.77 (t, J=4.5, 2H), 4.09 (t, J=5, 2H), 6.83 (d, J=8.5, 2H), 6.86 (s, 1H), 6.92 (s, 2H), 7.08 (d, J=8.5, 2H); 13C NMR (400 MHz, CDCl3) δ-2.32 (2xq), 14.13 (2xq), 15.20 (q), 19.07 (t), 22.65 (2xt), 29.03 (t), 29.18 (t), 29.37 (t), 30.08 (t), 30.41 (t), 30.54 (t), 30.80 (t), 31.68 (2xt), 66.85 (t), 67.49 (t), 69.05 (t), 114.55 (2xd), 119.71 (d), 126.93 (d), 128.74 (2xd), 135.61 (s), 136.09 (d), 136.65 (s), 138.06 (s), 140.35 (2xs), 143.53 (s), 156.97 (s); IR (neat) 2927, 2857, 1728, 1611, 1510, 1457, 1246, 1125 cm−1; MS (EI+) m/z 630 (M+). HRMS (Cl+) calcd. for C34H52O2S2Ge74 (M) 630.2621, found 630.2642.
A solution of n-BuLi (0.060 mL, 2.5M, 0.149 mmol) in hexanes was added drop-wise to a degassed solution of germyldithiophene 62 (19.0 mg, 0.030 mmol) in THF (1 mL) at −78° C. After stirring for 40 min at this temperature, a degassed solution of 1,2-diiodoethane (67.2 mg, 0.238 mmol) in THF (1 mL) was added by cannula at −78° C. The resulting mixture was stirred in the dark for 1 hr at this temperature, warmed to RT and stirred for a further 1 hr. The reaction mixture was partitioned between sat. Na2S2O3 (aq) (50 mL) and Et2O (50 ml), extracted with Et2O (2×50 mL), the organics combined and then dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petrol/EtOAc, 9/1) to give germyldithiopheneiodide 72 as a yellow oil (23.1 mg, 98%). Rf 0.42 (9/1, petrol/EtOAc); 1H NMR (CDCl3): δ 0.33 (s, 6H), 0.78-0.85 (m, 6H), 1.17 (t, J=7H, 3H), 1.17-1.27 (m, 14H), 1.50-1.54 (m, 4H), 2.46 (t, J=7.5, 2H), 2.58-2.67(m, 4H), 3.53 (q, J=7, 2H), 3.71 (t, J=5, 2H), 4.03 (t, J=5, 2H), 6.68 (s, 1H), 6.77 (d, J=8.5, 1H), 6.85 (s, 1H), 7.02 (d, J=8.5, 2H); 13C NMR (400 MHz, CDCl3) δ-2.43 (2xq), 14.10 (q), 14.20 (q), 15.17 (q), 19.03 (t), 22.62 (2xt), 28.90 (t), 29.15 (t), 29.31 (t), 29.95 (t), 30.05 (t), 30.76 (t), 31.65 (2xt), 32.35 (t), 66.84 (t), 67.48 (t), 69.03 (t), 73.63 (q), 114.55 (2xd), 126.20 (d), 128.72 (2xd), 135.57 (s), 136.04 (d), 136.53 (s), 138.81 (s), 140.90 (s), 141.06 (s), 147.48 (s), 156.98 (s); IR (neat) 2928, 2857, 1728, 1611, 1511, 1455, 1125 cm−1; MS (EI+) m/z 756 (M+). HRMS (EI+) calcd. for C34H51O2S2 Ge74I (M) 756.1587, found 756.1571.
To a degassed solution of triethylborate salt 9 (118 mg, 0.30 mmol) and germyldithiopheneiodide 72 (29.7 mg, 0.039 mmol) in THF (1 mL) at −78° C. was added Pd(PPh3)4 (6.0 mg, 0.0051 mmol) and the resulting mixture stirred at 60° C. for 24 hr. The reaction mixture was partitioned between water (100 mL) and Et2O (50 ml), extracted with Et2O (2×50 mL) and the organics combined and dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petro/EtOAc, 9/1) to give silyl protected germyltrithiophene 53 as a yellow oil (31.6 mg, 93%). Rf 0.52 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.25 (s, 9H), 0.31 (s, 6H), 0.75-0.83 (m, 9H), 1.14 (t, J=7, 3H), 1.19-1.25 (m, 20H), 1.47-1.55 (m, 6H), 2.50-2.70 (m, 8H), 3.50 (q, J=6.5, 2H), 3.68 (1, J=5, 2H), 4.00 (t, J=5, 2H), 6.74 (d, J=9, 2H), 6.82 (s, 1H), 6.83 (s, 1H), 6.96(s, 1H), 7.00 (d, J=9, 2H); IR (neat) 2928, 2858, 1729, 1611, 1584, 1511, 1456, 1248, 839 cm−1; MS (ES+) m/z 869 (MH+). HRMS (ES+) calcd. for C47H74O3S2Ge74I (MH) 869.3910, found 869.3901.
A solution of LDA (3.12 mL, 2.0M, 6.24 mmol) in hexanes/ethylbenzene/THF was added drop-wise to a degassed solution of 3-hexyl-thiophene (1.00 g, 5.94 mmol) in THF (10 mL) at −50° C. to give an orange solution. After stirring for 40 min at this temperature, a degassed solution of tert-butyldimethylsilyl chloride (1.34 g, 0.89 mmol) in THF (5 mL) was added by cannula at −50° C. The resulting mixture was warmed to −40° C., stirred for 30 min at this temperature, warmed to RT and stirred for a further 40 min to give a yellow solution. After quenching with sat. NH4Cl (aq) (50 mL), the mixture was extracted with Et2O (3×50 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. Purification was initially by vacuum distillation (105° C., 10−3 Torr) to remove starting material and then by reverse phase HPLC (MeOH/H2O, 19/1) to give silylthiophene 10 as a colorless oil (1.05 g, 63%). 1H NMR (CDCl3): δ 0.27 (s, 6H), 0.87 (t, J=7.5, 3H), 0.90 (s, 9H), 1.24-1.30 (m, 6H), 1.61 (t, J=8, 2H), 2.62 (t, J=8, 2H), 7.15 (s, 1H), 7.25 (s, 1H); 13C NMR (CDCl3) δ-4.88 (2xq), 14.16 (q), 16.87 (s), 22.67 (t), 26.39 (3xq), 29.14 (t), 30.02 (t), 30.70 (t), 31.73 (t), 125.42 (d), 136.63 (d), 136.91 (s), 144.47 (s); IR (neat) 2953, 2925, 2855, 1462, 1406, 1361, 1249, 1198, 1008, 938, 832 cm−1; MS (EI+) m/z 282 (M+); HRMS (EI+) calcd. for C16H30SSi (M) 282.1838, found 282.1827; Anal. calcd. for C16H30SSi: C 68.01, H 10.70, S 11.35, found C 68.45, H 11.04, S 11.45; HPLC purity 100.0%.
A solution of LDA (1.33 mL, 2.0M, 2.66 mmol) in hexanes/ethylbenzene/THF was added drop-wise to a solution of silylthiophene 10 (501 mg, 1.77 mmol) in THF (5 mL) at −50° C. and then warmed to −40° C. give an orange solution. After stirring for 40 min at this temperature the reaction was cooled to −50° C. and a solution of 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (162 mg, 0.87 mmol) in THF (1 mL) (×3) was added drop-wise by cannula. The resulting mixture was stirred for 30 min at 40° C., warmed to room temperature and stirred for a further 15 min. The reaction was then cooled to 0° C. and anhydrous HCl (0.71 ml, 1.0M, 0.71 mmol) in ether added. The mixture was left to stir at this temperature for 15 min and then allowed to warm to RT. The solvent was removed in vacuo and the residue taken up in dry Et2O. The solution was passed through a pad of dry celite, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (petro/DCM, 3/1) to give silylthiophene pinacolato-boronic ester 11 as a pale yellow oil (371 mg, 51%). Rf 0.40 (3:1, petrol/DCM); 1H NMR (CDCl3): δ 0.26 (s, 6H), 0.87 (t, J=7, 3H), 0.90 (s, 9H), 1.27-1.32 (m, 18H), 1.57 (t, J=8, 2H), 2.87 (t, J=8, 2H), 7.12 (s, 1H); 13C NMR (CDCl3) δ 4.83 (2xq), 14.17 (q), 16.86 (s), 22.67 (t), 24.86 (4xq), 26.44 (3xq), 29.08 (t), 29.98 (t), 31.72 (t), 32.02 (t), 83. 44 (s), 138.38 (d), 144.89 (s), 155.32 (s), (absent: SCB); IR (neat) 2955, 2927, 2857, 1525, 1470, 1435, 1370, 1332, 1298, 1271, 1250, 1214, 1166, 1144, 1047, 1008 cm−1; MS (ES+) m/z 409 (MH); HRMS (ES+) calcd. for C22H42BO2SSi (MH) 409.2768, found 409.2770.
To magnesium (1.01 g, 42 mmol) in THF (25 ml) was added 4-bromoanisole (5.21 ml, 42 mmol) and the mixture was heated briefly to initiate Grignard formation. After stirring for 1 hr the grey solution was added drop-wise to a solution of germyl chloride (1.25 g, 4.2 mmol) in THF at RT. The yellow reaction mixture was then left stirring at this temperature for 16 hrs before quenching dropwise with water until no effervescence occurs. The solvent was the removed in vacuo and the residue taken up in DCM (30 ml). To the solution was added 1N HCl (5 ml) with stirring and then conc. HCl (60 ml). The resultant mixture was stirred vigorously for 40 min before extracting the HCl layer with DCM (3×50 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. The residue was taken up in DCM (50 ml) and 0.5M NaOH (aq) (100 ml) and the aqueous layer extracted with DCM (3×50 mL). To the aqueous layer was then added 1N HCl (15 ml) with shaking and then conc. HCl (100 ml). The aqueous layer was then extracted with DCM (3×100 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo to give 12 as an orange/brown oil (1.25 g, 84%). 1H NMR (CDCl3): δ 1.96-2.02 (m, 2H), 2.83-2.90 (m, 2H), 3.75 (s, 3H), 4.84 (s, 1H), 6.65 (d, J=8.5, 2H), 6.88 (d, J=9, 2H), 6.99 (d, J=8.5, 2H), 7.40 (d, J=9, 2H); 13C NMR (CDCl3) δ 27.81 (t), 28.55 (t), 55.39 (q), 114.58 (2xd), 115.51 (2xd), 126.72 (s), 129.35 (2xd), 133.76 (2xd, s), 154.07 (s), 162.12 (s); IR (neat) 3019, 2931, 2839, 2361, 1591, 1514, 1442, 1403, 1290, 1254 cm−1; MS (EI+) m/z 372 (M+); HRMS calcd. for C15H16Cl2Ge74O2 (M) 371.9739, found 371.9749.
A solution of MeMgBr (1.0 mL, 3.0M, 3.03 mmol) in Et2O was added to a solution of dichlorogermane 12 (184 mg, 0.49 mmol) in THF (3 mL). The mixture was then refluxed at 110° C. for 16h before partitioning between sat. NH4Cl (aq) (100 mL) and Et2O (100 mL). After extracting further with Et2O (2×100 mL) the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (petrol/EtOAc, 3/1) gave dimethylgermane 13 as a pale yellow oil (125 mg, 74%). Rf 0.4 (petro/EtOAc, 3/1); 1H NMR (CDCl3): δ 0.25 (s, 6H); 1.11-1.18 (m, 2H), 2.51-2.57 (m, 2H), 3.73 (s, 3H), 4.67 (s, 1H), 6.64 (d, J=8.5, 2H), 6.84 (d, J=9, 2H), 6.95 (d, J=8.5, 2H), 7.29 (d, J=9, 2H); 13C NMR (CDCl3) δ-3.56 (2xq), 18.21 (t), 30.22 (t), 55.13 (q), 113.84 (2xd), 115.14 (2xd), 128.94 (2xd), 132.15 (s), 134.48 (2xd), 137.01 (s), 153.45 (s), 159.85 (s); IR (neat) 3401 (broad), 3020, 2931, 2905, 2838, 1612, 1592, 1569, 1513, 1500, 1462, 1443, 1358, 1279, 1246, 1181, 1093 cm−1; MS (EI+) m/z 332 (M+); HRMS calcd. for C17H22Ge74O2 (M) 332.0832, found 332.0824.
To a solution of dimethylgermane 13 (96.1 mg, 0.29 mmol) in acetonitrile (1 ml) was added 2-chlorodiethyl ether (0.070 mL, 0.64 mmol), tetra-n-butylammonium iodide (10.7 mg, 0.03 mmol) and cesium carbonate (153 mg, 0.44 mmol). The mixture was refluxed at 85° C. for 17 h then cooled and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (petrol/EtOAc, 9/1) to give the title compound 14 as a pale yellow oil (106 mg, 90%). Rf 0.3 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.25 (s, 6H); 1.12-1.19 (m, 5H), 2.52-2.56 (m, 2H), 3.52 (q, J=7, 2H), 3.70 (t, J=4.5, 2H), 3.73 (s, 3H), 4.01 (t, J=4.5, 2H), 6.64 (d, J=8.5, 2H), 6.84 (d, J=10.5, 2H), 6.95 (d, J=9, 2H), 7.29 (d, J=9, 2H); 13C NMR (CDCl3) 8-3.53 (2xq), 15.23 (q), 18.19 (t), 30.24 (t), 55.06 (q), 66.86 (t), 67.53(t), 69.08 (t), 113.81 (2xd), 114.55 (2xd), 128.71 (2×/d), 132.03 (s), 134.47 (2xd), 137.06 (s), 156.93 (s), 159.94 (s); IR (neat) 2930, 2871, 1611, 1593, 1568, 1511, 1500, 1458, 1280, 1247, 1181, 1125 cm−1; MS (EI+) m/z 404 (M+); HRMS calcd. for C21H30Ge74O3 (M) 404.1407, found 404.1393.
To oven dried Mg (120 mg, 5.00 mmol) in THF (3 ml) was added 4-bromotoluene (855 mg, 5.00 mmol) drop-wise. Grignard formation was initiated by heating and after the magnesium had disappeared it was added to a solution of dichlorogermane 12 (186 mg, 0.50 mmol) in THF (3 mL). The mixture was then refluxed at 110° C. for 16 h before partitioning between sat. NH4Cl (aq) (100 mL) and Et2O (100 mL). After extracting further with Et2O (2×100 mL) the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (petrol/EtOAc, 3/1) gave ditolylgermane 15 as a yellow oil (280 mg, 92%). R, 0.4 (petrol/EtOAc, 3/1); 1H NMR (CDCl3): δ 1.72-1.80 (m, 2H), 2.36 (s, 6H), 2.70-2.77 (m, 2H), 3.81 (s, 3H), 4.64 (s, 1H), 6.71 (d, J=8.5, 2H), 6.92 (d, J=8.5, 2H), 7.04 (d, J=8.5, 2H), 7.19 (d, J=8, 4H), 7.38 (d, J=8, 4H), 7.40 (d, J=8.5, 2H); 13C NMR (CDCl3) δ16.63 (t), 21.58 (2xq), 30.43 (t), 55.19 (q), 114.17 (2xd), 115.31 (2xd), 128.18 (s), 129.03 (2xd), 129.19 (4xd), 133.79 (2xs), 135.02 (4xd), 136.33 (2xd), 137.14 (s), 138.77 (2xs), 153.62 (s), 160.31 (s); IR (neat) 3409 (broad), 3012, 2921, 2861, 1593, 1568, 1512, 1442, 1392, 1281, 1247, 1180, 1089, 1031 cm−1; MS (EI+) m/z 484 (M+); HRMS (EI+) calcd. for C29H30Ge74O2 (M+) 484.1458, found 484.1446.
To a solution of ditolylgermane 15 (9.57 g, 20.0 mmol) in acetonitrile (40 ml) was added 2-chlorodiethyl ether (4.56 mL, 41.5 mmol), tetra-n-butylammonium iodide (739 mg, 2.0 mmol) and cesium carbonate (14.1 g, 40.0 mmol). The mixture was refluxed at 85° C. for 17 h then cooled and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (petrol/EtOAc, 9/1) to give the title compound 16 as a colourless oil (7.81 g, 70%). Rf 0.5 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ1.24 (t, J=7, 3H), 1.72-1.80 (m, 2H), 2.36 (s, 6H), 2.70-2.78 (m, 2H), 3.59 (q, J=7, 2H), 3.77 (t, J=5.5, 2H), 3.81 (s, 3H), 4.09 (q, J=5.5, 2H), 6.82 (d, J=8.5, 2H), 6.92 (d, J=8.5, 2H), 7.07 (d, J=8.5, 2H), 7.18 (d, J=8, 4H), 7.38 (d, J=8, 4H), 7.40 (d, J=8.5, 2H); 13C NMR (CDCl3) δ 15.29 (q), 16.57 (t), 21.55 (2xq), 30.39 (t), 55.11 (q), 66.91 (t), 67.59 (t), 69.12 (t), 114.07 (2xd), 114.66 (2xd), 127.96 (s), 128.75 (2xd), 129.13 (4xd), 133.76 (2xs), 134.98 (4xd), 136.27 (2xd), 137.22 (s), 138.70 (2xs), 157.04 (s), 160.37 (s); IR (neat) 3010, 2972, 2925, 1593, 1567, 1510, 1454, 1392, 1281, 1247, 1180, 1090, 1031 cm−1; MS (EI+) m/z 556 (M+); HRMS (EI+) calcd. for C33H38Ge74O3 (M+) 556.2033, found 556.2042.
To anisolegermane 16 (100 mg, 0.18 mmol) was added HCl (7.0 ml, 1.0M, 7.0 mmol) in Et2O and the reaction left to stir for 16 hrs. The solvent was then removed in vacuo to give chlorogermane 17 as a colourless oil (85.3 mg, 98%). 1H NMR (CDCl3): δ 1.24 (t, J=7, 3H), 1.851.92 (m, 2H), 2.37 (s, 6H), 2.80-2.87 (m, 2H), 3.60 (q, J=7, 2H), 3.77 (t, J=5, 2H), 4.08 (q, J=5, 2H), 6.81 (d, J=8.5, 2H), 7.07 (d, J=8.5, 2H), 7.23 (d, J=8, 4H), 7.45 (d, J=8, 4H); 13C NMR (CDCl3) δ 15.29 (q), 21.63 (t), 21.59 (2xq), 29.20 (t), 66.90 (t), 67.60 (t), 69.08 (t), 114.74 (2xd), 128.89 (2xd), 129.41 (4xd), 132.32 (2xs), 133.49 (4xd), 135.57 (s), 140.36 (2xs), 157.26 (s); IR (neat) 2973, 2924, 2868, 1610, 1584, 1511, 1453, 1393, 1300, 1247, 1177, 1125, 1090 cm−1; MS (EI+) m/z 483 (M+); HRMS (EI+) calcd. for C26H31ClGe74O2 (M+) 484.1224, found 484.1207; Anal. calcd. for C26H31ClGe74O2: C 64.58, H 6.46, Cl 7.33, found C 64.12, H 6.56, Cl 7.68.
A solution of LDA (4.71 mL, 2.0M, 1.13 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a degassed solution of silylthiophene 10 (1.18 g, 6.28 mmol) in THF (20 mL) at −50° C. This solution was warmed to −40° C., stirred for 40 min at this temperature and recooled to −50° C. It was then transferred by cannula to a degassed solution of chloroditolylgermane 17 (2.69 g, 5.56 mmol) in THF (20 mL) at −50° C. The resulting mixture was stirred for 1 hr at −40° C., warmed to RT and stirred for a further 1 hr. After quenching with sat. NH4Cl (aq) (50 mL), the mixture was extracted with Et2O (3×50 mL), the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography (petrol/EtOAc, 9/1) gave silylthiopheneditolylgermane 18 as a pale yellow oil (803 mg, 80%). Rf 0.3 (9/1, petrol/EtOAc); 1H NMR (CDCl3): δ 0.27 (s, 6H), 0.78 (t, J=7.5, 3H), 0.80-1.26 (m, 21H), 1.76-1.84 (m, 2H), 2.35 (s, 6H), 3.36-3.42 (m, 2H), 2.69-2.73 (m, 2H), 3.59 (q, J=7, 2H), 3.76 (t, J=5, 2H), 4.08 (q, J=5, 2H), 6.81 (d, J=8.5, 2H), 7.05 (d, J=8.5, 2H), 7.17 (d, J=8, 4H), 7.18 (s, 1H), 7.39 (d, J=8, 4H); 13C NMR (CDCl3) δ 4.60 (2xq), 14. 22 (q), 15.35 (q), 17.08 (s), 18.42 (t), 21.61 (2xq), 22.70 (t), 26.62 (3xq), 29.42 (t), 30.51 (t), 31.36 (t), 31.72 (t), 31.78 (t), 66.92 (t), 67.63 (t), 69.18 (t), 114.71 (2xd), 128.85 (2xd), 129.16 (4xd), 133.59 (2xs), 134.57 (s), 134.88 (4xd), 137.19 (s), 138.12 (d), 138.82 (2xs), 142.42 (s), 151.65 (s), 157.13 (s); IR (neat) 2955, 2929, 2857, 1610, 1509, 1457, 1391, 1300, 1278, 1250, 1177, 1122, 1087 cm−1; MS (EI+) m/z 730 (M+). HRMS (EI+) calcd. for C42H60Ge74O2SSi (M+) 730.3295, found 730.3298.
To silyl protected germylthiophene 18 (225 mg, 0.31 mmol) in DMF (3 mL) was added ceasium fluoride (234 mg, 1.54 mmol) and the mixture left to stir for 24 hrs at 110° C. The reaction mixture was partitioned between Et2O (40 mL) and water (75 ml) and the Et2O layer extracted with water (3×40 mL). The organic layer was dried (MgSO4), the solvent removed in vacuo and the residue purified by flash chromatography (petrol/EtOAc, 9/1) to give germylthiophene 19 as a pale yellow oil (182 mg, 95%). Rf 0.3 (petro/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.81 (t, J=7.5, 3H), 0.83-1.37 (m, 11H), 1.80-1.87 (m, 2H), 2.35 (s, 6H), 2.44 (t, J=8, 3H), 2.74-2.82 (m, 2H), 3.61 (q, J=7, 2H), 3.79 (t, J=5,2H), 4.10 (q, J=5, 2H), 6.84 (d, J=8.5, 2H), 7.09 (d, J=8.5, 2H), 7.12 (d, J=5, 1H), 7.20 (d, J=8, 4H), 7.43 (d, J=8, 4H), 7.54 (d, J=5, 1H); 13C NMR (CDCl3) δ 14. 28 (q), 15.39 (q), 18.41 (t), 21.64 (2xq), 22.73 (t), 29.43 (t), 30.61 (t), 31.59 (t), 31.77 (t), 31.83 (t), 66.95 (t), 67.67 (t), 69.21 (t), 114.77 (2xd), 128.89 (2xd), 129.24 (4xd), 130.09 (d), 130.33 (d), 133.51 (2xs), 134.86 (4d, s), 137.09 (s), 138.97 (2xs), 150.84 (s), 157.20 (s); IR (neat) 2929, 2860, 1610, 1510, 1457, 1392, 1300, 1258, 1245, 1178, 1123, 1087 cm−1; MS (EI+) m/z 616 (M+); HRMS (EI+) calcd. for C36H46Ge74O2S (M+) 616.2430, found 616.2435.
A solution of LDA (0.545 mL, 2.0M, 1.09 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a solution of germylthiophene 19 (224 mg, 0.36 mmol) in THF (3 mL) at −50° C. After stirring for 40 min at −40° C., a solution of degassed 12-diiodoethane (1.56 g, 5.52 mmol) in THF (2 mL) was added by cannula at −50° C. The resulting mixture was stirred in the dark for 1 hr at −40° C., warmed to RT and stirred for a further 1 hr. The reaction mixture was partitioned between sat. Na2S2O3 (aq) (200 mL) and Et2O (100 ml), extracted with Et2O (2×100 mL), the organics combined and then dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petrol/EtOAc, 9/1) to give germylthiopheneiodide 20 as a pale yellow oil (251 mg, 94%). Rf 0.5 (petrol/EtOAc, 9/1); 1H NMR (CDCl3): δ 0.79 (t, J=7.5, 3H), 0.87-1.30 (m, 11 H), 1.76-1.83 (m, 2H), 2.342.41 (m, 8H), 2.71-2.78 (m, 2H), 3.60 (q, J=7, 2H), 3.78 (t, J=5, 2H), 4.09 (q, J=5, 2H), 6.82 (d, J=8.5, 2H), 7.06 (d, J=8.5, 2H), 7.17 (s, 1H), 7.19 (d, J=8, 4H), 7.38 (d, J=8, 4H); 13C NMR (CDCl3) δ 14. 16 (q), 15.29 (q), 18.15 (t), 21.57 (2xq), 22.58 (t), 29.22 (t), 30.40 (t), 31.31 (t), 31.52 (t), 31.65 (t), 66.89 (t), 67.59 (t), 69.11 (t), 77.71 (s), 114.70 (2xd), 128.75 (2xd), 129.24 (4xd), 132.83 (2xs), 134.66 (4d, s), 136.72 (s), 139.15 (2xs), 139.75 (d), 152.70 (s), 157.13 (s); IR (neat) 2925, 2857, 1610, 1510, 1454, 1393, 1299, 1246, 1178, 1124, 1087 cm−1; MS (ES+) m/z 765 (MNa); HRMS (ES+) calcd. for C36H45Ge741NaO2S (MNa) 765.1295, found 765.1266.
To a degassed solution of silylthiophene pinacolato-boronic ester 11 (256 mg, 1.05 mmol) and germylthiopheneiodide 20 (155 mg, 0.21 mmol) in DMF (1 mL) was added Pd(PPh3)4 (23.1 mg, 0.02 mmol) and the resulting mixture stirred at 60° C. for 24 hr. The reaction mixture was partitioned between water (100 mL) and Et2O (50 ml), extracted with Et2O (2×50 mL) and the organics combined and dried (MgSO4). The solvent was removed in vacuo and the residue purification by flash chromatography (petrol/DCM, 2/1) to give silyl protected germyldithiophene 21 as a yellow oil (112 mg, 60 %). R, 0.5 (petrol/DCM, 2/1); 1H NMR (CDCl3): δ 0.27 (s, 6H), 0.75-1.36 (m, 34H), 1.76-1.84 (m, 2H), 2.32-2.39 (m, 8H), 2.71-2.80 (m, 4H), 3.59 (q, J=7, 2H), 3.76 (t, J=5, 2H), 4.08 (q, J=5, 2H), 6.82 (d, J=8.5, 2H), 6.99 (s, 1H), 7.07 (d, J=8.5, 2H), 7.11 (s, 1H), 7.18 (d, J=8, 4H), 7.42 (d, J=8, 4H); 13C NMR (CDCl3) δ 4.96 (2xq), 14. 11 (2xq), 15.21 (q), 16.94 (s), 18.23 (t), 21.50 (2xq), 22.56 (t), 22.66 (t), 26.41 (3xq), 29.25 (t), 29.31 (2xt), 30.41 (t), 30.71 (t), 31.33 (t), 31.67 (2xt), 31.78 (t), 66.84 (t), 67.53 (t), 69.06 (t), 114.61 (2xd), 128.42 (d), 128.71 (2xd), 128.97 (s), 129.08 (4xd), 133.26 (2xs), 134.72 (4xd), 135.06 (s), 136.49 (s), 136.99 (s), 138.34 (d), 138.87 (2xs), 140.18 (s), 141.12 (s), 151.03—(s), 156.99 (s); IR (neat) 2924, 2854, 1610, 1509, 1455, 1390, 1246, 1175, 1124, 1086, 1007 cm−1; MS (EI+) m/z 896 (M+). HRMS (ES+) calcd. for C52H74Ge74NaO2S2Si (MNa+) 919.4009, found 919.4001.
To further exemplify the invention, example 2 relates to a solution phase model of a high purity arylamine oligomer using a germyl linker. Assembly of the oligomer is a stepwise process in which each monomer unit is added sequentially through repetitive transition metal mediated coupling in order to obtain highly pure and well-defined structures. The model reactions for a solid phase synthesis is outlined in
Steps 3, 4 and 5 represent the repetitive steps for the oligomer build-up. The role of the TBDMS group is to protect the phenol during the Suzuki-type cross-coupling.
Step 1: (
Arylgermane 3 was prepared by transmetalation with lithiated (4-bromo-phenoxy)-tert-butyl-dimethyl-silane 22 in 77% yield. TBDMS protecting group in tert-butyl-[4-({2-[4-(2-ethoxy-ethoxy)-phenyl]-ethyl}-dimethyl-germanyl)-phenoxy]-dimethyl-silane 28 was then cleaved using tetrabutylammonium fluoride in THF to give gave germylphenol 29 in 76% yield, with no detectable cleavage of the germyl linker. Conversion of germylphenol 29 into germyltrifluoromethanesulfonate using trifluoromethanesulfonic anhydride in anhydrous pyridine 30 was achieved in 87% yield.
Step 2: (
The first TBDMS protected amine monomer 34 was attached to germyltrifluoromethanesulfonate 33 was cross-coupled with monomer 34, using a Suzuki-type protocol, with 5% mol Pd(PPh3)4 in 1,2-dimethoxyethane at 80° C., to to give germylamine 31 in 84% yield. No detectable cleavage of the germyllinker and of the TBDMS protecting group occurs under these conditions.
Step 3: (
Cleavage of the TBDMS protecting group in germylamine 31 was achieved using tetrabutylammonium fluoride in THF and gave germylphenol 32 in 90% yield with no detectable cleavage of the germyl linker.
Step 4: (
Conversion of the germylphenol 32 into the germyltrifluoromethanesulfonate 33 was achieved using trifluoromethanesulfonic anhydride in anhydrous pyridine. Under these conditions, compound 33 was prepared in 86% yield.
Step 5: (
Step 6: (
This step is carried out as described in step 5 in example 1.
Experimental Procedures
All compounds were characterised by NMR spectroscopy, elemental analysis and/or mass spectrometry and found to be consistent with the expected structures.
This compound was prepared in a similar way to that described in G. R. Pettit, M. P. Grealish, M. K. Jung, E. Hamel, R. K. Robin, J. -C. Chapuis, J. M. Schmidt, J. Med. Chem, 45, 12, 2002, 2534-2542.
tert-Butyldimethylsilylchloride (18.40 g, 12.2×10−2 mol) was added slowly to a solution of 4-bromophenol (19.99 g, 11.6×10−2 mol) and imidazole (16.2 g, 23.8×10−2 mol) in N,N-dimethylformamide (50 mL) at room temperature. The mixture was stirred at room temperature for 24 h. The mixture was then partitioned between water and hexane. The organic layer was separated off and the aqueous phase was further extracted with hexane. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a colourless oil (32.89 g, 11.5×10−2 mol).
Yield: 99%
Procedure A
A solution of p-toluidine (6.41 g, 5.98×10−2 mol), (4-bromo-phenoxy)-tert-butyl-dimethyl-silane 22 (15.64 g, 5.44×10−2 mol), sodium tert-butoxide (6.73 g, 7.00×10−2 mol), rac-binap (0.23 g, 0.37×10−3 mol), Pd2(dba)3, (dba=dibenzylidene acetone), (0.48 g, 0.52×10−3 mol) in toluene (200 mL) was stirred vigorously overnight at 100° C. The crude product was a brown oil. Purification by column chromatography (eluent: dichloromethane/hexane 1/3) gave the expected product as a colourless oil (12.6 g, 4.02×10−2 mol). Yield: 74%.
This compound was prepared according to procedure A from [4-(tert-butyl-dimethyl-silanyloxy)phenyl]-p-tolyl-amine 23 (7.00 g, 1.80×10−2 mol), 4-bromo-iodo-benzene (5.53 g, 1.95×10−3 mol), sodium tert-butoxide (3.71 g, 3.86×10−2 mmol), rac-binap (0.11 g, 0.17×10−3 mol) and Pd2(dba)3 (0.05 g, 0.06×10−3 mol) in toluene (150 mL). The reaction mixture was then cooled to room temperature and filtered. The filtrate was taken up in diethylether, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by column chromatography (eluent: dichloromethane/hexane 1/5) gave the expected product as a colourless solid (5.4 g, 1.15×10−2 mol). Yield: 52%.
Procedure B
A solution of n-butyllithium (2.5M in hexane) (2.61 mL, 6.53×10−3 mol) was added drop-wise to a solution of (4-bromo-phenyl)-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-p-tolyl-amine 24 (2.04 g, 4.35×10−3 mol) in tetrahydrofuran cooled at −78° C. The resulting mixture was stirred at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (1.21 g, 6.50×10−3 mol) was added to the resulting solution and after 15 minutes, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between water and dichloromethane. The organic layer was separated off and the aqueous phase was extracted with dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid. Recrystallisation from MeOH afforded the expected product as white needles (1.58 g, 3.06×10−3 mol). Yield: 70%.
Di-p-tolyl-amine (25.00 g, 12.7×10−2 mol), 4-bromo-iodobenzene (43 g, 15.2×10−2 mol), potassium hydroxyde (79.6 g, 141.9×102 mol) were suspended in o-xylene (100 mL) and the mixture was then heated to 100° C. To this suspension were added copper chloride (2.51 g, 2.5×10−2 mol) and 1,10-phenanthroline (4.57 g, 2.5×10−2 mol) and the mixture was stirred vigorously 1 h at 145° C. Toluene was then added and the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a brown oil. Purification by column chromatography (eluent: hexane) and recrystallisation from methanol gave the expected product as a white solid (24.4 g, 6.92×10−2 mol). Yield: 55%.
This compound was prepared according to procedure B from (4-bromo-phenyl)-di-p-tolyl-amine 26 (2.00 g, 5.68×10−3 mol), n-butyllithium (2.5M in hexane) (3.4 mL, 8.50×10−3 mol) and 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (1.58 g, 8.50×10−3 mol). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow solid. Recrystallisation from MeOH afforded the expected product as white needles (1.60 g, 4.00×10−3 mol). Yield: 71%.
A solution of n-butyllithium (2.5 M in hexane) (5.8 mL, 1.45×10−2 mol) was added drop-wise to a solution of (4-bromo-phenoxy)-tert-butyl-dimethyl-silane 22 (4.16 g, 1.45×10−2 mol) in tetrahydrofuran (40 mL) at −78° C. After being stirred for 45 min, the mixture was transferred by cannula to a solution of (2-[4-(2-ethoxy-ethoxy)phenyl]-ethyl)-dimethyl-germyl-chloride (2.25 g, 6.79×10−3 mol) in toluene (50 mL) at −78° C. The mixture was stirred for 3 h at room temperature. The reaction was then quenched with an aqueous solution of HCl (1 M) and extracted with diethylether. The organic fractions were collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent:hexane/ethyl acetate 10/1) gave the expected product as a colourless liquid (2.63 g, 5.23×10−3 mol).
Yield: 77%
Procedure C
A solution of tetrabutylammonium fluoride (1.54 g, 4.88×10−3 mol) in tetrahydrofuran (50 mL) was added drop-wise to a solution of tert-butyl-[4({2-[4-(2-ethoxy-ethoxy)phenyl]-ethyl}-dimethyl-germanyl)-phenoxy]-dimethyl-silane 28 (2.45 g, 4.88×10−3 mol) in tetrahydrofuran (100 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent:hexane/ethyl acetate 4/1) gave the expected product as a colourless liquid (1.42 g, 3.70×10−3 mol). Yield: 76%.
Procedure D
Trifluoromethanesulfonic anhydride (0.88 g, 3.12×10−3 mol) was added slowly to a solution of 4-({2-[4-(2-ethoxy-ethoxy)phenyl]-ethyl}dimethyl-germanyl)-phenol 29 (1.22 g, 3.14×10−3 mol) in pyridine (6 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min, then allowed to warm to room temperature and stirred at this temperature for a further 16 h. The reaction mixture was then poured into water and extracted with diethylether. The organic fractions were collected, washed sequentially with water, 10% aqueous HCl solution, water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent: hexane/ethyl acetate 5/1) gave the expected product as a colourless liquid (1.42 g, 2.72×10−3 mol). Yield: 87%.
Procedure E
A mixture of 4-({2-[4(2-ethoxy-ethoxy)phenyl]-ethyl}dimethyl-germanyl)-phenyl-trifluoromethanesulfonate 30 (0.40 g, 0.77×10−3 mol), [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-p-tolyl-amine 25 (0.40 g, 0.77×10−3 mol), Pd(PPh3)4 (44 mg, 3.8×105 mol), aqueous Na2CO3 (2M) (8 mL) in 1,2-dimethoxyethane (8 mL) was heated at 80° C. with vigorous stirring. After 2 h, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was then partitioned between dichloromethane and 2M Na2CO3 aqueous solution. The organic phase was separated and the aqueous phase was extracted further with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by column chromatography (eluent:hexane/ethyl acetate 19/1) gave the expected product as a colourless oil (0.49 g, 0.64×10−3 mol). Yield: 84%.
This compound was prepared according to procedure C from (4(tert-butyl-dimethyl-silanyloxy)-phenyl-[4′({2-[4-(2-ethoxy-ethoxy)phenyl]-ethyl}-dimethyl-germanyl)-biphenyl-4-yl]-p-tolyl-amine 31 (0.46 g, 0.60×10−3 mol) and tetrabutylammonium fluoride (0.20 g, 0.63×10−3 mol) in tetrahydrofuran (23 mL) After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the organic solution was washed with water. The organic phase was then separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent:hexane/ethyl acetate 7/3) gave the expected product as a colourless oil (0.35 g, 0.54×10−3 mol). Yield: 90%.
This compound was prepared according to procedure D from 4{[4′-({2-[4(2-ethoxy-ethoxy)phenyl]-ethyl}dimethyl-germanyl)biphenyl-4-yl]-tolyl-amino}-phenol 32 (0.33 g, 0.50×10−3 mol) and trifluoromethanesulfonic anhydride (0.14 g, 0.50×10−3 mol) in pyridine (5 mL). The reaction mixture was poured into water and extracted with Et2O. The organic fractions were collected, washed sequentially with water, 10% aqueous HCl solution, water and brine. The organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent: hexane/ethyl acetate 10/1) gave the expected product as a colourless glassy solid (0.34 g, 0.44×10−3 mol). Yield: 86%.
This compound was prepared according to procedure E from 4{[4′-({2-[4(2-ethoxy-ethoxy)phenyl]-ethyl}dimethyl-germanyl)-biphenyl-4-yl]-p-tolyl-amino}phenyl-trifluoromethanesulfonate 33 (0.30 g, 0.39×10−3 mol), [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-p-tolyl-amine 25 (0.20 g, 0.39×10−3 mol), Pd(PPh3)4 (22 mg, 1.90×10−5 mol) and aqueous Na2CO3 (2M) (4 mL) in 1,2-dimethoxyethane (8 mL). After removal of the solvent under reduced pressure, the residue was partitioned between dichloromethane and 2 M Na2CO3 aqueous solution. The organic phase was separated and the aqueous phase was extracted with further portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by column chromatography (eluent:hexane/ethyl acetate 20/1) gave the expected product as a colourless oil (0.28 g, 0.28×10−3 mol). Yield: 71%.
This compound was prepared according to procedure C from the V-[4-(tert-butyl-dimethyl-silanyloxy)phenyl]-N4-[4′-({2-[4-(2-ethoxy-ethoxy)-phenyl]-ethyl}-dimethyl-germanyl)-biphenyl-4-yl]-N4-N4′-di-p-tolyl-biphenyl-4,4′-diamine 34 (0.27 g, 0.26×10−3 mol) and tetrabutylammonium fluoride (0.09 g, 0.28×10−3 mol) in tetrahydrofuran (7 mL). After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and washed with water. The organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent: hexane/ethyl acetate 3/1) gave the expected product as a colourless glassy solid (0.18 g, 0.20×10−3 mol). Yield: 75%.
This compound was prepared according to procedure D from 4[(4′-{[4′-({2-[4-(2-ethoxy-ethoxy)-phenyl]-ethyl}-dimethyl-germanyl)-biphenyl-4-yl]-p-tolyl-amino}-biphenyl-4-yl)-p tolyl-amino]-phenol 35 (0.18 g, 0.20×10−3 mol) and trifluoromethanesulfonic anhydride (0.06 g, 0.20×10−3 mol) in pyridine (5 mL). The reaction mixture was poured into water and extracted with diethylether. The organic fractions were collected, washed sequentially with water, 10% aqueous HCl solution, water and brine. The organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluent:hexane/ethyl acetate 10/1) gave the expected product as a colourless glassy solid (0.19 g, 0.18×10−3 mol). Yield: 92%.
This compound was prepared according to procedure E from 4-[(4′-{[4′-({2-[4(2-ethoxy-ethoxy)-phenyl]-ethyl}-dimethyl-germanyl)-biphenyl-4-yl]-p-tolyl-amino}-biphenyl-4-yl)-p-tolyl-amino]-phenyl-trifluoromethanesulfonate 36 (0.16 g, 0.15×10−3 mol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-di-p-tolyl-amine 27 (0.06 g, 0.15×10−3 mol), Pd(PPh3)4 (9 mg, 0.78×10−5 mol) and aqueous Na2CO3 (2M) (2 mL) in 1,2-dimethoxyethane (5 mL). After removal of the solvent under reduced pressure, the residue was partitioned between dichloromethane and 2 M Na2CO3 aqueous solution. The organic phase was separated and the aqueous phase was extracted with further portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by column chromatography (eluent:hexane/ethyl acetate 17/1) gave the expected product as a white solid (0.13 g, 0.11×10−3 mol). Yield: 75%.
A solution of N4-[4′-(Di-p tolylamino-biphenyl-4-yl]-N4-[4′-({2-[4-(2-ethoxy-ethoxy)-phenyl]-ethyl}-dimethyl-germanyl)-biphenyl-4-yl]-N4,N4′-di-p-tolyl-biphenyl-4,4′-diamine 37 (0.13 g, 0.11×10−3 mol) in trifluoroacetic acid (1% in dichloromethane) (5 mL) was stirred at room temperature for 16 h. The solvent was then removed in vacuo, and the crude material was purified by column chromatography (eluent:hexane/ethyl acetate 10/1) to give the expected product as a white solid (0.08 g, 0.07×10−3 mol). Yield: 72%.
To further exemplify the invention, example 3 relates to assembly of a bithiophene unit in a stepwise process in which each monomer unit is added sequentially to the solid support.
Experimental
All compounds were characterised by gel phase NMR spectroscopy and by elemental analysis and were found to be consistent with the expected structures. Hypogel 200-OH is a low Mw cross-linked polystyrene resin and was purchased from Fluka chemicals.
Bromination of “Hypogel 200-OH” 39
in this and all subsequent structures.
Carbon tetrabromide (26 g, 78.4 mmol) was added to a suspension of Hypogel 200-OH (24.55 g, 19.6 mmol) in/dichloromethane (250 ml). This mixture was cooled/to 0° C., and triphenylphosphine (10.30 g, 39.3 mmol) was added. The mixture was stirred at room temperature under nitrogen for 24 h. After removal of the solvent by filtration, the resin was washed extensively with N3N-dimethylformamide (1×300 mL), tetrahydrofuran/water (1:1) (2×300 mL), tetrahydrofuran (2×300 ml), methanol (2×300 mL) and was dried for 16 h at 50° C. under vacuo to give 39 as pale yellow granules (25 g). Loading level: 0.8 mmol.g−1 (estimated from Br analysis). Elemental analysis: C, 76.1; H, 7.9; Br 6.5%).
Immobilisation of Linker 40
4-{2-[(4-Methoxy-phenyl)-di-p-tolyl-germanyl]-ethyl}-phenol (4.12 g, 8.51 mmol), tetra-n-butylammonium iodide (0.485 g, 1.31 mmol) and cesium carbonate (4.28 g, 13.1 mmol) was added to a suspension of resin 39 (5.45 g, 4.38 mmol) in acetonitrile (30 ml). This mixture was stirred at 85° C. for 22 h. After removal of the solvent by filtration, the resin was washed extensively with acetonitrile (3×100 mL), N,N-dimethylformamide (2×100 mL), tetrahydrofuran/water (1:1) (3×100 mL), tetrahydrofuran (2×100 mL), methanol (2×100 mL) and was dried for 16 h at 50° C. under vacuo to give 40 as pale yellow granules (7.71 g). Loading level: 0.5 mmol.g−1 (estimated from Ge). Elemental analysis: C, 78.0; H, 7.7; Ge,3.5; Br, <1.5%).
Electrophilic Ipso-Cleavage Arylgermane 41
A solution of 1.0M HCl in diethylether (35 mL, 35 mmol) was added to resin 40 (7.30 g, 6.3 mmol). This mixture was stirred at room temperature under nitrogen for 20 h. After removal of the solvent by filtration, the resin was washed with anhydrous diethylether (2×50 mL) and dried at 50° C. under vacuo for 16 h to give resin 41 as pale yellow granules (6.4 g). Loading level: 0.5 mmol.g−1 (estimated from Ge and Cl loadings. Elemental analysis: C, 76.7; H, 7.9; Ge, 3.6; Cl 2.2%.
Immobilization of Thiophene Monomer 10 to Give Resin 42
A solution of LDA (3.26 mL, 2.0M, 6.5 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a degassed solution of silylthiophene 10 (1.80 g, 6.4 mmol) in THF (10 mL) at −50° C. This solution was warmed to 40° C., stirred for 40 min at this temperature and recooled to −50° C. It was then transferred by cannula to a degassed suspension of germylchloride resin 41 (3.35 g, LL=0.6 mmolg−1, 2.1 mmol) in THF (10 mL) at −50° C. The resulting mixture was stirred for 1 hr at 40° C., warmed to RT and stirred for a further 16 hr. After quenching with sat. NH4Cl (aq) (100 mL), the solvent was removed by filtration and the resin washed with DMF (100 mL×3), THF:H2O 1:1 (100 mL×3), THF (100 mL×3) and MeOH (100 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 42 as yellow grains (2.679). Elemental analysis: C, 83.3; H, 7.7; N, 0.2; S, 0.4; Ge, 1.9%.
Deprotection of Silyl Protected Thiophene to Give Resin 43
To silyl protected germylthiophene resin 42 (2.00 g, LL=0.6 mmolg−1, 1.24 mmol) in DMF (5 mL) was added ceasium fluoride (1.32 g, 8.68 mmol) and the mixture left to stir for 72 hrs at 110° C. The solvent was then removed by filtration and the resin washed with DMF (75 mL×2), THF:H2O 1:1 (75 mL×3), THF (75 mL×3) and MeOH (75 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 43 as beige grains (1.58 g). Elemental analysis: C, 84.0; H, 7.9; N, 0.2; S, 0.5; Ge, 1.8%.
Iodination of Resin Bound Thiophene to Give Resin 44
A solution of LDA (1.10 mL, 2.0M, 2.19 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a suspension of germylthiophenes resin 43 (1.18 g, LL=0.6 mmolg−1, 0.73 mmol) in THF (10 mL) at −50° C. After stirring for 40 min at −40° C., a solution of degassed 1,2-diiodoethane (1.03 g, 3.65 mmol) in THF (10 mL) was added by cannula at −50° C. The resulting mixture was stirred in the dark for 1 hr at −40° C., warmed to RT and stirred for a further 1 hr. The solvent was then removed by filtration and the resin washed with Na2S2O3 (aq) (75 mL×3), THF:H2O 1:1 (75 mL×3), THF (75 mL×3) and MeOH (75 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 44 as beige grains (0.98 g). IR (neat) 3024, 2919, 1600, 1509, 1492, 1451, 1244, 1106, 1028 cm−1. Elemental analysis: C, 83.0; H, 7.7; N, 0.3; S, 0.4; Ge, 1.7%.
Suzuki Cross-Coupling on Resin 44 to Give Resin 45
To a degassed solution of silylthiophene pinacolato-boronic ester 11 (502 mg, 1.23 mmol) and germylthiopheneiodide resin 44 (655 mg, LL=0.6, 0.41 mmol) in DMF (5 mL) was added Pd(PPh3)4 (23.1 mg, 0.02 mmol) and the resulting mixture stirred at 60° C. for 24 hr. The solvent was then removed by filtration and the resin washed with DMF (50 mL×2), THF:H2O 1:1 (50 mL×3), THF (50 mL×3) and MeOH (50 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 45 as beige grains (595 mg). IR (neat) 3024, 2919, 1600, 1509, 1492, 1451, 1244, 1104, 1028 cm−1. Elemental analysis: C, 82.6; H, 7.4; N, 0.2; S, 0.8%.
The following steps were carried out to demonstrate the “double coupling” on the resin
Iodination of Resin Bound Thiophene 46
A solution of LDA (1.10 mL, 2.0M, 2.19 mmol) in hexanes/THF/ethylbenzene was added drop-wise to a suspension of germylthiophene resin 45 (314 mg, LL=0.6 mmolg−1, 0.19 mmol) in THF (2 mL) at −50° C. After stirring for 40 min at 40° C., a solution of degassed 1,2-diiodoethane (267 mg, 0.95 mmol) in THF (1 mL) was added by cannula at −50° C. The resulting mixture was stirred in the dark for 1 hr at −40 C., warmed to RT and stirred for a further 1 hr. The solvent was then removed by filtration and the resin washed with Na2S2O3 (aq) (50 mL×3), THF:H2O 1:1 (50 mL×3), THF (50 mL×3) and MeOH (50 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 46 as beige grains (272 mg).
Suzuki Cross-Coupling on Resin Bound Thiophene 47
To a degassed solution of silylthiophene pinacolato-boronic ester 11 (208 mg, 0.51 mmol) and germylthiopheneiodide resin 46 (272 mg, LL=0.6, 0.17 mmol) in DMF (2 mL) was added Pd(PPh3)4 (9.8 mg, 0.008 mmol) and the resulting mixture stirred at 60° C. for 24 hr. The solvent was then removed by filtration and the resin washed with DMF (50 mL×2), THF:H2O 1:1 (50 mL×3), THF (50 mL×3) and MeOH (50 mL×3). The resin was then dried in vacuo at 60° C. to give the required resin 47 as beige grains (262 mg). Elemental analysis: C, 81.8; H, 7.0; N, 0.2; S, 0.8%.
To further exemplify the invention, example 4 relates to assembly of a triarylamine trimer unit in a stepwise process in which each monomer unit is added sequentially to the solid support.
Experimental
All compounds were characterised by gel phase NMR spectroscopy and by elemental analysis and were found to be consistent with the expected structures.
Attachment of Arylamine Monomer 24 to Give Resin 48
A solution of n-butyllithium (2.5 M in hexane) (3.4 mL, 5.4×10−3 mol) was added dropwise to a solution of (4-Bromo-phenyl)-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-p-tolyl-amine 24 (2.53 g, 5.4×10−3 mol) in tetrahydrofuran (20 mL) at −78° C. After being stirred for 45 min, the mixture was transferred by cannula to a suspension of resin C (3.00 g, 1.5×103 mol) in toluene (30 mL) at −78° C. The resulting mixture was stirred for 18 h at room temperature. An aqueous solution of HCl (1 M) was then added and the mixture stirred another 30 min. After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×75 mL), tetrahydrofuran/water (1:1) (2×75 mL), tetrahydrofuran (2×75 mL), methanol (2×75 mL) and was dried for 18 h at 50° C. under vacuo to give resin 48 as pale yellow granules (3.23 g).
Elemental analysis: C, 80.2%; H, 8.0%; N, 0.5%; Ge, 2.7%; Cl, <0.5%
Deprotection of Silyl Protected Resin 48 to Give Resin 49
Procedure F
Tetrabutylammonium fluoride (1.34 g, 4.25×10−3 mol) was added to a suspension of resin 48 (2.43 g, 1.22×10−3 mol) in tetrahydrofuran (20 ml). This mixture was stirred under nitrogen at room temperature for 20 h. After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×75 mL), tetrahydrofuran/water (1:1) (2×75 mL), tetrahydrofuran (2×75 ml), methanol (2×75 mL) and was dried for 16 h at 50° C. under vacuo to give resin 49 as pale yellow granules (2.33 g).
Elemental analysis: C, 80.8%; H, 7.7%; N, 0.7%; Ge, 2.8%
Triflation of Resin Bound Arylamine 49 to Give Resin 50
Procedure G
Trifluoromethanesulfonic anhydride (0.50 mL, 2.97×10−3 mol) was added slowly to a suspension of resin 49 (1.61 g, 0.81×10−3 mol) swollen in pyridine (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min, then allowed to warm to room temperature and stirred at this temperature for a further 16 h. After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×75 mL), tetrahydrofuran/water (1:1) (2×75 mL), tetrahydrofuran (2×75 ml), methanol (2×75 mL) and was dried for 16 h at 50° C. under vacuo to give resin 50 as pale yellow granules (1.73 g).
Elemental analysis: C, 76.3%; H, 6.7%; N, 0.7%; S, 1.3%; F, 2.2%; Ge, 2.7%; N, 0.7%;
Suzuki Cross-Coupling on Resin 50 to Give Resin 51
Procedure H
Resin 50 (1.34 g, 0.67×10−3 mol), [4(tert-butyl-dimethyl-silanyloxy)-phenyl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-p-tolyl-amine 25 (1.73 g, 3.35×10−3 mol), Pd(PPh3)4 (0.15 g, 0.13×10−3 mol), aqueous Na2CO3 (2M) (10 mL) in 1,2-dimethoxyethane (10 mL) were stirred at 80° C. for 18 h. After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×50 mL), tetrahydrofuran/water (1:1) (2×50 mL), tetrahydrofuran (2×50 ml), methanol (2×50 mL) and was dried for 16 h at 50° C. under vacuo to give resin 51 as dark brown granules (1.25 g).
Elemental analysis: C, 77.1%; H, 7.0%; N, 1.0%; F, 2.2%; Ge, 2.5%
Deprotection of Silyl Protected Resin 51 to Give Resin 52
This compound was prepared according to procedure F. Resin 51 (0.94 g, 0.47×10−3 mol) and tetrabutylammonium fluoride (0.74 g, 2.35×10−3 mol) were added together with tetrahydrofuran (10 mL). After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×30 mL), tetrahydrofuran/water (1:1) (2×30 mL), tetrahydrofuran (2×30 ml), methanol (2×30 mL) and was dried for 16 h at 50° C. under vacuo to give resin 52 as dark brown granules (0.91 g).
Elemental analysis: C, 78.5%; H, 7.0%; N, 1.0%; Ge, 2.4%
Triflation of Resin Bound Arylamine 52 to Give Resin 53
This compound was prepared according to procedure G. Resin 52 (0.70 g, 0.35×10−3 mol) and trifluoromethanesulfonic anhydride (0.30 mL, 1.75×10−3 mol) were added together in tetrahydrofuran (10 mL). After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×30 mL), tetrahydrofuran/water (1:1) (2×30 mL), tetrahydrofuran (2×30 mL), methanol (2×30 mL) and was dried for 16 h at 50° C. under vacuo to give resin 53 as brown granules (0.65 g).
Elemental analysis: C, 67.9%; H, 6.3%; N, 1.1%; S, 1.1%; Ge, 2.2%
Suzuki Cross-Coupling on Resin 53 to Give Resin 54
This compound was prepared according to procedure H. Resin 53 (0.53 g, 0.35×10−3 mol) was reacted in 1,2-dimethoxyethane (5 mL) with 27 (1.73 g, 3.35×1104 mol), Pd(PPh3)4 (0.15 g, 0.13×10−3 mol) and aqueous Na2CO3 (2M) (5 mL). After removal of the solvent by filtration, the resin was washed extensively with N,N-dimethylformamide (1×30 mL), tetrahydrofuran/water (1:1) (2×30 mL), tetrahydrofuran (2×30 mL), methanol (2×30 mL) and was dried for 16 h at 50° C. under vacuo to give resin 54 as brown granules (0.47 g).
Elemental analysis: C, 72.0%; H, 6.2%; N, 1.3%; Ge, 2.2%
A suspension of resin 54 (0.33 g) in trifluoroacetic acid (10 % in dichloromethane) (5 mL) was stirred at room temperature for 16 h. The resin was separated off by filtration and washed with dichloromethane. The organic washings were concentrated 50° C. under vacuo to give a dark brown oil. Purification by column chromatography (eluent ethylacetate:hexane 1:20) gave the expected product which was confirmed by 1H and 13C nmr spectroscopy.
| Number | Date | Country | Kind |
|---|---|---|---|
| 02088763 | Apr 2002 | GB | national |
| 02088755 | Apr 2002 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB03/01664 | 4/17/2003 | WO |
