Marys Medicine


Ch02_p 45.78

Modern Organocopper Chemistry. Edited by Norbert Krause Copyright > 2002 Wiley-VCH Verlag GmbH ISBNs: 3-527-29773-1 (Hardcover); 3-527-60008-6 (Electronic) 2Transmetalation Reactions Producing Organocopper Reagents Paul Knochel and Bodo Betzemeier Organocopper reagents constitute a key class of organometallic reagents, with nu-merous applications in organic synthesis [1]. Their high reactivities and chemo-selectivities have made them unique intermediates. Most reports use organocopperreagents of type 1 or 2, which are prepared from organolithiums. This trans-metalation procedure confers optimal reactivity, but in many cases it permitsonly the preparation of relatively unfunctionalized organocopper reagents. Morerecently, substantial developments have been taking place in transmetalations toorganocopper reagents starting from organometallic species that tolerate the pres-ence of functional groups [2], while synthetic methods permitting the preparationof functionalized organolithiums and organomagnesium compounds have alsobeen developed. All organometallics in which the metal M is less electronegativethan copper, and all organometallic species of similar electronegativity but withweaker carbon-metal bonds, are potential candidates for transmetalation reac-tions [3]. Thus, reaction conditions allowing the transmetalation of organo-boron,-aluminium, -zinc, -tin, -lead, -tellurium, -titanium, -manganese, -zirconium and-samarium compounds have all been found, resulting in a variety of new organo-copper reagents of type 3. Their reactivity is dependent on the nature of the origi-nal metal M, which in many cases is still intimately associated with the resultingorganocopper reagent (Scheme 2.1) [3–5].
In this chapter, we will emphasize these recent developments, especially those that allow the preparation of organocopper species not accessible through thestandard procedures involving organolithiums as precursors and their use in re-actions with organic electrophiles.
2.2Transmetalation of Functionalized Organolithium and Organomagnesium Reagents Many functional groups are incompatible with organolithium reagents. Execu-tion of transmetalations at very low temperatures, however, enables functionalized 2 Transmetalation Reactions Producing Organocopper Reagents Transmetalations producing organocopper reagents.
alkenyllithiums and aryllithiums to be prepared, and subsequent further trans-metalation at low temperatures provides the corresponding copper reagents [6].
Thus, treatment of 4-bromobenzonitrile 4 with nBuLi at 100 C in a THF/ether/pentane mixture provides the corresponding aryllithium within 5 min. (Scheme2.2), and subsequent treatment with the THF-soluble copper salt CuCN2LiCl [7]then affords the functionalized arylcopper compound 5. Treatment of this with2-cyclohexenone in the presence of TMSCl [8] furnishes the expected Michaeladduct 6 in 93% yield.
Scheme 2.2. Preparation of functionalized arylcopper reagents from functionalized aryllithiums.
In some cases it can be advantageous first to transmetalate the functionalized aryllithium reagent to the corresponding zinc reagent and then to perform asecond transmetalation to afford the corresponding organocopper species. Thus,2-iodo-1-nitrobenzene 7 is converted into the corresponding lithium reagent bytreatment with phenyllithium [9]. Subsequent transmetalation, firstly with ZnI2 at 2.2 Transmetalation of Functionalized Organolithium and Organomagnesium Reagents 80 C and then with CuCN2LiCl [7] at 30 C, provides the arylcopper 8. Thisreacts with 3-iodo-2-cyclohexenone to give the expected addition-elimination prod-uct 9 in 70% yield.
This method can be extended to the preparation of alkenylcopper compounds.
Thus, treatment of the iodoalkenyl azide 10 with nBuLi at 100 C (Scheme 2.3),followed by transmetalation with ZnI2 in THF and then by a second transmeta-lation with CuCN2LiCl, produces the copper species 11. This then effects a cis-selective carbocupration of ethyl propiolate to furnish the (E,E) diene 12 in 81%yield.
Scheme 2.3. Preparation of an azido-alkenylcopper reagent from an alkenyl iodide.
In general, the preparation of functionalized organolithiums is difficult, al- though direct lithiation with lithium powder in the presence of a catalytic amountof 4,40-di-t-butylbiphenyl (DTBB) as introduced by Yus [10] is a very generalapproach to a broad range of polyfunctional organolithiums [11–16], which may beconverted into the corresponding organocopper compounds by treatment withCuCN2LiCl [6]. Organomagnesium compounds are less reactive than organo-lithiums and tolerate a wider range of functional groups. Mild methods are re-quired for their preparation and excellent results have been obtained by insertion ofhighly reactive ‘‘Rieke-magnesium'' into alkyl or aryl halides [17]. Unfortunately,the presence of such important electron-withdrawing functional groups as esters orcyano functions inhibits the formation of Grignard reagents [18]. Complemen-tarily, halogen-magnesium exchange [19] has proven to be an excellent method forpreparation of functionalized organomagnesium compounds. Thus, treatment of4-iodobenzonitrile 13 with iPrMgBr or iPr2Mg in THF at 25 C furnishes thecorresponding organomagnesium reagent, which is transmetalated to produce thedesired functionalized organocopper 14. Treatment of 14 with allyl bromide pro-duces the allylated product 15 in 75% yield (Scheme 2.4) [20].
This iodine-magnesium exchange can also be performed with heterocyclic iodides, such as the functionalized pyridine 16 [21] or the iodouracil derivative 17(Scheme 2.5) [22]. In both cases, the intermediate organomagnesium reagent can Scheme 2.4. Preparation of functional arylcoppers from functionalized arylmagnesium com-pounds.
2 Transmetalation Reactions Producing Organocopper Reagents Scheme 2.5. Preparation of highly functionalized, six-membered heterocyclic copper reagents.
be converted into the corresponding organocopper compound (18 and 19, respec-tively) and then treated with several electrophiles such as allyl bromide or benzoylchloride, resulting in the expected products 20 and 21 in good yields.
The preparation of polyfunctional 5-membered heterocycles can be achieved in the same manner. The ester-substituted imidazole 22 undergoes a smooth iodine-magnesium exchange at 40 C within 1 h (Scheme 2.6). After transmetalation withCuCN2LiCl, the copper reagent 23 is obtained. Treatment of this with benzoylchloride furnishes the benzoylated imidazole 24 in 67% yield [23]. In the case of the2,3-iodoindole derivative 25, it is possible to perform a selective iodine-magnesiumexchange at position 2, furnishing the 3-iodo-2-indolylcopper reagent 26 after trans-metalation with CuCN2LiCl. Treatment of 26 with allyl bromide provides themonoallylated indole derivative 27 in 92% yield [24].
Scheme 2.6. Preparation of highly functionalized, five-membered heterocyclic copper reagents.
2.2 Transmetalation of Functionalized Organolithium and Organomagnesium Reagents Remarkably, halogen-magnesium exchange can also be extended to aryl and heteroaryl bromides [24, 25]. Thus, the functionalized aryl bromides 28 and 29(Scheme 2.7) were converted, at 0 C and at 30 C, respectively, into the corre-sponding Grignard reagents. After treatment with CuCN, the copper derivative 30and 31 were obtained. Subsequent treatment with typical electrophiles such asbenzoyl bromide or allyl bromide furnished the products 32 and 33, in 70 and 80%yields.
Scheme 2.7. Preparation of functionalized arylcoppers from aryl bromides.
The rate of bromine-magnesium exchange largely depends on the electron den- sity on the aromatic ring, although also being accelerated by the presence of che-lating groups [25]. In the case of polyhalogenated heterocycles, these effects enableselective exchange reactions to be accomplished. Thus, the tribromoimidazole 34(Scheme 2.8) can be successfully converted first into the magnesium derivativeand then into the copper reagent 35, by treatment with iPrMgBr followed by Stepwise BraMg exchange reactions.
2 Transmetalation Reactions Producing Organocopper Reagents CuCN2LiCl. This can then be selectively allylated with allyl bromide to provide thedibromoimidazole 36, which can now be magnesiated by treatment with a furtherequivalent of iPrMgBr, providing the ester-substituted imidazole 37 in 55% yieldafter carboxylation with ethyl cyanoformate [25].
The halogen-magnesium reaction can be extended to electron-poor hetero- aryl chlorides. Thus, tetrachlorothiophene 38 (Scheme 2.9) undergoes chlorine-magnesium exchange at 25 C, providing the corresponding Grignard reagent in2 h. Treatment with CuCN2LiCl gives the copper reagent 39, and allylation withethyl (2-bromomethyl)acrylate produces the functionalized thiophene 40 in almostquantitative yield.
Scheme 2.9. Execution of a ClaMg exchange reaction.
All the allylation reactions can be performed using only catalytic amounts of CuCN2LiCl, with yields the same as those obtained when a stoichiometric amountof the copper salt is deployed. The halogen-magnesium exchange reaction can alsobe extended to the solid phase, allowing a variety of polyfunctional copper speciesto be generated on a resin. Thus, various aryl or heteroaryl iodides or bromides canbe attached to Wang resins and treated with an excess of iPrMgBr (3–8 equiv.) at30 C to 15 C to provide the expected functionalized Grignard reagent. Trans-metalation with CuCN2LiCl then gives, as expected, the corresponding copper re-agent, which can react with various electrophiles such as acid chlorides or allylichalides. After cleavage from the resin, a range of functionalized products may beobtained. Use of the resin-bound bromothiophene 41 as starting material furnishesthe copper reagent 42, which produces the carboxylic acid 43 after allylation andcleavage from the resin (Scheme 2.10) [19, 24].
Scheme 2.10.
Generation and reaction of functionalized organocopper reagents on the solid 2.3 Transmetalation of Organoboron and Organoaluminium Reagents Functionalized organocopper reagents also undergo 1,4-additions. Thus, the alkylcopper 45, prepared from the corresponding Grignard reagent 44, reacts withcyclohexenone at 78 C to give the expected product 46 [26]. Arylcopper com-pounds such as 47 add to 2-enones in the presence of TMSCl and CuCN2LiCl [27](Scheme 2.11).
Scheme 2.11. Michael additions of functionalized organocopper reagents derived from Grignardcompounds.
It is also possible to perform copper-catalyzed alkylation of arylmagnesium compounds. Thus, the copper reagent 48 undergoes a selective cross-coupling [28]with ethyl 4-iodobutyrate to furnish the desired product 49 in 69% yield (Scheme2.12) [29].
Scheme 2.12.
Alkylation of organocopper reagents derived from Grignard compounds.
2.3Transmetalation of Organoboron and Organoaluminium Reagents Direct transmetalation of organoboranes to organocopper reagents is not a generalreaction. Because of their similar bond energies and electronegativities, this trans-metalation is limited to the preparation of alkenylcopper and unfunctionalized 2 Transmetalation Reactions Producing Organocopper Reagents alkylcopper compounds. In the latter case, the reaction is favored by the formationof an ate-complex [30]. Thus, treatment of tripropylborane with MeLi produces thelithium organoboronate 50, which is converted into the copper boronate 51. Treat-ment of 51 with benzoyl chloride is not selective, since both the methyl group andthe propyl group are transferred, affording a mixture of two ketones (Scheme 2.13).
Scheme 2.13.
Acylation of organocopper reagents derived from organoboranes.
The transmetalation of dialkenylchloroboranes of type 52 with methylcopper (3 equiv.) provides an alkenylcopper compound 53, which undergoes cross-couplingwith allylic halides to produce mixtures of SN2 and SN20 products. Interestingly,this method is also useful for the preparation of functionalized alkenylcopperssuch as 54 (Scheme 2.14) [31].
Scheme 2.14.
Allylation of alkenylcopper species derived from alkenylboranes.
Better results can be obtained by generating the boronate species with the aid of sodium methoxide. In this case, satisfactory transmetalation occurs on treatmentwith CuI. Thus, the functionalized copper reagent 55 can be alkynylated with1-bromo-1-hexyne at 40 C, furnishing the enyne 56 in 75% yield (Scheme 2.15)[32].
In the presence of a polar cosolvent such as hexamethylphosphoric triamide (HMPA), it is possible to generate the fluorine-substituted copper compound 57, Scheme 2.15.
Alkynylation of alkenylcopper reagents obtained from alkenylboranes.
2.3 Transmetalation of Organoboron and Organoaluminium Reagents obtained through a 1,2-migration of a butyl group. After acylation, this providesuseful unsaturated ketones such as 58 (Scheme 2.16) [33].
Scheme 2.16. Preparation of fluorinated ketones by way of fluorinated alkenylcopper species.
Thus, direct transmetalation of organoboranes to form organocopper com- pounds is a capricious reaction, not really generally applicable. Much more generalaccess to organocopper compounds can, on the other hand, be achieved by priorconversion of the organoboranes into organozinc compounds. After addition ofCuCN2LiCl [7], the desired copper compounds are then cleanly generated and canbe treated with a broad range of electrophiles, giving excellent yields (Scheme 2.17;see also Sect. 2.4) [34].
Scheme 2.17. Preparation of organocopper reagents from organoboranes.
A smoother transmetalation procedure should be ensured by the more electro- negative character of aluminium, as first demonstrated by Wipf and Ireland [35].
Thus, hydroalumination of 1-hexyne with DIBAL-H, followed by addition of thecuprate 59, bearing non-transferable alkynyl groups, provides the copper interme-diate 60. This adds smoothly to 2-cyclohexenone to produce the Michael adduct 61,in 72% yield (Scheme 2.18) [36].
Scheme 2.18. Michael additions using alkenylcopper species derived from alkenylaluminiums.
2 Transmetalation Reactions Producing Organocopper Reagents Alternatively, by performing a zirconium-catalyzed Negishi methylalumination on 1-hexyne, it is possible to produce stereochemically pure alkenylcopper species62, which adds to enones in a 1,4-fashion, to give compounds such as 63 (Scheme2.18) [35, 36].
Wipf has shown that this method is quite general and tolerates several func- tional groups, such as ethers, thioethers, silanes, halides, aromatic rings, andolefins. The iodoalkyne 64 is readily carbometalated and after treatment withthe dialkynylcuprate 59 furnishes the functionalized copper reagent 65, whichsmoothly undergoes 1,4-addition reactions with enones. Thus, in the case of 2-cyclohexenone, the functionalized ketone 66 is produced in 85% yield (Scheme2.19) [2, 36].
Scheme 2.19. Michael addition of a functionalized alkenylcopper species.
The scope of this transmetalation is very much a function of the availability of interesting alkenylaluminium species [37]. Stannylalumination of alkynes alsoproceeds through a stannylcopper intermediate 68, obtained by transmetalation ofthe stannylated aluminium precursor 67. This reaction enables regioselective stan-nylation of alkynes to be accomplished (Scheme 2.20) [38].
Scheme 2.20.
Stannylation of terminal alkynes with stannylcopper reagents derived from stanny- lated aluminium compounds.
2.4Transmetalation of Functionalized Organozinc Reagents 2.4.1Preparation of Organozinc Reagents Organozinc compounds have been known for more than 150 years, but theirapplication in organic synthesis was formerly rather limited [39], due to their 2.4 Transmetalation of Functionalized Organozinc Reagents moderate reactivity. Only when it was realized that organozincs undergo smoothtransmetalations to give a broad range of organometallics did their synthetic ap-plications begin to increase exponentially. Transmetalation of organozinc reagentsto give organopalladium intermediates [40] and their transmetalation to organo-copper compounds proved to be particularly important [7, 34, 41, 42]. Since it ispossible to prepare organozinc compounds bearing a large range of organic func-tional groups, this methodology broadens the scope of organocopper chemistryconsiderably. This high functional group compatibility is a function of the pro-nounced covalent character of the carbon-zinc bond, while the excellent trans-metalation capability of organozincs for production of other organometallics is aconsequence of the presence of low-lying empty p-orbitals. Especially useful forthis transmetalation are THF-soluble copper salts of the type CuCN2LiX [7, 41].
After transmetalation, the resulting copper species, tentatively represented asRCu(CN)ZnX, reacts with most of those electrophiles Eþ that also react with themore classical diorganolithium cuprates (R2CuLi), to afford products of type R-E(Scheme 2.21).
Scheme 2.21. Preparation of zinc-copper reagents.
Notable exceptions are epoxides and alkyl halides, which do not react directly with RCu(CN)ZnX, although reaction conditions for performing alkylation reac-tions are available [43]. There are two classes of organozinc compounds: organo-zinc halides (RZnX) and diorganozincs (R2Zn). The reactivity of diorganozincs isslightly higher, but the major difference relevant to this second class of organozinccompounds is the absence of zinc salts (ZnX2), which is highly important forapplications in asymmetric addition reactions [44]. The preparation methods aredifferent. Whereas organozinc halides are obtained either by transmetalationreactions or by direct insertion of zinc dust into alkyl halides, diorganozincsare best prepared by means either of an iodine-zinc exchange reaction or of aboron-zinc exchange reaction (Scheme 2.22).
Scheme 2.22. Preparation of organozinc reagents.
2 Transmetalation Reactions Producing Organocopper Reagents Preparation of Organozinc HalidesFunctionalized organozinc halides are best prepared by direct insertion of zinc dustinto alkyl iodides. The insertion reaction is usually performed by addition of aconcentrated solution (approx. 3 M) of the alkyl iodide in THF to a suspension ofzinc dust activated with a few mol% of 1,2-dibromoethane and Me3SiCl [7]. Pri-mary alkyl iodides react at 40 C under these conditions, whereas secondary alkyliodides undergo the zinc insertion process even at room temperature, while allylicbromides and benzylic bromides react under still milder conditions (0 C to 10 C).
The amount of Wurtz homocoupling products is usually limited, but increaseswith increased electron density in benzylic or allylic moieties [45]. A range of poly-functional organozinc compounds, such as 69–72, can be prepared under theseconditions (Scheme 2.23) [41].
Scheme 2.23. Preparation of functionalized zinc reagents by direct insertion of zinc.
Insertion of zinc dust into aryl or heteroaryl iodides is also possible, but polar co- solvents are required in some cases [48, 49]. The use of highly activated zinc (Riekezinc) prepared by reduction of zinc halides with lithium results in faster insertion(Scheme 2.24) [50–52].
Scheme 2.24. Preparation of functionalized arylzinc reagents.
2.4 Transmetalation of Functionalized Organozinc Reagents Crucially, this allows organozinc reagents to be prepared from less reactive aryl bromides and secondary or tertiary alkyl bromides. Alternatively, organozinc io-dides can be prepared by means of a palladium(0)-catalyzed reaction between alkyliodides and Et2Zn (Scheme 2.25) [53–56].
Scheme 2.25. Pd(0)-catalyzed formation of alkylzinc iodides.
The palladium(0)-catalyzed insertion proceeds through a radical insertion mechanism, allowing radical cyclizations to be performed. This procedure con-stitutes a new, stereoselective preparation of cyclic zinc reagents from unsaturated,open-chain compounds. Since the cyclization is radical in nature, the relative ster-eochemistry of the starting alkyl iodide does not need to be controlled. Thus, theunsaturated iodide 73, used as a 1:1 mixture of diastereomers, produces a cyclicorganozinc reagent after Pd(0)-catalyzed iodine-zinc exchange, by way of the tran-sition state 74. This then, after transmetalation with CuCN2LiCl, gives the stereo-merically pure organocopper 75. Allylation with ethyl 2-(bromomethyl)acrylateaffords the cyclopentane derivative 76 almost as a single stereoisomer (Scheme2.26) [54].
This reaction can also be applied to the preparation of heterocyclic organocopper reagents such as 77 from readily available secondary alkyl iodides. Ring-closure inthis case is catalyzed by Ni(acac)2 rather than by Pd(0), affording new heterocyclicmolecules such as 78 (Scheme 2.26) [55]. These cyclization reactions are key stepsin the preparation of such natural products as (–)-methylenolactocin 79 [57] andmethyl epijasmonate 80 [58] (Scheme 2.27).
2 Transmetalation Reactions Producing Organocopper Reagents Scheme 2.26. Radical cyclizations resulting in cyclic copper organometallics (dppf ¼ 1,10-bis(diphenylphosphino)ferrocene).
Scheme 2.27. Preparation of (–)-methylenolactocin 79 and methyl epijasmonate 80.
Various other less general methods for the preparation of organozinc halides are available, transmetalation from organomagnesium compounds being of interest.
Thus, iodine-magnesium exchange in ethyl 2-iodobenzoate 81 produces a magne-sium intermediate, which is transmetalated with ZnBr2 to give the correspondingzinc reagent 82. This undergoes smooth Ni(0)-catalyzed cross-coupling with func-tionalized alkyl iodides (Scheme 2.28) [59].
2.4 Transmetalation of Functionalized Organozinc Reagents Scheme 2.28. Preparation of a functionalized arylzinc halide by transmetalation of an organo-magnesium compound.
Finally, the use of homoallylic zinc alcoholates as masked allylic zinc reagents has been described [60]. Thus, the ketone 83 was treated with nBuLi, producing ahighly sterically hindered lithium alkoxide that, after conversion to the corre-sponding zinc alkoxide, underwent a fragmentation reaction to form the allyliczinc reagent 84. After transmetalation with CuCN2LiCl, this organozinc speciesunderwent an intermolecular addition to the double bond, furnishing the spiro-organometallic compound 85. Benzoylation of this produced the ketone 86, in adiastereomeric ratio of >98:2 and in 60% yield (Scheme 2.29) [61].
Scheme 2.29.
Organozinc reagent prepared by an ene reaction. Preparation of Diorganozinc ReagentsOther than transmetalation reactions from organolithium and organomaganesiumcompounds, there are two general methods for preparing diorganozincs. These areboron-zinc exchange and iodine-zinc exchange [42]. The iodine-zinc exchange re-action is catalyzed by the presence of copper(I) salts and is radical in nature. It isbest performed with Et2Zn [62, 63], and usually takes place within 12 h at 50 C. Itis also possible to perform the exchange under irradiation conditions [64]. Providedthat the presence of metal salts does not perturbthe further course of the reaction,iodine-zinc exchange can be performed by using iPr2Zn generated in situ by treat- 2 Transmetalation Reactions Producing Organocopper Reagents ment of iPrMgBr with ZnBr2 (0.5 equiv.). With this reagent, the exchange reactionoccurs very rapidly (25 C, 1 h), allowing complex secondary diorganozincs to beprepared (Scheme 2.30) [65].
Scheme 2.30. Preparation of a diorganozinc compound by iodine-zinc exchange.
Because of the radical character of the exchange, it is not possible to prepare chiral diorganozinc reagents in this way [66]. The most general and practicalpreparation of diorganozincs is the boron-zinc exchange reaction, which hasseveral advantages. It tolerates various functional groups and, since the startingorganoboranes used for the exchange are prepared from olefins, numerous func-tionalized olefins are available as starting materials. More importantly, boron-zincexchange proceeds with retention of configuration. Thus, chiral organoboranes areexcellent precursors for chiral secondary alkylzinc reagents (Scheme 2.31) [42].
Scheme 2.31. Boron-zinc exchange for the preparation of chiral organozinc reagents.
In the case of primary organoboranes, the exchange reaction is best performed with Et2Zn, whereas less reactive secondary organoboranes require the use ofiPr2Zn. Thus, a wide variety of terminal olefins have been converted into primarydiorganozincs such as 87–89 (Scheme 2.32).
Scheme 2.32. Preparation of polyfunctional primary dialkylzinc compounds by boron-zincexchange.
2.4 Transmetalation of Functionalized Organozinc Reagents Remarkably, this reaction sequence permits the preparation of diorganozincs bearing acidic hydrogen atoms in the molecule. The unsaturated nitroalkane 90and the unsaturated alkylidenemalonate 91 are smoothly converted into the corre-sponding diorganozinc reagents by the sequence shown in Scheme 2.33. Trans-metalation with CuCN2LiCl provides the expected organocopper reagents 92 and93. After allylation with an excess of allyl bromide, the desired products 94 and 95are obtained in excellent yields [70].
Scheme 2.33. Preparation of organocopper reagents bearing acidic hydrogens.
As mentioned above, chiral diorganozincs can be prepared by this procedure.
Thus, treatment of 1-phenylcyclopentene (96) with (–)-IpcBH2 provides a chiralorganoborane (99% ee after recrystallization). Treatment of this with Et2BH at60 C for 16 h gives a diethylorganoborane, which undergoes transmetalationwith iPr2Zn to afford the chiral organozinc reagent 97. After further transmeta-lation with CuCN2LiCl, the chiral secondary organocopper reagent 98 is formed.
Allylation of this with allyl bromide gives the cyclopentane 99 in 44% overall yield(94% ee and 98:2 trans:cis ratio; Scheme 2.34) [71].
Scheme 2.34. Preparation of chiral alkylcopper reagents (Ipc ¼ isopinocampheyl).
The same method can be applied to the preparation of chiral acyclic organo- copper reagents of somewhat lower configurational stability [72]. Chiral cyclic or-ganocopper compounds can also be prepared by diastereoselective hydroborationof prochiral allylic ethers [73]. Mixed secondary organozinc reagents of the typeFGaRZnCH2SiMe3 (FG ¼ functional group; CH2SiMe3: non-transferable group)can also be prepared [74–76].
2 Transmetalation Reactions Producing Organocopper Reagents 2.4.2Substitution Reactions with Copper-Zinc Reagents Organocopper reagents prepared from organozinc species undergo SN20 reactionswith allylic halides or allylic phosphates in high yields. These reactions display ex-cellent SN20 regioselectivity. The polyfunctional organozinc species 100, obtainedfrom the corresponding olefin by a hydroboration/boron-zinc exchange sequence,can be smoothly allylated in the presence of the THF-soluble salt CuCN2LiCl [7,70] to give the polyfunctional quinoline derivative 101. Selective double SN20 reac-tion is observed with 1,3-dichloropropene reagent 102, producing the unsaturatedselenide 103 in 89% yield and with high regioselectivity (Scheme 2.35) [77].
Scheme 2.35.
Copper(I)-mediated allylation reactions.
In most allylation reactions, only a catalytic amount of CuCN2LiCl is required [41]. Use of the chiral ferrocenylamine 104 as a catalyst makes enables asymmetricallylation of diorganozinc reagents to be effected with allylic chlorides (Scheme2.36) [78]. Related electrophiles such as propargylic bromides [79] and unsaturatedepoxides [80] also undergo SN20-substitution reactions (Scheme 2.37).
Scheme 2.36. Enantioselective allylation with diorganozinc reagents.
2.4 Transmetalation of Functionalized Organozinc Reagents Scheme 2.37.
Substitution reactions of propargylic bromides and unsaturated epoxides with Substitution reactions also proceed well with cationic h5-cycloheptadienyliron com- plexes such as 105 [81] and related chromium complexes [82], and have foundapplications in natural product synthesis (Scheme 2.38).
Scheme 2.38. Reactions between copper-zinc reagents and cationic metal complexes.
Alkyl iodides do not react with zinc-copper reagents. However, use of copper species R2Cu(CN)(MgX)2Me2Zn, obtained by treatment of the cuprate Me2Cu(CN)-(MgCl)2 with a diorganozinc compound R2Zn, results in a cross-coupling reactionat 0 C in DMPU. The reaction tolerates a number of functional groups, as wellas alkyl iodides containing acidic hydrogens, such as 106. The desired cross-coupling product 107 is produced in good yield (Scheme 2.39) [43].
Scheme 2.39.
Cross-coupling between copper-zinc reagents and alkyl iodides.
2 Transmetalation Reactions Producing Organocopper Reagents Cross-coupling between functionalized zinc-copper reagents and 1-iodoalkynes or 1-bromoalkynes is very fast [83]. This smooth cross-coupling occurs at lowtemperatures (55 C) and offers high stereoselectivity in reactions with chiralsecondary organozinc-copper reagents such as 108 (obtained by a hydroboration/boron-zinc exchange sequence), producing the alkyne 109 in 42% overall yield(Scheme 2.40) [73].
Scheme 2.40.
Alkynylation of chiral secondary copper-zinc reagents.
Alkynylation of zinc-copper compounds has been used for the synthesis of polyfunctional acetylenic ethers [84] and for the preparation of building blocksfor pharmaceutically active compounds [85]. Whereas cross-coupling between non-activated iodoalkenes and zinc-copper reagents only proceeds at elevated tem-peratures and in polar solvents such as NMP or DMPU (60 C, 12 h) [86], alkenyliodides conjugated with electron-withdrawing groups react under milder con-ditions. Thus, 3-iodo-2-cyclohexenone undergoes the addition-elimination reactionwith the zinc-copper reagent 110 at 30 C within 1 h, affording the functionalizedenone 111 in excellent yield (Scheme 2.41) [46].
The same mechanism is operative for the preparation of squaric acid derivatives of type 112. Treatment of 3,4-dichlorocyclobutene-1,2-dione with two different zinc-copper reagents provides the double addition-elimination product 112 in 67% yield(Scheme 2.41) [87].
Scheme 2.41.
Substitution reactions with copper-zinc reagents by addition-elimination mecha- 2.4 Transmetalation of Functionalized Organozinc Reagents The reaction between zinc-copper reagents and acid chlorides is very general and provides a useful synthesis of ketones [7, 34, 41, 42]. This acylation has also beenused to prepare various indoles substituted in position 2 (Scheme 2.42) [88].
Scheme 2.42.
Synthesis of 2-substituted indoles by acylation of functionalized organozinc 2.4.3Addition Reactions with Copper-Zinc Reagents Zinc-copper compounds readily undergo Michael addition reactions in the pres-ence of TMSCl, selectively affording 1,4-adducts [7, 34, 41, 42]. In the caseof b-disubstituted enones, the 1,4-addition proceeds well in the presence ofBF3OEt2 (Scheme 2.43) [89].
Scheme 2.43. Michael additions of copper-zinc reagents to enones.
Prostaglandin derivatives may be prepared by the addition of copper-zinc re- agents to substituted cyclopentenones [90–92]. In the presence of a copper(I)-monosubstituted sulfonamide, dialkylzincs also add to enones [93]. The additionof zinc-copper compounds to unsaturated esters is difficult, and only efficient if aleaving group is present in the b-position. Alkylidenemalonates, on the other hand,readily undergo Michael additions [94]. The b-phenylsulfonylalkylidenemalonate113 undergoes an addition-elimination process to provide functionalized alkylide-nemalonates such as 114 in excellent yields [95]. Similarly, the b-phenylsulfonyl-nitroolefin 115 readily reacts with copper-zinc organometallics to provide nitrocompounds such as 116, which readily undergo intramolecular Diels-Alder reac-tions (Scheme 2.44) [96].
2 Transmetalation Reactions Producing Organocopper Reagents Scheme 2.44.
Addition-elimination reactions involving copper-zinc reagents.
In general, copper-zinc compounds, unlike organolithium-derived organocopper reagents, undergo clean addition reactions to nitroolefins. After Michael addition,the resulting zinc nitronates can be oxidatively converted into polyfunctional ke-tones, such as 117 (Scheme 2.45) [96].
Scheme 2.45.
Addition of zinc-copper reagents to nitroolefins.
Addition to unsaturated aldehydes results either in the 1,2- or in the 1,4-addition product, depending on the reaction conditions. Thus, in the case of cinnam-aldehyde, the 1,2-addition product is produced in the presence of BF3OEt2 and the1,4-addition product is obtained in the presence of Me3SiCl (Scheme 2.46) [97].
Scheme 2.46. Reactions between zinc-copper compounds and unsaturated aldehydes.
Acetylenic esters react well with copper-zinc compounds. Propiolic esters are especially reactive [83], but other acetylenecarboxylic acid derivatives such as di-methyl acetylenedicarboxylate or propiolamide 118 undergo highly stereoselectivecis addition (Scheme 2.47) [46].
2.5 Transmetalation of Organotin,Organosulfur,and Organotellurium Reagents Scheme 2.47.
Addition of zinc-copper compounds to propiolic acid derivatives.
Finally, zinc-copper exchange by treatment of FGaRZnI with Me2Cu(CN)Li2 provides copper species that add smoothly to various alkynes and which can also beused to perform cyclization reactions (Scheme 2.48) [98].
Scheme 2.48. Intermolecular and intramolecular carbometalation of alkynes with copper-zincreagents.
Organozinc copper reagents have very broad synthetic potential and a number of typical experimental procedures have recently been published [99, 100].
2.5Transmetalation of Organotin, Organosulfur, and Organotellurium Reagents Transmetalations of alkenylstannanes with copper salts are reversible if they areperformed with CuCl in polar solvents [101]. This has found application in cycli-zation reactions (Scheme 2.49) [102].
Scheme 2.49.
Cyclization of alkenylcopper compounds generated from organostannanes.
2 Transmetalation Reactions Producing Organocopper Reagents Transmetalation of this type has also been used to assist palladium(0)-catalyzed cross-coupling reactions in sterically congested substrates. Transmetalation of stan-nanes into alkenylcopper intermediates considerably accelerates subsequentpalladium(0)-catalyzed cross-coupling with arylsulfonates (Scheme 2.50) [103].
Scheme 2.50.
Copper(I) chloride as a promoter of Stille cross-coupling.
These transmetalations may be performed not only with copper(I) halides in DMF [104], but also by using Me2CuLiLiCN. This transmetalation has been usedin the synthesis of prostaglandin derivatives (Scheme 2.51) [105].
Scheme 2.51. Prostaglandin synthesis using SnaCu transmetalation.
As well as alkenylstannanes [106–108], other classes such as a-heteroatom- substituted alkyltributylstannanes [109] and, more importantly, allylic stannanes[110, 111] also undergo these SnaCu transmetalations. Otherwise difficult to pre-pare, allylic copper reagents may, however, be obtained by treatment of allylic stan-nanes (produced in turn from organolithium, magnesium, or zinc organometallics)with Me2CuLiLiCN. They enter into cross-coupling reactions with alkyl bromides[110] or vinyl triflates (Scheme 2.52) [111].
Michael additions [112] and other reactions typical of organocopper species can also be performed with silylcopper reagents such as TBDMSCu, prepared bySn/Cu exchange [113] between Me3SnSiMe2(tBu) and Bu(Th)CuLiLiCN (Th ¼2-thienyl) (Scheme 2.53) [113, 114].
Transmetalation of thioethers to organocopper compounds can also be per- formed in some special cases. Thus, treatment of the ester 119 with Me2CuLiLiCNprovides the copper reagent 120, which can be treated successfully with severalelectrophiles such as allyl bromide or acid chlorides to afford the expected productssuch as 121 (Scheme 2.54) [115, 116].
This reaction can be extended to cyanoketone dithioacetals [117]. Alkenyltellu- 2.5 Transmetalation of Organotin,Organosulfur,and Organotellurium Reagents Scheme 2.52.
Cross-coupling of allylic copper compounds.
Scheme 2.53. Preparation of silylcuprates by Sn/Cu-transmetalation.
Scheme 2.54.
Sulfur/copper exchange reaction.
rium species also undergo exchange with Me2CuLiLiCN. The synthetic impor-tance of this exchange is due to the easy availability of (Z)-alkenyltellurium speciesby reduction of alkynyl tellurides such as 122 (Scheme 2.55) [118].
Scheme 2.55.
Te/Cu exchange reactions of (Z)-alkenyltellurium species.
2 Transmetalation Reactions Producing Organocopper Reagents 2.6Transmetalation of Organotitanium and Organomanganese Reagents Transmetalations with first row transition metal elements such as titanium ormanganese have produced useful synthetic applications. Organotitanate species oftype 123 show the advantage of high SN20 selectivity in the anti stereochemistry ofthe resulting copper(I) intermediates (Scheme 2.56) [119, 120].
Scheme 2.56.
Copper(I)-catalyzed anti-SN20 substitution of allylic phosphates.
Organomanganese reagents are very useful organometallics, reacting with high chemoselectivity with acid chlorides [121] and several other classes of electrophiles[122]. The scope of organomanganese reagents can be greatly increased by use ofcopper(I) catalysis. Especially impressive is the performance of Michael additions[123–128]. Thus, the Michael addition between BuMnCl and pulegone 124, fur-nishing 125, proceeds in excellent yield in the presence of Li2CuCl4 (3 mol%)(Scheme 2.57) [128].
Scheme 2.57.
Copper-catalyzed Michael addition reactions between organomanganese reagents and pulegone.
Acylation reactions can also be greatly improved in this way, with t-alkyl- or sec- alkyl-manganese reagents reacting with acid chlorides in excellent yields [123]. Therelated addition-elimination to 3-ethoxy-2-cyclohexenone is also improved, result-ing after acidic aqueous workup in 3-methyl-2-cyclohexenone [125]. The perilla-ketone 126 was prepared in an improved yield using copper(I) catalysis (Scheme2.58) [129].
2.7 Transmetalation of Organozirconium and Organosamarium Reagents Scheme 2.58. Preparation of perilla-ketone using copper-catalyzed acylation.
Alkylation of organomanganese reagents with alkyl bromides can also be im- proved by addition of CuCl (3 mol%). The reactions proceed at room temperatureand are complete within a few hours [123, 130]. The opening of epoxides is alsoimproved under these conditions. The reaction also features good chemoselectivity,tolerating the presence of sensitive functions such as ketones (Scheme 2.59) [130].
Scheme 2.59.
Copper-catalyzed alkylation of alkyl manganese reagents.
Benzylic organomanganese reagents prepared by direct insertion of activated man-ganese metal display the same behavior (Scheme 2.60) [131]. Excellent results arealso obtained for 1,4-additions of organomanganese reagents to unsaturated estersin the presence of CuCl (3 mol%) [127].
Scheme 2.60.
Copper-catalyzed acylation of benzylic manganese reagents.
2.7Transmetalation of Organozirconium and Organosamarium Reagents Transmetalation reactions of organozirconium reagents were pioneered bySchwartz [130–132], with improved procedures developed more recently byLipshutz [133] and Wipf [134]. The hydrozirconation of 1-hexene with H(Cl)ZrCp2at 25 C under sonication conditions produces the n-hexylzirconium complex 127,which adds to cyclohexenone in the presence of CuBrMe2S (10 mol%) to affordthe desired product 128 in 79% isolated yield (Scheme 2.61) [134].
2 Transmetalation Reactions Producing Organocopper Reagents Scheme 2.61.
Copper-catalyzed 1,4-addition of alkylzirconium derivatives.
Similarly, alkenylzirconium species prepared by the hydrozirconation of alkynes add in a conjugated fashion to enones. Formation of an intermediate zincate priorto transmetalation to the copper species facilitates the Michael addition (Scheme2.62) [135]. This methodology has been applied to the preparation of protectedmisoprostol 129 (Scheme 2.63) [136, 137].
Scheme 2.62. ‘‘Michael addition of an alkenylzirconium compound'', by successive trans-metalation into zinc and copper intermediates.
Scheme 2.63.
Synthesis of protected misoprostol 129.
The mechanism and the nature of the reaction intermediates have been carefully studied by Wipf, revealing an activation of the carbonyl group of the enone by thezirconium complex. Remarkably, a variety of primary and secondary alkylzirco-nium complexes can be added to enones in 1,4-fashion under mild conditions [134,138]. Interestingly, treatment of zirconocyclopentadienes such as 130 with alkynessuch as dimethyl acetylenedicarboxylate in the presence of CuCl gives benzenederivatives such as 131 [136, 137]. A transmetalation from Zr to Cu has been pos-tulated in this reaction. Annelation reactions involving a similar transmetalation of130 and cross-coupling with 1,2-diodobenzene proceeds in high yield to afford 132(Scheme 2.64) [139, 140].
2.7 Transmetalation of Organozirconium and Organosamarium Reagents Scheme 2.64.
Copper-catalyzed reactions of zirconocyclopentadienes.
Cross-coupling reactions between alkenylzirconocenes such as 133 and aryl or alkenyl iodides occur readily in the presence of CuCl and Pd(PPh3)4, producingtetrasubstituted olefins such as 134 in good yields (Scheme 2.65) [141, 142].
Scheme 2.65.
Cross-coupling between alkenylzirconocene complexes and aryl iodides.
Carbocupration of alkynes by zirconacyclopentane derivatives can be performed according to the same procedure. Thus, the zirconocyclopentane 135, obtained bytreatment of Bu2ZrCp2 with 1,6-heptadiene, reacts at room temperature with phe-nylacetylene to afford the adduct 136 through a carbocupration-reductive eliminationmechanism. Cross-coupling followed by intramolecular carbocupration takes place inthe case of the reaction with 1-bromohexyne, producing 137 (Scheme 2.66) [143].
Scheme 2.66.
Copper-catalyzed reactions of zirconacyclopentane derivatives.
2 Transmetalation Reactions Producing Organocopper Reagents Finally, spiro-compounds such as 138 can be prepared by treatment of zircona- cylopentadienes such as 139 with 3-iodo-2-cyclohexenone in the presence of CuCl(2 equiv.) (Scheme 2.67) [144].
Scheme 2.67.
Spirometalation of zirconacyclopentadienes.
Very few transmetalations between organolanthanides and organocopper re- agents have been reported. Organosamarium(III) reagents, prepared by treatmentof SmI2 with alkyl halides in THF/HMPA, undergo easy conjugate addition tounsaturated ketones and nitriles in the presence of TMSCl, producing the corre-sponding Michael adducts. Functionalized alkyl bromides such as 140 react chemo-selectively with cyclohexenone in the presence of TMSCl and CuBrMe2S (0.1equiv.) to afford the polyfunctional ketone 141 in 60% yield (Scheme 2.68) [145].
Scheme 2.68.
Copper-catalyzed 1,4-addition of organosamarium reagents.
Transmetalations of various organometallic species with copper salts have beenfound to produce highly useful organocopper reagents of great synthetic interest.
Many different organometallic precursors have proved valuable, depending on thefunctionality present in the copper reagent. The scope of organocopper chemistryhas been greatly enhanced by these new transmetalation reactions and these re-agents have found many applications in organic synthesis.
1 B. H. Lipshutz, S. Sengupta, Org.
22 M. Abarbri, P. Knochel, Synlett React. 1992, 41, 135.
2 P. Wipf, Synthesis, 1993, 537.
23 F. Dehmel, M. Abarbri, P. Knochel, 3 E. Negishi, Organometallics in Organic Synlett 2000, 345.
Synthesis, Wiley: New York, 1980.
24 M. Abarbri, J. Thibonnet, 4 N. Krause, Angew. Chem. 1999, 111, L. Be´rillon, F. Dehmel, 83; Angew. Chem. Int. Ed. Engl. 1999, J. Org. Chem. 2000, 65, 4618.
25 M. Abarbri, F. Dehmel, P. Knochel, 5 G. Boche, F. Bosold, M. Marsch, Tetrahedron Lett. 1999, 40, 7449.
K. Harms, Angew. Chem. 1998, 110, 26 B. H. Lipshutz, D. A. Parker, S. L.
1779; Angew. Chem. Int. Ed. Engl.
Nguyen, K. E. McCarthy, J. C.
1998, 37, 1684.
Barton, S. E. Whitney, H. Kotsuki, 6 C. E. Tucker, T. N. Majid, P.
Tetrahedron 1986, 42, 2873.
Knochel, J. Am. Chem. Soc. 1992, 27 G. Varchi, A. Ricci, G. Cahiez, P.
Knochel, Tetrahedron 2000, 56, 2727.
7 P. Knochel, M. C. P. Yeh, S. C.
28 G. Cahiez, C. Chaboche, M.
Berk, J. Talbert, J. Org. Chem. 1988, Je´ze´quel, Tetrahedron 2000, 56, 2733.
29 W. Dohle, L. Be´rillon, M. Wimmer, 8 Y. Horiguchi, S. Matsuzawa, P. Knochel, manuscript in E. Nakamura, I. Kuwajima, Tetrahedron Lett. 1986, 27, 4025.
30 N. Miyaura, N. Sasaki, M. Itoh, 9 J. F. Cameron, J. M. J. Fre´chet, A. Suzuki, Tetrahedron Lett. 1977, J. Am. Chem. Soc. 1991, 113, 4303.
10 C. Najera, M. Yus, Recent Res. Devel.
31 H. Yatagai, J. Org. Chem. 1980, 45, in Organic Chem. 1997, 1, 67.
11 C. Gomez, F. F. Huerta, M. Yus, 32 H. C. Brown, G. Molander, J. Org.
Tetrahedron Lett. 1997, 38, 687.
Chem. 1981, 46, 645.
12 C. Gomez, F. F. Huerta, M. Yus, 33 J. Ichikawa, S. Hamada, T. Sonoda, Tetrahedron 1998, 6177.
H. Kobayashi, Tetrahedron Lett. 1992, 13 D. J. Ramon, M. Yus, Tetrahedron Lett.
1993, 34, 7115.
34 P. Knochel, Synlett, 1995, 393.
14 C. Gomez, F. F. Huerta, M. Yus, 35 R. E. Ireland, P. Wipf, J. Org. Chem.
Tetrahedron 1998, 54, 1853.
1990, 55, 1425.
15 F. Foubelo, A. Gutierrez, M. Yus, 36 P. Wipf, J. H. Smitrovich, C.-W.
Tetrahedron Lett. 1997, 38, 4837.
Moon, J. Org. Chem. 1992, 57, 3178.
16 A. Guijarro, M. Yus, Tetrahedron 37 P. Wipf, L. Lim, Angew. Chem. 1993, 1995, 51, 231.
105, 1095; Angew. Chem. Int. Ed. Engl.
17 R. D. Rieke, Science 1989, 246, 1260.
1993, 32, 1068.
18 T. P. Burns, R. D. Rieke, J. Org.
38 S. Sharma, A. C. Oehlschlager, Chem. 1987, 52, 3674.
J. Org. Chem. 1989, 54, 5064.
¨nder, L. Boymond, L.
39 E. Frankland, Liebigs Ann. 1849, 71, Be´rillon, A. Lepreˆtre, G. Varchi, S. Avolio, H. Laaziri, G.
40 E. Negishi, Acc. Chem. Res. 1982, 15, Que´guiner, A. Ricci, G. Cahiez, P.
Knochel, Chem. Eur. J. 2000, 6, 767.
41 P. Knochel, R. Singer, Chem. Rev.
20 L. Boymond, M. Rottla 1993, 93, 2117.
Cahiez, P. Knochel, Angew. Chem.
42 P. Knochel, J. J. Almena Perea, 1998, 110, 1801; Angew. Chem. Int. Ed.
P. Jones, Tetrahedron 1998, 54, 8275.
Engl. 1998, 37, 1701.
43 C. E. Tucker, P. Knochel, J. Org.
21 L. Be´rillon, A. Lepreˆtre, A. Turck, Chem. 1993, 58, 4781.
N. Ple´, G. Que´guiner, G. Cahiez, 44 K. Soai, S. Niwa, Chem. Rev. 1992, 92, P. Knochel, Synlett 1998, 1359.
2 Transmetalation Reactions Producing Organocopper Reagents 45 S. C. Berk, M. C. P. Yeh, N. Jeong, 65 L. Micouin, P. Knochel, Synlett P. Knochel, Organometallics 1990, 9, 66 R. Duddu, M. Eckhardt, 46 H. P. Knoess, M. T. Furlong, M. J.
M. Furlong, H. P. Knoess, S.
Rozema, P. Knochel, J. Org. Chem.
Berger, P. Knochel, Tetrahedron 1991, 56, 5974.
1994, 50, 2415.
47 C. Janikaram, P. Knochel, 67 L. Schwink, P. Knochel, Tetrahedron Tetrahedron 1993, 49, 29.
Lett. 1994, 35, 9007.
48 T. N. Majid, P. Knochel, Tetrahedron 68 A. Devasagayaraj, L. Schwink, Lett. 1990, 31, 4413.
P. Knochel, J. Org. Chem. 1995, 60, 49 T. M. Stevenson, A. S. B. Prasad, J. R. Citineni, P. Knochel, 69 A. Longeau, F. Langer, P.
Tetrahedron Lett. 1996, 37, 8375.
Knochel, Tetrahedron Lett. 1996, 37, 50 L. Zhu, R. M. Weymeyer, R. D.
Rieke, J. Org. Chem. 1991, 56, 1445.
70 F. Langer, L. Schwink, 51 R. D. Rieke, M. V. Hanson, J. D.
A. Devasagayaraj, P.-Y. Chavant, Brown, Q. J. Niu, J. Org. Chem. 1996, P. Knochel, J. Org. Chem. 1996, 61, 52 M. V. Hanson, R. D. Rieke, J. Am.
71 C. Darcel, F. Flachsmann, Chem. Soc. 1995, 117, 10775.
P. Knochel, Chem. Commun. 1998, ¨ ller, R. Lentz, C. E.
72 A. Boudier, F. Flachsmann, P. Knochel, J. Am. Chem. Soc. 1993, P. Knochel, Synlett 1998, 1438.
73 A. Boudier, E. Hupe, P. Knochel, ¨ ller, C. E. Tucker, Angew. Chem. 2000, 112, 2396; Angew.
A. Vaupel, P. Knochel, Tetrahedron Chem. Int. Ed. Engl. 2000, 39, 2294.
Lett. 1993, 34, 7911.
74 S. Berger, F. Langer, C. Lutz, 55 A. Vaupel, P. Knochel, Tetrahedron P. Knochel, T. A. Mobley, C. K.
Lett. 1994, 35, 8349.
Reddy, Angew. Chem. 1997, 109, 1603; ¨ ller, A. Vaupel, C. E.
Angew. Chem. Int. Ed. Engl. 1997, 36, ¨ demann, P. Knochel, Chem. Eur. J. 1996, 2, 1204.
75 C. Lutz, P. Knochel, J. Org. Chem.
57 A. Vaupel, P. Knochel, Tetrahedron 1997, 62, 7895.
Lett. 1995, 36, 231.
76 P. Jones, P. Knochel, J. Chem. Soc.
¨ ller, P. Knochel, Synlett Perkin Trans. 1 1997, 3117.
77 H. G. Chen, J. L. Gage, S. D.
59 R. Giovannini, T. Stu Barrett, P. Knochel, Tetrahedron A. Devasagayaraj, G. Dussin, Lett. 1990, 31, 1829.
P. Knochel, J. Org. Chem. 1999, 64, ¨ bner, P. Knochel, Tetrahedron Lett. 2000, 41, 9233.
60 P. Jones, P. Knochel, J. Org. Chem.
79 M. J. Dunn, R. F. W. Jackson, J.
1999, 64, 186.
Chem. Soc. Chem. Commun. 1992, 319.
61 N. Millot, P. Knochel, Tetrahedron 80 B. H. Lipshutz, K. Woo, T. Gross, Lett. 1999, 40, 7779.
D. J. Buzard, R. Tirado, Synlett 1997, 62 M. J. Rozema, A. Sidduri, P. Knochel, J. Org. Chem. 1992, 57, 81 W. Blankenfeldt, J.-W. Liao, L.-C.
Lo, M. C. P. Yeh, Tetrahedron Lett.
63 M. J. Rozema, C. Eisenberg, 1996, 37, 7361.
¨ tjens, R. Ostwald, K. Belyk, 82 J. H. Rigby, M. Kirova-Snover, P. Knochel, Tetrahedron Lett. 1993, Tetrahedron Lett. 1997, 38, 8153.
83 M. C. P. Yeh, P. Knochel, 64 A. B. Charette, A. Beauchemin, Tetrahedron Lett. 1989, 30, 4799.
J. F. Marcoux, J. Am. Chem. Soc.
¨ rensen, A. E. Greene, 1998, 120, 5114.
Tetrahedron Lett. 1990, 31, 7597.
85 E. J. Corey, C. J. Helal, Tetrahedron 105 J. R. Behling, K. A. Babiak, J. S. Ng, Lett. 1997, 38, 7511.
A. L. Campbell, R. Moretti, 86 S. Marquais, G. Cahiez, M. Koerner, B. H. Lipshutz, J. Am.
P. Knochel, Synlett 1994, 849.
Chem. Soc. 1988, 110, 2641.
87 A. Sidduri, N. Budries, R. M. Laine, 106 E. Piers, E. J. McEachern, P. A.
P. Knochel, Tetrahedron Lett. 1992, Burns, J. Org. Chem. 1995, 60, 2322.
107 E. Piers, J. M. Chong, Can. J. Chem.
88 H. G. Chen, C. Hoechstetter, 1988, 66, 1425.
P. Knochel, Tetrahedron Lett. 1989, 108 E. Piers, H. E. Morton, J. M.
Chong, Can. J. Chem. 1987, 65, 78.
89 M. C. P. Yeh, P. Knochel, W. M.
109 J. R. Falck, R. K. Bhatt, J. Ye, J. Am.
Butler, S. C. Berk, Tetrahedron Lett.
Chem. Soc. 1995, 117, 5973.
1988, 29, 6693.
110 B. H. Lipshutz, R. Crow, S. H.
90 H. Tsujiyama, N. Ono, T. Yoshino, Dimock, E. L. Ellsworth, R. A. J.
S. Okamoto, F. Sato, Tetrahedron Lett.
Smith, J. R. Behling, J. Am. Chem.
1990, 31, 4481.
Soc. 1990, 112, 4063.
91 T. Yoshino, S. Okamoto, F. Sato, 111 B. H. Lipshutz, T. R. Elworthy, J. Org. Chem. 1991, 56, 3205.
J. Org. Chem. 1990, 55, 1695.
92 K. Miyaji, Y. Ohara, Y. Miyauchi, 112 B. H. Lipshutz, J. I. Lee, Tetrahedron T. Tsuruda, K. Arai, Tetrahedron Lett.
Lett. 1991, 32, 7211.
1993, 34, 5597.
113 B. H. Lipshutz, D. C. Reuter, E. L.
93 M. Kitamura, T. Miki, K. Nakano, Ellsworth, J. Org. Chem. 1989, 54, R. Noyori, Tetrahedron Lett. 1996, 37, 114 B. H. Lipshutz, S. Sharma, D. C.
94 G. Cahiez, P. Venegas, C. E.
Reuter, Tetrahedron Lett. 1990, 31, Tucker, T. N. Majid, P. Knochel, J. Chem. Soc., Chem. Commun. 1992, 115 M. Hojo, S. Tanimoto, J. Chem. Soc.
Chem. Commun. 1990, 1284.
95 C. E. Tucker, P. Knochel, Synthesis 116 M. Hojo, H. Harada, A. Hosomi, Chem. Lett. 1994, 437.
96 C. Jubert, P. Knochel, J. Org. Chem.
117 M. Hojo, H. Harada, C. Watanabe, 1992, 57, 5431.
A. Hosomi, Bull. Chem. Soc. Jpn.
97 M. C. P. Yeh, P. Knochel, L. E. Santa, 1994, 67, 1495.
Tetrahedron Lett. 1988, 29, 3887.
118 J. V. Comasseto, J. N. Berriel, Synth.
98 S. A. Rao, P. Knochel, J. Am. Chem.
Commun. 1990, 20, 1681.
Soc. 1991, 113, 5735.
119 M. Arai, E. Nakamura, B. H.
99 P. Knochel, M. J. Rozema, C. E.
Lipshutz, J. Org. Chem. 1991, 56, Tucker, in Organocopper Reagents, A Practical Approach, R. J. K. Taylor 120 M. Arai, B. H. Lipshutz, (Ed.), Oxford University Press, E. Nakamura, Tetrahedron 1992, Oxford, 1994, pp. 85–104.
100 P. Knochel, P. Jones (Eds.), 121 G. Friour, G. Cahiez, J. F.
Organozinc Reagents: A Practical Normant, Synthesis 1984, 37.
Approach; Oxford University Press, 122 G. Cahiez, An. Quim. 1995, 91, 561.
Oxford, 1999.
123 G. Cahiez, S. Marquais, Pure Appl.
101 V. Farina, S. Kapdia, B. Krishnan, Chem. 1996, 68, 53.
C. Wang, L. S. Liebeskind, J. Org.
124 G. Cahiez, M. Alami, Tetrahedron Chem. 1994, 59, 5905.
1989, 45, 4163.
102 E. Piers, E. J. McEachern, P. A.
125 G. Cahiez, M. Alami, Tetrahedron Burns, Tetrahedron 2000, 56, 2753.
Lett. 1989, 30, 3541.
103 X. Han, B. M. Stoltz, E. J. Corey, 126 G. Cahiez, M. Alami, Tetrahedron J. Am. Chem. Soc. 1999, 121, 7600.
Lett. 1989, 30, 7365.
104 E. Piers, T. Wong, J. Org. Chem.
127 G. Cahiez, M. Alami, Tetrahedron 1993, 58, 3609.
Lett. 1990, 31, 7423.
2 Transmetalation Reactions Producing Organocopper Reagents 128 G. Cahiez, S. Marquais, M. Alami, 138 P. Wipf, W. Xu, J. H. Smitrovich, Org. Synth. 1993, 72, 135.
R. Lehmann, L. M. Venanzi, 129 G. Cahiez, P.-Y. Chavant, E. Me´tais, Tetrahedron 1994, 50, 1935.
Tetrahedron Lett. 1992, 33, 5245.
139 T. Takahashi, M. Kotora, Z. Xi, 130 D. B. Carr, J. Schwartz, J. Am.
J. Chem. Soc. Chem. Commun. 1995, Chem. Soc. 1979, 101, 3521.
131 M. Yoshifuji, M. J. Loots, 140 T. Takahashi, R. Hara, Y. Nishihara, J. Schwartz, Tetrahedron Lett. 1977, M. Kotora, J. Am. Chem. Soc. 1996, 132 J. Schwartz, M. J. Loots, H. Kosugi, 141 R. Hara, Y. Nojshihara, P. D.
J. Am. Chem. Soc. 1980, 102, 1333.
Landre´, T. Takahashi, Tetrahedron 133 B. H. Lipshutz, E. L. Ellsworth, Lett. 1997, 38, 447.
J. Am. Chem. Soc. 1990, 112, 7440.
142 M. Kotora, C. Xi, T. Takahashi, 134 P. Wipf, J. H. Smitrovich, J. Org.
Tetrahedron Lett. 1998, 39, 4321.
Chem. 1991, 56, 6494.
143 Y. Liu, B. Shen, M. Kotora, T.
135 B. H. Lipshutz, M. R. Wood, J. Am.
Takahashi, Angew. Chem. 1999, 111, Chem. Soc. 1993, 115, 12625.
966; Angew. Chem. Int. Ed. Engl. 1999, 136 K. A. Babiak, J. R. Behling, J. H. Dygos, K. T. McLaughlin, J. S. Ng, V. J.
144 C. Xi, M. Kotora, N. Nakajima, Kalish, S. W. Kramer, R. L. Shone, T. Takahashi, J. Org. Chem. 2000, 65, J. Am. Chem. Soc. 1990, 112, 7441.
137 B. H. Lipshutz, M. R. Wood, J. Am.
145 P. Wipf, S. Venkatraman, J. Org.
Chem. Soc., 1994, 116, 11689.
Chem. 1993, 58, 3455.


Microsoft word - man1251_1262.doc

M.A. Al-Bayati/Medical Veritas 4 (2007) 1251–1262 Analysis of causes that led to the development of vitiligo in Jeanett's case with recommendations for clinical tests and treatments Mohammed Ali Al-Bayati, Ph.D., DABT, DABVT Toxicologist & Pathologist Toxi-Health International 150 Bloom Drive, Dixon, CA 95620 Phone: +1 707 678 4484 Fax: +1 707 678 8505

Notas a los estados financieros a diciembre 31 de 1999

EMPRESA DE DESARROLLO URBANO DE BOLÍVAR S.A. NIT: 890.481.123-1 NOTAS A LOS ESTADOS FINANCIEROS A JUNIO 30 DE 2015 1. NOTAS DE CARÁCTER GENERAL 1. NATURALEZA JURIDICA, OBJETO SOCIAL ACTIVIDADES QUE DESAROLLA O COMETIDO ESTATAL. NATURALEZ-A JURIDICA La Empresa de Desarrollo Urbano de Bolívar -EDURBE S.A., es una Empresa Industrial y Comercial del estado, del Orden Distrital, constituida el 24 de Diciembre de 1981, mediante Escritura Número 2069 de la Notaria 2da de Cartagena, su capital es netamente público y sus