Schwartz Reagent Review

PII: S0040-4020(96)00754-5
Tetrahedron,Vol. 52. No. 40, pp. 12853-12910. 1996 Copyright8 1996 Elsevier ScienceLtd Printed in Great Britain. All rightsreserved 0040-4020/96 $15.00 + 0.00
TETRAHEDRON REPORT NUMBER 406
SYNTHETIC APPLICATIONS 0F
ORGAN~CHL~R~Z~RCON~CENE C0MPLEXEs
PeterWipt*and Heike Jahn
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Contents
1. 2. 3. 4. Introduction Background Preparation of Zirconocene Hydrochloride (Schwartz Reagent) Hydrozirconation A. B. C. D. E. 5. 6. 7. 8. 9. Functional group compatibility of hydrozirconation Hydrozirconation of alkenes and allenes Hydrozirconation-isomerization Hydrozirconation of alkynes Bimetallic zirconocenes 12854 12855 12856 12858 12860 12864 12867 12869 12872 12875 12876 12877 12878 12879 12879 12880 12881 12889 12889 12891 12893 12894 12897 12901 12853
Halogenation of Organozirconocenes Oxidation and Hydrogenation Carbon Monoxide and Isonitrile Insertion into Organozirconocenes Conversion of Organozirconocenes to Organophosphorus, -selenium and -tellurium Compounds, and Amines Transmetalation of Organozirconocenes A. B. C. D. E. F. G. H. Zirconium+aluminum Zirconium+boron Zirconium-+copper Zirconium+mercury Zirconium+nickel Zitconium+palladium Zirconium+tin Zirconium+zinc
10. 11.
Cationic Zirconocene Complexes Concluding Remarks
12854
P. WIPF and H. JAI-IN
1. Introduction Organozirconocenes have emerged as one of the most useful classes of transition metal derivatives for use in organic synthesis. A wide range of zirconocene-mediated transformations and the relative ease of preparation of alkenyl- and alkylchlorozirconocenes contribute to the broad appeal of this chemistry. Hydrozirconation of alkynes or alkenes is often performed at room temperature and does not require special glassware or glove-box techniques. The relative stability of organozirconocenes is reflected by a considerable tolerance toward functional groups (FG) in the substrate. The polarization of the carbon-zirconium bond is comparable to Grignard reagents, however, due to the steric crowding around the zirconium atom, the organometallic bond is quite shielded and only small electrophiles attack the complex directly. Much of the development of the chemistry of organozirconocenes has therefore focused on indirect reaction pathways where other metals participate in carbon-carbon bond formations, or where access to the metal center is facilitated by the preparation of formally cationic complexes.
\z(+C chemoselectivity, regioselectivity,

H stereoselectivity
CpjrO* a3qH
WW
Zr(lV) ff (14e )
ligand abstraction
Ag+
WG) Zr(lV) ff (16eJ
M-X
transmetalation * 1-< W=G) M = Al, B, Cu, Hg, Ni, Pd, Sn, Zn
co / \ H
Br2
7 0 Cp2Zr
4,
--_
Br\H R
Figure 1. Summary of typical preparation and reactions of organozirconocenes.
This review summarizes the preparation of organochlorobis(cyciopentadienyl)zirconium(lV) complexes and their subsequent organic transformation and transmetalation chemistry. The discussion will mainly focus on developments since 1990, since excellent reviews are available that cover the earlier work. ,2Ws For a treatment of the wealth of chemistry of zirconium(ll) complexes and their applications in carbometalation,scyclozirconation,7 and Ziegler-Natta olefin polymenzation,s~g~lothe reader is referred to a series of recent reviews in these areas.ltlt*lls
Organochlorozirconocene complexes
12855
2. Background Zirconium is among the twenty most abundant elements in the earth crust and therefore very s readily available and relatively inexpensive compared to other transition metals.14 After the preparation of the first zirconocene, Cp2ZrBr2, in 1953, 1s further development of the chemistry of Group 4 metallocenes was initially slow, but rapidly expanded in the 1970 and the rate of s, publication is still increasing at a considerable pace. 1s Landmark events for applications of organochlorobis(cyclopentadienyl)zirconium(lV) complexes in organic chemistry were the preparation of zirconocene hydrides by Wailes and Weigold in 197017 and the use of hydrozirconation for the functionalization of organic compounds by Schwartz et al. in 1974.18 Whereas the metathetical exchange reaction between a metal halide and a main group organometallic represents the most general route toward transition metal derivatives, hydrozirconation targets readily available alkene and alkyne precursors and thus by-passes alkyl or alkenyl halides and strongly basic lithium or magnesium reagents for the use of organozirconocenes in organic synthesists Two cyclopentadienyl groups occupy three coordination sites each in organochlorobis(cyclopentadienyl)zirconium(lV) complexes and provide effective .steric shielding as well as electron donating power to the metal (Figure 2). Carbon-zirconium bond lengths vary between 2.3 and 2.5 A,tsa and both the methyl-zirconium and the hydrogen-zirconium bond energies range around 75-85 kcal/mol.~lzl The chlorine-zirconium bond distance is relatively constant at 2.4 to 2.5 A, and its bond dissociation enthalpy lies close to 110 kcal/mol.lsa It can be assumed that with increasing bulkiness of the carbon center, the strength of the C-Zr bond decreases.21 Representative 9lZr NMR chemical shifts have recently been rep0rted.P
nn
Figure 2. Bond lengths, bond angles, and stereo-representations of the x-ray structure of
Cp2Zr(CI)Me.a
12856
P. WIPF and H. JAHN
3. Preparation of Zirconocene
Hydrochloride
(Schwartz Reagent)
The zirconium hydride CppZr(H)CI was first prepared by Wailes et al. by reduction of Cp2ZrCI2 with 0.25 equiv of LiAIH4 in THF as well as by magnesium metal reduction of Cp2ZrCl2.17 Due to the pioneering studies of Schwartz and his group on the synthetic use of CmZrHCI, this reagent is also generally referred to as Schwartz reagent The use of LiAIH4 as reducing agent can lead to . considerable overreduction to the very insoluble CppZrHp, and the more hindered LiAl(O-&Bu)3H was recommended as a more selective agent (Scheme 1).*4
L.iiIH,, THF CPnZrfJ2 b
CPPZM2
Scheme 1
Alternatively, Red-AI (Na[AlH2(OCH2CH20Me)2]) was applied by Schwartz and coworkers for the preparation of Cp2ZrHCI. In this protocol, however, a ca. 30% contamination of the reagent with sodium chloride remained.25 To prevent isolation problems resulting from impurities and overreduction, Buchwald et al. have developed an experimentally simple procedure for large scale preparations of pure Schwartz reagent. 26 Since a relatively rapid reaction between Cp2ZrH2 and CH2Cl2 forms Cp2ZrHCI which is only slowly transfoned further into Cp2Z1Cl2,~~ they introduced a washing step with CH2Cl2 which converts most of the zirconocene dihydride to the desired monohydride after the reduction. The use of filtered solutions of LiAIH4 in Et20 prevented contamination with salt impurities and simplified the product isolation by filtration of the precipitated reagent. The poor solubility of Schwartz reagent in commonly used organic solvents such as THF, benzene, toluene and CH2Cl2 is advantageous for its preparation, but undesirable for subsequent transformations, and more soluble derivatives bearing substituents on the Cp-rings such as Cp*CpZrHCl,a (Me5C5)2ZrHCI = Cp*2ZrHCl,nla and [(Me2Si)(C5H4)2ZrHCl]a have been prepared. A protocol for a polymer-supported version is also available.31 However, these reagents are also less readily accessible and more expensive than Cp2ZrHCI. In general, the preparation of modified Schwartz reagents with more highly solubilizing substituents is plagued by overreduction to the dihydndes.32 An indirect route to Cp 2ZrHCI used an exchange reaction between the dihydride and the dichloride.30 Related hydride transfers can be used for the in sifu preparation of organozirconocenes. Eker and coworkers reported an improved hydrozirconation rate in a mixture of (MeCp)2ZrCl2 and [(MeCp)2Zrtl2]2 in THF or toluene. The small quantity of (MeCp)2ZrHCI generated in the equilibrium was available for the in situ hydrozirconation step and its greater solubility increased the rate of the overall process.~l~
12857
Recently, CppZr(H)OTf, a more soluble alternative for Schwartz reagent was reported by Luinstra et al. for the hydrozirconation of alkenes. 35 Substitution of the chloride in Schwartz reagent for the larger triflate anion gave a well-defined and very reactive dimeric hydrozirconating reagent, which was soluble in THF up to a concentration of 0.1 M and reacted with TMS-acetylene to give the monoalkenyl complex Cp2Zr[(E)-CH=CH(SiMe3)](0Tf). Cp2Zr(H)OTf was synthesized by treatment of the borohydride complex CppZrBHq(OTf), obtained almost quantitatively from the synproportionation of Cp2Zr(OTf)2= and Cp2Zr(BH4)2, with 1 equiv of NEt3 in toluene. Sometimes it is more convenient to generate Schwartz reagent in situ and carry out the hydrozirconation in the same reaction vessel because CpqZrHCl does not have an extended shelflife.37 In situ procedures using t-BuMgCP or LiEtgBHa in conjunction with Cp2ZtClp have been reported. Lipshutz et al. developed a useful in situ protocol for alkynes. Treatment of Cp2ZrCl2 with LiEtgBH in THF led to the formation of Cp2Zr(H)CI. Subsequently added terminal alkynes underwent hydrozirconation without compromising acid-sensitive functional groups.ss In 1991, Negishi et al. further extended their in situ procedure with t-BuMgCI to the hydrozirconation of alkynes.4 Treatment of 1-octyne with CBuZrCp2CI, preformed quantitatively by treatment of Cp2ZrClp with t-BuMgCI, cleanly produced (e-1 -octenyl zirconocene chloride. Subsequent protonolysis gave 1-octene in 95% yield. The mechanism for the zirconocene transfer from kBuZrCp2CI to 1-octyne is not clear, but both a p-elimination to give Schwartz reagent followed by reaction with the alkyne or a concerted sixelectron process are feasible (Scheme 2).
=C6H13
Cp&lZr
Scheme 2
A combination of (CCqHg)3AI and CppZrClp can also be used as hydrometalating reagent.41 In this case, however, only organoaluminum compounds are formed via hydrozirconation and transmetalation. Recently, a new in situ preparation of Schwartz reagent by the reaction of LiH with Cf~ZrCl2 was reported. This method is useful for the synthesis of labeled reagents using Li2H or Li3H, allowing for the selective isotope-labeling of an acetylene or an olefin substrate (Scheme 3).4
TMEDA n-BuLi + 3H2 * Li3H CpzZrC12,THF * Cp2Zr3HCI + LiCl
- n-Bu3H
Cp2Z?HCl
Scheme 3
12858
P. WIPF and H. JAHN
It is important to note that these in situ generated reagents are not necessarily structurally identical with isolated CppZrHCl and can lead to undesirable side-products or different kinetic behavior. Especially the presence of metal salts, e.g. aluminum halides, MgCl2, or LiCI, can inhibit further transformations of the zirconocene.@J t Although the molecularity of Schwartz reagent is not firmly established, solid-state infrared spectra suggest hydride bridging ligands .a The dihydride (Cp3ZrHg)x is polymeric, relatively unreactive, insoluble, and therefore a poor hydrozirconating agent.tzlM In addition to the hydrozirconation of alkynes and alkenes, both mono- and dihydride have been used as GO and C=N reducing agents.47 The hatnium analog of the Schwartz reagent, CpzHfHCI, is difficult to obtain in pure form and of considerably higher cost. Based on the limited number of applications of hafnocene hydrochloride, it appears to be somewhat more sensitive to steric demand and more efficacious in apolar solvents.4aa Attempted hydroboration or hydrozirconation of dolabellatrienone intermediate 1 with Schwartz reagent were unsuccessful; however, reaction of 1 with Cp3HfHCI in benzene at 50 for 10 h led to selective hydrometalation of the vinyl group vs. the unusually C reactive endocyclic double bonds. The desired alcohol 3 was obtained after oxidation with t-butyl hydroperoxide (Scheme 4).49
Dolabellatrienone
Scheme 4
In apolar solvents such as benzene and hexane, the low solubility of Cp2ZrCl2 can induce a disproportionation of organochlorobis(cyclopentadienyl)zirconium(IV) complexes to the corresponding bis(organo)zirconium compounds and precipitated Cp3ZrCl3,50 similar to the Schlenk equilibrium.
4. Hydrozlrconation The insertion of CC-double and -triple bonds into the Zr-H bond represents the default stepping stone for the preparation of synthetically useful organochlorobis(cyclopentadienyl)zirconium(lV) complexes. This process is closely related to the hydroboration reaction, but, interestingly, hydrozirconation via a four-atom, concerted transition state is formally symmetry-
Organochlorozirconocene
complexes
12859
allowed due to the vacant d-orbitals on Zr ,61 whereas hydroboration is formally symmetryforbidden.= The actual mechanistic details of the hydrozirconation process are still poorly understood; the insolubility and the oligomeric character of Schwartz reagent obscure the reaction kinetics. It is, however, clear that the solvent has a major effect on the reaction rate (figure 3).% Hydrozirconation is orders of magnitude faster in THF than in hydrocarbon solvents such as benzene, and the most efficient solvent identified so far appears to be oxetane.sTherefore, there is a direct correlation between the donor-capabilities of the solvent and the rate of hydrozirconation, which is indicative of a rate-limiting dissociation of the oligomer before hydrometalation occurs. In oxetane solution, the reaction becomes first order both in CpeZrHCl and alkene, whereas in THF it is zeroth order in Schwartz reagent. Accordingly, we can hypothesize that in the strongly solvolytic oxetane deaggregation of zirconocene hydrochloride and hydrozirconation have comparable rates, or hydrozirconation is actually rate-limiting. Further kinetic studies are clearly needed to provide a better experimental understanding of this fundamental process.
Cp2Zr(H)CI (0.6 mmol), Solvent (1 mL) B (0.6 mmol) 0 C * -Zr(Cl)Cpp
Half-life [min] (GC) Benzene THF Oxetane Morpholine 10% Oxetane/THF 25% Oxetane/THF 10% OxetaWBenzene 10% Oxetane/CH&lp THF (2 equiv CppZrHCI) THF (2 equiv Hexene) Oxetane (2 equiv Cp2ZrHCI) Oxetane (2 equiv Hexene) 2210 113 37 40 95 60 545 109 105 56 22 24 -Zr(CI)Cp2 THF: Oxetane: k., a> k2 k., -- k2 iI fast
k-1
Cp2Zr(H)CI
IIkl
Solvent kz Alkene
!I Cp2Zr(H)Cl
Figure 3. Experimental comparison of the solvent dependence of the rate of hydrozirconation of 1-hexene.ss
In an ab initio MO study on hydrozirconation, Morokuma and coworkers have concluded that attack of ethylene and acetylene at Zr is most favorable between the Cl and H ligands.55 Further insertion of olefin into the organochlorobis(cyclopentadienyl)zirconium(lV) complex is substantially more difficult than hydrozirconation, a result that is experimentally well established. The n-complex shown in Scheme 5 represents a transient structure or a saddle point according to Morokuma s calculation. Since the electron configuration of Zr(lV) is do, stabilization of such a complex by metal+olefin backdonation is not possible. Thermodynamically, the o-bound 160. zirconocene is favored by >10 kcal/mol. This represents a major difference to derivatives of late-transition metals, which generally do not readily exhibit hydrometalation reactions due to the stability of their alkene
12860
P. WIPF and H. JAHN
complexes.1 The calculated activation barrier for the hydrozirconation of ethylene is very small, between 0 and 15 kcal/mol at the MP2 and RHF level, respectively (Figure 4). Most of the RHF activation energy is derived from distortion of the Cp2Zrcomplex. In the transition state, fomation of the Zr-C bond has progressed further than formation of the new H-C bond. The final product is the result of an overall &addition of zirconium and hydrogen across the W-double or triple bond, a result that is in agreement with all available experimental evidence.
J ____
fCp2ZrHCrlX _
Zr(lV) B (l&J
1 \,J
Zr(lV) B (Me )
k
Zr(lV) B (Me3
Scheme 5
* ;.! ..__......_ .._1.. _. .._ ,..

Cl
CP2Z{.
CH2 A.. :I CH2
;/
i................. reaction coordinate +
Figure 4. Calculated relative energies for the hydrozirconation of ethylene.55 In the final products the methyl group was allowed to rotate to the most stable conformation.
A. Functional
Group Compatibility of Hydrozirconation
The chemoselectivity of Schwartz reagent toward alkynes and alkenes and thus its general functional group compatibility is limited. Most epoxides, isonitriles, aldehydes, ketones, nitriles and esters are reduced competitively with the hydrozirconation of alkenes and alkynes.llsaQ Enones and
complexes
12861
enoates undergo 1,2-reduction.== Silyl estersa t-butyl esters,61 and even benzyl esters and nittiles,~ however, are tolerated by an equivalent of reagent in the presence of a particularly reactive site of unsaturation, such as a terminal alkyne or vinyl function. Hydrozirconation of 4-pentenoate 443 and 4pentynoate 662 led to the organozirconocenes 5 and 7, respectively, in high yield, and no significant level of reduction of the ester functions was detected in the reaction mixture (Scheme 6). In both cases, hydrozirconation in THF or CH2Cl2 was complete in less than 30 min at room temperature or 0 C.
-0TIPS 4 0
CzTiroF
Cp2(CI)Zry 5 0
OTIPS
Scheme 6
An interesting protocol for the protection of carbonyl functions during hydrozirconation was recently reported by Lipshutz et al. Triisopropyl (TIPS) acyl silanes 6 and 10 were readily converted to the corresponding zirconocenes and resisted further 1,2-addition (Scheme 7)63 Further transformations of the zirconium moiety, for instance via transmetalation to copper(l), were successful, and the aldehyde could subsequently be regenerated by desilylation with TBAF (Scheme 8).
0 TIPS TIPS 1. Cp2ZrHCI, THF, r.t. 2. H20; 63%
+0
10
Scheme 7
Obviously, alcohols and acids are not compatible with the strongly hydridic character of Cp2ZrHCI and are converted to the corresponding anions under the reaction conditions. Silyl ethers are generally stable, even though exceptions are known. 64 The trimethylsilyl ethers of unsaturated alcohols yield different compounds on reaction with CppZrHCl depending on the length and branching of the alkenyl chain. Hexenol derivative 15 gave the usual product of hydrozirconation 16, whereas
12862
P. WPF and H. JAI-IN
the silylated 2-methylbut-3-en-2-01 17 underwent reductive cleavage of the Si-0 bond to afford trimethylsilane and the yellow complex 18 as main products (Scheme 9).w
12
2. Me&u(CN)Li2, THF, -78 C
13 1. -78 86%, C, ? 0 2. n-Bu4NF, 93% 1 CHO
Scheme 8
WTMS 15 m THF, r.t.; 80% cp2zrwCTMS 16
Cp&HCl
18
I
Scheme 9
CO, benzene, r.t., 90 min; 80%
Acetals, THP-ethers,60 oxazolines, amides, imides,ss carbamatesss sulfides, halides,so~74and alkyl and aryl ethers are generally stable under mild reaction conditions, if these functional groups are not in vinylic, allylic or possibly homoallylic positions of the alkene moiety. Secondary catboxamides can be reduced to imines with excess Cp2ZrHCI. 470 Annby and Karlsson have found that internally unsaturated ethers,= sulfides, phenylsulfones and ammonium iodides underwent substantial elimination of the functional group after rearrangement of the zirconium moiety towards the carbon bearing the heteroatom.s~s6~sMQ Th process can be synthetically useful. The first example of a IS zirconium-promoted ring opening was reported by Wipf and Smitrovich in 1991 .ss They found that
12863
hydrozirconation of 3,4-dihydro-2Hpyran led to the acyclic compound Cp2ZrCIO(CH2)3CH=CH2 (21) which could be further hydrozirconated and added to an organic electrophile (Scheme 10).
n
Ko/
Cp;jrHCI, THF, 40 C 20 min 20
Cp2ZrHCI, THF
50C
Cpn(CI)Zr-OZr(CI)Cp2 22
1Q
I Scheme 10
CuBr*SMez (catJ -hOH
85%
In an extension of this protocol, Cenac et al. found that hydrozirconation of phosphorus-, nitrogen- or oxygen-containing unsaturated five membered rings such as phospholene, 1-benzyl9pyrroline or 2,5- and 2,3-dihydrofuran followed by addition of various electrophiles led via ring opening to a variety of acyclic unsaturated phosphanes, alcohols, ethers and esters (Scheme 11).7c For elimination to occur, the overlap between the zirconium-carbon bond and the leaving group has to be stereoelectronically favorable. Hydrozirconation-acylation of bicyclic ether 26, for example, does not lead to ring opening at 40 (Scheme 12).71 C
1. Cp2ZrHCI, THF, -20 C, 15 min; then r.t., 1 h ) 0 24 2. HOS02CF3, -78 C, 20 min; then r.t. 90% HO25
0-
Scheme 11
9
, 0 TBSO 26
2. Cp2ZrHCI, 40 C, -9 1. C(l). PhCOCl THF
Ph 0
66%
TBSO 27
Scheme 12 As previously noted, the reactivity of the organozirconocene products of hydrozirconation of alkenes and alkynes is much lower than that of Schwartz reagent, and, in the absence of metal
12864
P. WIPF and H. JAHN
catalysts, even addition to aldehydes and acid chlorides is extremely sluggish. Accordingly, any improvement in the double/triple bond-chemoselectivity of the hydrotirconation step will directly translate into a wider range of functionalized organozirconocenes available for further transformations.
6. Hydrozirconation of Alkenes and Allenes Empirically, the rate of hydrozirconation appears to decrease in the order of: terminal alkyne > terminal monosubstituted alkene = internal alkyne > internal disubstituted alkene = 2,2-disubstituted terminal alkene = conjugated polyene > trisubstituted alkene. For example, an enyne is selectively hydrozirconated at the alkyne moiety, 72 and an unsymmetrical diyne reacts preferentially at the less substituted triple b0nd.n For cyclic alkenes, the rate of hydrozirconation is strongly dependent on the ring size and ring strain. Bicyclic alkenes, for example, react quite readily, whereas cycloheptene and cyclooctene are very resistant substrates. Even in the latter cases, a large deuterium incorporation from CppZrDCl is noticed, indicating a possible thermodynamic instability of the cycloheptyl and cyclooctyl zirconocenes due to transannular interactions. 2 In general, tetrasubstituted alkenes do not react. Due to the rapid p-elimination of secondary alkylchlorozirconocene species, migration of the zirconium along the carbon chain produces terminal organometallics even with internal alkenes (see Section 4C). Under mild conditions. isomerization does not proceed beyond a tertiary position,1 but with increased temperature, this limitation can be overcome. Hydrozirconation of the trisubstituted alkene 28 followed by copper(l)-catalyzed acylation provided a mixture of four ketones in 85% yield (Scheme 13).74 In spite of the apparent instability of the tertiary zirconocene 36, the phenyl ketone 31 derived from 36 via 37 and 38 accounts for almost 8% of the product.
\ t!l
28
1. Cp&HCI,
THF, 60 C 85% (29+30)/N s 12 : 1 &* iPh + +Ph +$-
2. PhCOCI, Cu(l)
ir
36
37
Scheme 13
1286.5
The control of the selectivity of hydrozirconation of cyclohexenes with Schwartz reagent appears more facile. The hydrozirconation/copper-catalyzed acylation sequence of protected cyclohexenol 39 provides some interesting insight into the stereochemical course of these reactions (Scheme 14).74 Predominant attack of Zr-H from the cyclohexene a-face led to the trans-isomer 43, whereas the analogous but less favorable addition from the p-face of the molecule resulted in a cis relationship between zirconium and silyloxy substituents. Subsequent Cu(l)-assisted acylation provided ethyl ketones 46 and 41 in 52% yield in an 8 : 1 ratio.
TBDPSO 39 OTBDPS OTBDPS
1.
Cp,ZrHCl,
THF, 40 C
2. CH&H2COCI, Cut11
CHBCH2COCl CuBr . SMe2
cP2z(-_r K~oTBDp_?__________ cp2z+ cp2RoTBDpft Cp>r&OTBDPS
42
Cl
43
44
v OTBDPS 45
cp2z(
Scheme 14
Kinetically controlled hydrozirconation appears to select for Zr-C bond formation at the site of the more negative electrostatic potential. Hydrozirconation of styrene results in 2:l to 1O:l ratios of terminal and benzylic zirconocenes. 162 For the alkyl-substituted styrene 46, the site of kinetic attack of zirconium is the benzylic position, and isomerization slowly converts this species to the terminal zirconocene (Scheme 15).x This regioselectivity can be explained by preferential addition of zirconium at the alkene terminus with the more negative atomic charge. The presence of the phenyl ring significantly polarizes the double bond and increases the relative atomic charge at the distal vs. the proximal sp2-carbon (Figure 5) .7sn Accordingly, kinetically controlled attack by Schwartz reagent favors formation of the benzylic organometallic to give 47 or 49 after exposure to oxygen. This analysis can also be nicely visualized by a representation of the electron-density surface encoded with the electrostatic potential. 7s Thermodynamic equilibration promotes formation of the sterically less hindered zirconocene precursor of primary alcohol 46.
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peJ 8 u! pel(nseJ uog!sod leu!wJel
~*eue3ouo~J!zou86Jo
eq1 40 uo!ln(os
Jeuv
eyl 48 UO!l8UO3J!ZOJpr(q 8s euelle r(q peMo(lo4 a0 QL- be ZI$&D 01 lUe68eJ Z&I~AM@S Gu!ppe ISJ!~ uopUJo4susJl Iln4ssewns e Jo4 18!3nJ3 eJ8 eJni8Jedwel uo!pseJ eq1 pue syJe68eJ 40 uo!yppe 40 JepJo eyl pu8 SUO!lne3eJd ~e~ueuJ!Jedxe le!Deds seJ!nbeJ seuel(8 40 UO!~~UODJ!ZOJ~A~ eql
zd3(13)Jz
JHl W c euJeq@ (~ pel8los! s8u1 LS epr(qepl8 el6u!s hey 8 SBM elduJ8xe ~04 99
13(H)JZzd3
II OP 2 30 1
+OSdtBl ON! uowesu! Jeu8
dnycom cypp8 pu8 ep!uekms!
8 pue nx pu8 4d!M r(q v up8Jno *seuer(lod
40 s!seyuk
pea86n!uo3
let04 eq1 u! uo!peeJ 40 suo!~8z!leuo!goun4
euega 40 UO!ISUO~J!ZOJ~&
12868
regiochemistry of hydrozirconation-isomerization is influenced by steric hindrance and the presence of chelating heteroatoms and aryl rings.* Hydrozirconation of oxazoline 62 and oxazine 63 followed by cleavage of the Zr-C bond with deuterium oxide revealed several positional isomers (Scheme 19).et The terminal alkene 65 provided the secondary zirconocene 66,@ and the zirconocene 66, prepared from Cp2ZrClp and organolithium reagent derived from 67,m did not isomerize to the terminal methylene carbon (Scheme 20). In contrast, hydrozirconation of alkene 70 let to a kinetically controlled formation of the primary zirconocene 69 followed by a rapid p-elimination to give alkoxide 71. The secondary zirconocene 66 reacted smoothly with carbon monoxide and isocyanide and decomposed only slowly at 145 in toluene. In a related study, treatment of Cp2ZrClp with C methoxymethyl Grignard reagent led to the 3-membered metallacycle 72,w which upon exposure to Schwartz reagent inserted its CH2 group into the Zr-H bond in an ylide-type fashion.% 64%D
28% D
38% D 1. Cp$HCl (2 equiv), dioxane, 40 20 h; k, * 2. D20
37% D
Scheme 19
Cp&HCI, -OK 66
THF, r.t.
1O-40%
Bu$Sn
/LJ
0 67
1. n-BuLi, THF, -78 C
* 2. Cp2ZrC12,-78+20 C Cp2(C )Zr--&o 74%
JXJ
MeOCH&lgCI (2 equiv)
Cp&Clp, CH~(0kle)~, -5 C /\ ) CpdCI)Zr--0 34% 72
CP2ZrHCl 4ooc
Cp2Zr(CI)CH3 + Cp2Zr(CI)OMe
Scheme 20
12869
Aryl rings appear to electronically favor the kinetic attack of zirconocenes at the benzylic position.7sl@r Since the major driving force for isomerization of alkylzirconocenes is steric hindrance, any increase in the size of the zirconium complex would be expected to facilitate the migration. This has indeed been confirmed experimentally. Annby and Karlsson have reported the preferential preparation of terminal alkylzirconocenes from conjugated aromatic olefins with Cp CpZrHCI (Cp = r$CgMe9) (Scheme 2l).s4 The o-deuterated alkane 74 was obtained in much lower yield using standard Schwartz reagent.
90-l00 %D
1. Cp~ri-lCI, dioxane, r *.;;;0C.2 h: -a ) &+

O-5 %D 65 - 75%
I 2. dioxane,45 20 h; 1.2 eq. Cp*CpZrnCl, D20 C,
5%D
c&r-i 95 %D 66%
c 26%
Scheme 21
Little is known about the mechanism of zirconium migration along an alkyl chain. Spectroscopic monitoring of the reaction only reveals starting material and terminal zirconocene. Accordingly, the rate of isomerization of secondary zirconocenes is faster than the rate of hydrozirconation of internal alkenes, and the organic group appears to remain associated with the zirconium complex throughout this process.1
D. Hydrozirconation
of Alkynes
Syn-addition of Schwartz reagent onto a terminal alkyne followed by treatment with electrophiles provides a trans-functionalized alkene with a high (>98%) level of stereochemical purii.~ This protocol has become very popular in organic synthesis and is relatively insensitive to the presence of functional groups. Photochemical isomerization of alkenylzirconocenes allows, in principle, the preparation of both (E)- and (Z)-isomers of the organometallic reagent.ae Alternatively, the oxidative insertion of zirconocene Cp2Zr into 2-haloalkenes allows the synthesis of internalized organochlorozirconium(lV) complexes 78 (Scheme 22).so
12870
P. WIPF and H. JAHN
Ph
JL 76
CP2Zr
t CP2zBU2
1
*[
Ph$Cp ]-
-$gy
T
00
ph+Ph
Scheme 22
For unsymmetrically substituted internal alkynes, hydrozirconation provides mixtures of regioisomers that are enriched in alkenylzirconocene placing the zirconium-carbon bond geminal to the sterically less demanding substituent. 99 The initial (kinetic?) selectivity is low, but excess Schwartz reagent readily isomerizes the adduct presumably via the dimetalated alkane to give improved thermodynamically controlled regioselectivity (Scheme 23).ss~t~
-e-J 60
Cp2ZrHCl (0.93 equivj benzene, 2 h, r.t. w cp2(c,)zr2 55 + dr(c,)cp2 b:::::;t. 89 + *
: 11
: 45
Cp2ZrHCl (0.93 equiv) benzene, 2 h, r.t. + cp2(c,)Zr)$+ 84 &c,)cp2 bLE:9t.64 + 65 >98 : 2
: 18
Scheme 23 The hydrozirconation of more highly substituted internal alkynes reveals a more complex picture for regioisomeric product formation. En route to rapamycin, Schreiber and coworkers reported a mixture of isomers and saturated alkane in the hydrozirconation-bromination of thioether 88 (Scheme 24).lcl On small scale, the reaction was cleaner and provided mostly the less hindered bromide 87. In contrast, Ireland and Smith et al. obtained the vinyl bromides 91 and 93 in 78% and 83% yield, respectively (Scheme 25).1@1@3
1. Cp&HCi, toluene, 1 h, 40 C ) 2. Brz, -78 30 min C,
66
5.
ploy Br 67 (39%)
qy
BrT
66 (13%)
69 (15-20%)
Scheme 24
complexes
12871
1. Cp2ZrHCl(3 equiv), THF, 75 min, 40 C 2. NBS (3.5 equiv), 30 min, r.t. Br
1. Cp2Zrl-U (3 equiv), benzene, 1 h, 45 C 2. NBS (2 equiv), r.t.
Scheme 25
The hydrozirconation of silyl ether 94 in THF or CH2Cl2 gave a 3:l ratio of regioisomers 95 and 96 besides minor amounts of trans-isomer 97 (Scheme 26). The use of Cp2HfHCI did not 04 improve this regioselectivity.
TBSO
1. CppZrHCI, THF or CH2C12, 0.5 -1 h, 40 C 2. 12,40 5 min C, ) TB;>+TBsq 95 96
+ y& 3.1 97 (trace)
Scheme 26
Reaction of phenyl(trimethylsilyI)acetylene with Schwartz reagent yields the 5-CH-ago& alkenylzirconocene chloride 96, and subsequent halogen exchange with LiBr or Lil produces the alkenylzirconocene halide 100 (Scheme 27). In contrast, hydrozirconation of (trimethylsilyl)acetylene gives 99, positioning the bulky SiMe3 substituent at the B-position of the o-alkenyl ligand, which lacks the 5-agostic metal-C-H interaction that is characteristic of lOO.l@
MeBSi+Ph CpnZrHCl ?oluene, 17 h, 18 OC; 39% MesSi e toluene. 4 h, 18 C; 44% I * SiMe3 JV CICp2Zr.._\ 98 =*k LiX, Et20, 5 h. 18 C 89% (X = Br), 87% (X = I) Ph
loo
Scheme 27
12872
P. WIPF and H. JAHN
E. Bimetallic Zirconocenes The first bimetallic zirconocenes prepared by hydrozirconation of unsaturated organometallics were Zr-Al, Zr-B, and Zr-Zn derivatives obtained by Schwartz and coworkers (Figure 6).lcrjetcz The direction of the addition to the double bond was dependent on the steric bulk of the substituents. Biszirconocene 105 could be prepared by tandem hydrozirconation of acetylene, and the agostically stabilized 106 was obtained by hydrozirconation of an alkynylzirconium species. cc,lrJe Carbozirconation of pentynylalane gave the Zr-Al bimetallic species 107.l@
Figure 6
The synthetic chemistry of 1sl-bimetallics containing zirconium has not yet been extensively applied, but since these early studies, many additional combinations of zirconium with zinc,tto~ltt
tin,112,113,114,115,116 reported. bimetallic aluminum,117 as well as boron,ll6,119,120,121.122,l~,lz4,1~ and Re-carbenes have been Hydrozirconation species, of alkynyl and alkenyl Ru-complexes
gave 1,2- and 1 ,l
respectively.l~lln
The Lipshutz group has prepared gemstannazirconocene alkenes and reacted them with a$unsaturated enones and allylic halides. 112.11s~ttsTreatment of tin acetylenes with Cp2ZrHCI followed by proton quench afforded the (Z)-vinylstannanes in high yields, 11s which, for example, were useful reagents in the preparation of tetronasin segments. 114 Similarly, l-tributylstannylbutynB-ol benzyl ether 106 was hydrozirconated and selectively halogenated with iodine to give iodide 110 (Scheme 26). The long carbon-tin bond, the sensitivity of the hydrozirconation reaction to steric affects, and the polarizability of the carbon-tin bond were instrumental in directing the Cp2(CI)Zr moiety geminal to the trialkyltin group.
12873
I-
-l
BuaSn Cp2ZrHCI, THF, PhAOA 109 = SnBus 15 min, r.t. * r Ph 12,o Oc;90% * PhrodinBug 110 P
ZrCp2CI
109
Scheme 28
Suzuki and coworkers have reported the hydrozirconation of allenylstannane 111 to give (E)allylzirconocene species with a y-Bug% substituent, and applied them in highly regio- and stereoselective reactions with aldehydes and ketones to give vicinal tin alkoxides 113 (Scheme 29).115 Further in situ treatment with Lewis (BF3-OEt2) or protic acids (CqCOOH) effected a 8elimination to give terminal 1,Sdienes with high (E)-selectivity.
=./
SnBu3 111
C&ZrHCI, CHpClp, 10 min. r.t.
/ CICp2ZrwSnBu3 112 I
~I-C,~H~~CHO, * r.t., 30 min
gZrCP2CI
~C,oH21+ SnBu3 113
BFB*OEtB (or CF$OOH), 10 min; 92% * M n-C1oH21 114, E:Z

= 9614
Scheme 29
Knochel et al. investigated the hydrozirconation of various alkenyltinc- and alkynylzinc halides with Cp2ZrHCI to give 1,l-dimetalloalkanes and 1,l-dimetalloalkenes of zinc and zirconium, and studied their further reactions with aldehydes and ketones. 111 The reaction tolerated the presence of a wide range of functional groups in the dimetallic species as well in the carbonyl compounds; however only a moderate stereoselectivity was observed. The addition of a suspension of CppZrHCl in CH2Cl2 to a solution of alkenylzinc halide 115 afforded instantaneously a yellow solution of the relatively unstable 1 ,l -bimetallic 118, to which the aldehyde or ketone was immediately added (Scheme 30). The hydrozirconation of alkynylzinc halides 118 afforded 1,l-dimetalloalkenes of type 119, which reacted with aldehydes to provide allenes 120. Itis interesting to note that with alkene 115, the zirconium is adding geminal to the zinc substituent to give the sterically more hindered complex.
12874
P. WIPF and H. JAHN
\ (3
115 Ph+ZnX 116
ZnBr
Cp$MiCI, CHpClp, -0 1 min, 25 C 116
ZnBr zrCppCl
PhCHO; -e 63% 117
Ph
CpnZrHC1.CH#.&. * 10 min, 25 C
Ph Hznx H ZrCppCl 119
Scheme 30
Srebnik et al. reported the preparation and selective reaction of highly functionalized zirconium-boron 1 ,I -dimetallic reagents.118 Hydrozirconation of various B-alkenyl borabicyclo[3.3.1]nonanes (B-alkenyl-9-BBN) with Schwartz reagent afforded 1,l -bimetallics of boron and zirconium (Scheme 31). These compounds reacted selectively with bromine to afford abromoboranes, whereas olefination of ketones, even in the presence of zinc chloride, was not accomplished. Hydrozirconation was performed in CH2Cl2 and THF, whereas diethyl ether, hexanes and benzene were found to be unsuitable. Both electronic and steric factors greatly influenced the course of hydrozirconation of B-alkenylboranes.
121 _B d
CpzZrHCI, 0 1 h CH$&, C, *
ds
122
-35 1 h; 97% Br*, CHPCIP, C, *
A0
123
Scheme 31
Bimetallics based on zirconium and trialkylboranes have a poor stability; these compounds are very sensitive to moisture and oxygen and decompose rapidly in CDC13. To achieve a higher degree of stability, oxygenated boranes were used by Srebnik et al. The (Qalkenylboronic ester 125, prepared by hydroboration of alkynes with HBBr2.Me2S followed by the esterification of the intermediate boronic acid derivative with pinacol, was hydrozirconated with 3 equiv of Schwartz reagent to give fairly stable bimetallic agents (Scheme 32). In situ addition of N-halosuccinimide or bromine provided a-halo boronic esters.116~tzt ltzs1124Vtz6 This concept can also be applied to a diastereocontrolled hydrozirconation. Optically pure lalkenyl boranes derived from monoterpenes, 1,Bdiols and 1,2-amino alcohols were investigated, and Kneopentyl oxazaborolidine derivatives were found to provide excellent diastereoselectivities. Hydrozirconation of optically pure 1-alkenyl boranes 128 with Cp2ZrHCl to give the optically active 1,l -bimetallic 129, followed by cleavage of the more reactive C-Zr bond with D20 and alkaline oxidation of the C-B bond afforded optically active 1-deuterio primary alcohols 130 (Scheme 33). (1 R,PS)-KNeopentyl norephedrine-derived oxazaborolidines in THF afforded the best chemical yields combined with high diastereoselectivities.tzo
complexes
12875
124
1. HBBr2. SMe; 2. H2Q, NaOH; * 3. pinacol;78 %
Cp2ZrHCl equiv), (3 c CH2C12, 99 % r.t.; 125
NBS,CH2C12, 10 min;98 % 127 Br
Scheme 32
Cp&HCI, THF t
1. D20
AH 130, 85%D; 80%ee (R-isomer)
2. H202,NaOH;90%
Scheme 33
5. Halogenation
of Organozirconocenes
Electrophilic halogenation of alkyl- and alkenylzirconium(lV) complexes with Br3, 12, Kbromoor chlorosuccinimide, or iodobenzene dichloride affords the corresponding organic halides.l8~7*~99 The reaction proceeds with retention of configuration at carbon,99?129 and has become widely used especially for the conversion of alkynes to vinyl halides. tct~1921t9911~ Hydrozirconation-halogenation has been used for the synthesis of an intermediate of the immunosuppressive agent FK-506!m Homologation of the aldehyde 131 to the vinyl bromide 132 was achieved in three steps via conversion of the aldehyde function into a teninal acetylene, methylation of the acetylene and a stereo- and regioselective hydrozirconation reaction, followed by treatment of the vinylzirconium intenediate with Kbromosuccinimide (Scheme 34).
12876
P. WIPF and H. JAHN
OHC v 131
Oh& %OTIPS
1. (Me0)2POCHNs, KOtBu; 95%; 2. n-BuLi, Mel; 93%; 3. Cp&HCl; NBS, 99%
132
Scheme 34
Hydrozirconation-iodination was used for the synthesis of steroid side chains, for example by Mandai et al. for the preparation of protected (Q-4-hydroxy-4-methyl-l pentenyl iodide,rsr and was a key reaction for the regioselective preparation of segment 136 by Nicolaou et al. as part of their strategy toward the total synthesis of rapamycin (Scheme 35&t=
1. Cp2ZrC12,THF/PhH, -
-f
133 OEE 2.
WJWCH&H~~)~A~H~IN& r.t., 1.5 h; 1 54%
12,THF, r.t.,
h;
134
1. Cp#HCl(2 2 ;;;u;o;lb
equiv), F
.
-
135
15rnin; 95%
136
Scheme 35
The reaction of homoallylic zirconocenes with halogen sources can lead to cyclization to give cyclopropanes.78
6. Oxidation and Hydrogenation The oxidation of alkylchlorozirconocenes with basic H303, f-B&OH, peracids, CrQCl3, MoOPh, or 03 leads to alcohols in modest yields. 1~1~ Stoichiometrfc TEMPO can also be used for this conversion.134 The stereorandom reaction with molecular oxygen appears to produce alkylperoxide complexes that are rapidly decomposed by reaction with remaining alkylzirconocene under retention of configuration. Accordingly, alcohol formation occurs with ca. 50% racemization (from 03 reaction) and 50% retention (from peroxide substitution) of configuration.1~1~ Hydrohafniation-oxidation has been used in cases where hydroboration failed.49 The oxidation of alkenylchlorozirconocenes with 03 or peroxides, however, does not give the expected carbonyl compounds.1 Similarly, the catalytic hydrogenation of organozirconocenes is not a very clean reaction and requires high temperatures.ls.tss
12877
7. Carbon
Monoxide and isonitriie insertion into Organoxirconocenw
Dicyciopentadienylzirconium alkenyi chlorides do not generally undergo carbon-carbon bond forming reactions, except with C07*.srlt~ and isonitrilesl~s,l~ll~~141~1~via insertion into the C-Zr bond. Both alkyl- and aikenylzirconocene chlorides are readily carbonyiated with retention of configuration using carbon monoxide. The acylzirconocene chlorides thus obtained can be converted into aldehydes, carboxyiic acids, esters, and acyl bromides by treatment with dilute HCI, NaOWHgO3, Brg/MeOH, and NBS, respectively. 7897 insertion of isonitriles into alkylzirconocenes produces iminoacyls which can be converted to imidoyl iodides by treatment with iodine. Decomposition of the imidoyl iodide leads to a nitrile in what amounts to an overall alkene hydrocyanation sequence (Scheme 36) .t4c Alternatively, as reported by Negishi and coworkers, treatment of the iminoacyl complex with dilute acid provides a reliable route for the one-pot conversion of alkynes and alkenes into one-carbon homologated aldehydes (Scheme 36).1ss
24 h
TMSN
WCWP2
TMSN AI -TMSI I 59%
1. Cp&HCI, r.t., 1 h n-CsH13a 141
THF. n-C6H,3~CHo 142
2. n-BuCN, O-+45 C, 3h 3. HOAc, -78 c; 75%
Scheme 36
The Negishi protocol has been used by Wipf and Xu for the preparation of a y&unsaturated aidehyde on route to curacin A (Scheme 17).sz
12878
8. Conversion of Organozlrconocenes to Organophorphorus, -selenium and -tellurium Compounds, and Amines As mentioned previously, hydrozirconation of carbon-carbon multiple bonds leads generally to &-addition products in which the zirconium moiety is linked to the less hindered carbon atom. Zablocka et al. published the first example of a regio- and diastereoselective preparation of both aand p-zirconated products of dihydrophospholes. Hydrozirconation of the dihydrophosphole 143 with Cp2ZrHCI at 40 afforded quantitatively the stable a-substituted phospholane 145 (Scheme 37). C The exclusive formation of this regioisomer is most likely due to the coordination of zirconium to the phosphane group, which provided extra stabilization for the a-metalated phospholane. Hydrozirconation of the isomeic dihydrophosphole 144 at room temperature gave regioselectively the j3-zirconated phospholane 146. Increasing the temperature to 40 oC subsequently afforded the thermodynamically more stable product 145. Somewhat surprisingly, treatment of either the organozirconium complex 145 or 146 with chlorophosphanes gave rise to the same diphosphane 147.143
0\
P
hh
143 Cp~zrHcI, THF
P bh
144 Cp2ZrHCI, THF, 20 C
ZrCp2Cl d P Ph 146
Ph
ph 147
66_90%
Scheme 37
Further investigations by Zablocka et al. have demonstrated the feasibility of an inversion of configuration at carbon during the electrophilic cleavage of the Zr-C bond of the a-zirconated phospholane 145. In the presence of a strong phosphorus-zirconium interaction, the formation of a cationic zirconium, resulting from backside electrophilic cleavage with inversion at carbon, was postulated (Scheme 38).1 The 1,l-diphosphine 147 was isolated in the form of the optically active diphosphine disulfide; addition of sulfur on phosphine occurred with retention of configuration. The authors concluded that the stereochemistry of the cleavage reaction depended on the availability of a vacant orbital on the metal. In the 18-electron complex 145, a closed transition state would not be possible, and backside attack with inversion at carbon was favored.
complexes
12879
(Rp)-145
Ph2P i-l
c
.. (W-147
pPh
S8, THF, r.t.; 75 % w
(Rp)-149
Scheme 38
The reaction of alkenylchlorobis(cyclopentadienyl)zirconium(lV) complexes with phenyltellurenyl iodide and arylselenenyl bromides has been used for the preparation of vinylic rmilarly, treatment of alkylzirconocenes tellurides and selenides.7*~1~~t~~l47 S with O(mesitylsulfonyl)hydroxylamine leads to primary alkyl amines. 14 Other heteroatom electrophiles such as SO2 and NO tend to attack both the Zr-C CTand the cyclopentadienyl-Zr bonds.14slsQtsl
9. Tranrmetalation of Organozirconocenes In spite of the substantial polarization of the zirconium-carbon bond reflected by the electronegativity of zirconium in the range of 1.2 to 1.3 on the Pauling scale, the organometallic chemistry of zirconocenes would be limited as a consequence of the steric shielding effect of the cyclopentadienyl ligands if it were not for the ease of transmetalation reactions of these complexes. Especially alkenyl zirconocenes participate in a wide range of ligand transfer reactions, and transmetalation from alanes, for example, is also a method for the preparation of zirconium organometallics. The transfer of alkyl ligands from zirconocenes is more difficult and requires extensive optimization of reaction conditions. Both processes are, unfortunately, mechanistically obscure, and much of the progress in synthetic applications in this area is based on empirical trials. However, the in situ transfer of organic substituents from zirconium to other metals opens unique manifolds for consecutive reaction processes that rapidly increase the structural complexity of the substrate and the usefulness of the overall process.
A. Zirconium+Aluminum Organochlorobis(cyclopentadienyl)zirconium(lV) complexes can be used as precursors of alanes, which find broad use in organic synthesis. 1 Transmetalation reactions from zirconium to aluminum were first reported by Schwartz and Carr in 1977.152This group showed that simple mixing of CppZrRCl with AICl3 rapidly yielded the corresponding organoaluminum dichlorides (Scheme 39).
12880
P. WJPF and H. JAHN
Subsequent acylation with acetyl chloride provided the a&unsaturated ketone 152 in high yield. Wiihout transmetalation to aluminum, alkenylzirconocenes cannot be acylated with acid chlorides.25 For the mechanism of the transmetalation from Zr to Al, a transition state involving a transition metal main group metal complex containing a bridging alkyl (or vinylic) group was suggested.lc71152 Ligand transfer occurs with retention of configuration.107
AA
150
AIC13, CH2C12.0 C
Zrcp&I
-p L
uAlC12 151
Scheme 39
The equilibrium in the transmetalation reaction depends strongly on the difference in the electronegativity of the two metals: however, even organic transformations that are seemingly contrathermodynamic can be effected by judicious choice of metal ligands and selective trapping of one species.19 A trialkylalane will transfer a ligand to Cp2ZrCl2, whereas the direction of transmetalation will be opposite from an alkenyl zirconocene to R2AICl.lc7 Conversion of an alane to an ate complex with BuLi will increase its tendency to donate a ligand to zirconium.ls Negishi et al. developed a new method for the stereo- and regioselective synthesis of trisubstituted olefins via carbometalation of alkynes with organoalane-zirconocene dichloride complexes.lm Terminal and internal triple bonds can be stereoselectively carbometalated. The formation of an organozirconium species was proposed, which rapidly exchanges the alkyl group with alkylalanes.1~ The actual mechanism of the Cp2ZrCI2-assisted carboalumination, and if indeed organozirconocenes are directly involved in this process, is still not clear.157 Recently, an extension of this methodology to the zirconium-catalyzed alkylalumination of monosubstituted alkenes was reported.19
6. Zlrconlum+Boron Caulton first reported the methyl group transfer from dimethylzirconocene to BHgaTHF, resulting in a mixture of methylboranes .ts Subsequently, Fagan et al. published the synthesis of substituted boroles from the corresponding zirconium metallacycles,leJ and Fryzuk and coworkers synthesized substituted dienes via hydrozirconation of 1,9enynes and transmetalation to diphenylbromoborane.161 More recently, Cole and coworkers have investigated the migration of alkyl groups and 1-alkenyl groups from zirconium to various, structurally different boron compounds. Thus, they demonstrated that simple 1-hexenyl groups readily transmetalate to chloro- and bromoboranes in nonpolar solvents to give regio- and stereochemically pure 1-alkenylboranes (Scheme 40).raOla311s4
12881
CH2CI2, 0 OC to r.t.; GO%
Scheme 46
Further studies by Cole examined alkyldihaloboranes and dialkylhaloboranes for transmetalation of alkenyl- and alkylzirconocenes.l@ n-Octyldibromoborane reacted with one equivalent of 1-hexylzirconocene chloride to yield the dialkylbromoborane in 80% conversion within 2 h.lss In an extension of this methodology, Srebnik et al. presented a CppZrHCI-catalyzed hydroboration of terminal and internal alkynes with pinacolborane (PBH) with excellent syn-selectivity and regioselectivity (Scheme 41) .lm Addition of 1-octyne to a solution of PBH containing 5 mol% Cp2ZrHCI afforded vinyl borane 159 in 93% yield after stirring for 24 h at room temperature. The proposed mechanism included the initial hydrozirconation of the alkyne to give the alkenylzirconocene chloride, followed by vinyl-hydride exchange to give the product 159 under regeneration of CppZrHCI.
o B-H
W&342)5
158
O,Br(CHd&Hs 0 159
OXBd d
0 157
CppZrHCl(5 mol%), CH2C12,24 h, 25 93% C;
(98 : 2)
160
Scheme 41
C. Zirconium+Copper Transmetalation of organic ligands from zirconium to copper has become a very intensely researched process due to the wide application of organocopper reagents in synthetic chemistry.t~l~ The first example of a successful transfer of vinyl groups from zirconocene to copper(l) salts was reported by Schwartz and coworkers in 1977. 170 Thermal decomposition of the yellow-green copper complexes 162, obtained by addition of CuCl to the alkenyl zirconocene 161, led to the formation of a copper mirror and the (E,f)-diene 163 in 90% yield (Scheme 42). In situ conversion of the alkenyl organometallic intermediates to the corresponding ate complexes with Lil allowed conjugate addition reactions to a&unsaturated ketones. However, in these procedures, stoichiometric amounts of copper(l) salts were necessary, and alkyl groups did not transmetalate at a synthetically useful rate.170
12882
P. WIPF and H. JAHN
CuCI, THF,
f-BU *
tl
*
)
ZrCp&I 161
?-BUM t-Bu 183
6h,0C
- cue; 90%
1 . LilI ii, C, I 2. CuOTf,73% C to -36 14 h; 3. H30+; -76

1 *
f-B.2 164
Scheme 42
Subsequent to the pioneering studies of Schwartz and coworkers on Zr-Cu transmetalation,171 many modified transmetalation reactions between organozirconium species and copper(l) salts have been repotted.168 An improved route to vinylic cuprates from monosubstituted acetylenes via a vinylzirconate intermediate was developed by Lipshutz and Ellsworth using dilithium cyanodimethylcuprate, Me2Cu(CN)Li2, as a catalyst [Me2Cu(CN)Li2 was prepared from 2 equiv of MeLi and CuCN in THF at -78 transmetalation with Me2CuLi was not successfull.172 The C; extension of this methodology by the Lipshutz group led to the synthesis of vinylic lithiocuprates containing internal electrophiles and the development of a short, efficient prostaglandin synthesis from alkyne precursors and functionalized cyclopentenones, e. g. for PGE1,55 and misoprostol.17 sl174Hydrozirconation of 4-methyl-4-[(trimethylsilyl)oxy]-1 -octyne 166 with Schwartz reagent to give the alkenylzirconium intermediate, followed by addition of 2 equivalents of n-BuLi or MeLi and sequential addition of 1 equivalent each of copper cyanide and methyllithium gave the cyanocuprate. Subsequent treatment with (+/-)-methyl 7-[5-oxo-3-[(triethyIsilyl)oxy]-1 -cyclopenten-lyllheptanoate (166) yielded protected misoprostol 169 in 73% yield (Scheme 43).
1.2 eq. MeLi. -30 to -76 OC; cp,zrHcI :fl1 166 THF, r.t. RI I 2. CuCN;
e
3. 1 eq. MeLi (in THFkumene)
167
-30 to -78 73% C;
EtgSiO~~R1 169
R, = CH$Z(CH3)(0TMS)-C.,H9 Fi2 = (CH2)&02CH3
Scheme 43
12883
Wipf and Smitrovich reported the first example for the use of alkyl zirconocenes and catalytic copper(l) salts for conjugate addition reactions in 1991 .Sz Independently, this process was also investigated by Venanzi and Lehman .I75 Besides CuBr-SMep, other Cu(l) and Cu(ll) salts such as CuBr, Cul, CuCN, Cu(acac)p, (QHgC2)CuCNLi2, and Cu(OT92 catalyzed the 1,Caddition of functionalized zirconocene to alkenones (Scheme 44) .4sls2115s In contrast to most recently reported transmetalation protocols for cuprates that involve the transfer of kinetically labile alkenyl groups,168 this methodology allows alkyl transfer via relatively stable, easily accessible zirconocene derivatives. The tendency of alkyl zirconium complexes to migrate along a linear chain toward the sterically least hindered position via insertion - P-hydride elimination reactions can be used to prepare primary organometallics from internal alkenes or mixtures of isomers. Primary, secondary, and functionalized alkyl groups can be transferred. Conjugate additions to enones and vinyl sulfones occur readily, whereas a$-unsaturated aldehydes lead to mixtures of 1,2- and 1,4-addition products and cl& unsaturated alkyl esters do not react.43 In an asymmetric variant of this method, alkyl groups can be added to acyl oxazolidinone 178 with s90% de (Scheme 45).17s
2. CuBrSMe2 (cat.),
BF3 0Et3, 40 10 min; 78% C,
m
174
1.
Cp2ZrHCI: THF,40 OC, min; 15
..
2. CuBrMepS (cat.), 40 OC, 10 min;

51% Ph 176 Ph
Scheme 44
12884
P. WPF and H. JAHN
1. Cp&(H)CI, TBBO177
THF * TBSO
Ph
2. CuBrSMe:! (3 x 5mol%) 2 h, 21 C BFg0Et2 (1 .O equiv) PhdN O 178
92% de
Scheme 45
Mechanistically, the copper-catalyzed addition of alkylzirconocenes to enones proved to have distinctively different features than the analogous process involving alkenylzirconocenes:43 The yield depended significantly on the presence of ionic impurities in the Schwartz reagent: Both alkali cations and halide anions inhibited the formation of the conjugate addition product. LiCI, Nal, MgBrp and ZnCl2, for instance, were not tolerated. Since these compounds are side products of the in situ preparation of Schwartz reagent with LiEt3BHss and t-BuMgCl,ss or were added to facilitate ligand transfer from alkenylzirconocenes, 170 these protocols are not useful for hydrozirconation/copper-catalyzed conjugate addition sequences. ?? The concentration of the reactants, especially enone and alkylzirconocene, is an important parameter in the copper-catalyzed conjugate addition. Desirable concentrations of the reactants are >0.5 M. Kinetics and NMR investigations indicate that the formation of an enone-zirconocenecopper complex is crucial for conjugate addition to occur. ?? EtgB and AI(OEt)3 led to an enhanced activity, but optimal conditions were achieved in the presence of 1 equiv of the strongly Lewis-acidic BFg-etherate.
??
Based on these observations, it can be hypothesized that for alkenylzirconocenes, the organic ligand is actually transferred to Cu(l) presumably via ate complex 181 (Figure 7). The organocopper species 182 is then responsible for further addition to @-unsaturated ketones. Alkenyl groups are better bridging ligands and are therefore exchanged more readily between metals.177 The alkylzirconocene species 183 probably does not undergo the analogous exchange reaction with copper(l) alone or in the presence of alkali halides. Product formation occurs via the x-complex 185 between copper(l), enone, and zirconocene. The formation of this complex is disrupted by the presence of alkali halides whereas Lewis acids facilitate the breakdown of 185 to give product enolate. Further mechanistic studies are needed to clarify the order of events in these conjugate additions and elucidate the actual structure of the enone-metal complex. The formation of copper(O) mirror during the reaction highlights the possibility of redox-based side reactions. However, the absence of typical alkenes and alkane disproportionation products of organocopper reagents supports the hypothesis that no actual transmetalation occurs prior to product formation.
12885
\--\ ZfcppCl
180
1. Lil
f-w)
R \
\
183
I- [ R+cu I 1
cp/p
2. CuOTf Li+ 181 182 -Li+ X 1 LiX
conjugate addition -
Fu TfO
pmdu&s
184
Zrcp2Cl
Cu(U enone \
LiX L
Figure 7
Wipf and Xu have developed a selective, one-pot synthesis of ketones from acid halides and alkenes or alkynes based on the hydrozirconation-copper(l)-catalyzed addition methodology.74 Addition of aryl, alkyl, functionalized or sterically hindered acid chlorides and catalytic amounts of CuBrSMe to alkyl- and alkenyl zirconocenes provided the corresponding ketones in moderate to high yields even in the presence of very labile functionality (Scheme 46). No overaddition of the organometallic reagent, a side reaction that is typical for ketone synthesis from acid halides, was observed.74l17a
1. CppZrHCI, THF, 20 C, 20 min; A187 2. CuBrSMep (cat.), 35 20 min; C, 79% 0
Scheme 46
This methodology was used by Srebnik and Zheng for the synthesis of enol borates from gemborazirconocene alkanes and their regioselective conversion to a-bromo ketones (Scheme 47).179 In the presence of copper(l)-safts,s+%los gemborazirconocenes also added across Michael acceptors (methyl acrylate) to afford 1,Caddition product 195, whereas treatment with propargyl bromide yielded the a-allenic boronic ester 196. Subsequent addition of benzaldehyde to the boryl allene 196
12886
P. WIF and H. JAHN F
afforded the corresponding 1,Sdienyl allylic alcohol 197, whereas addition of an a&unsaturated aldehyde such as crotonaldehyde led to trienes 198 or 199, depending on the reaction conditions.l2s.r80,181
1. Cp&HCI,
CH&lp, r.t.;
2. n-PrCOCI, CuBrMe2S (15 mol%)
192
Cp2ZrHCI, CH2C12 196 + rrBu AA 194
ZrCppCl
~C02Me 1. CuBrSMep (10 mol%); 2. sat. aq. NaHC03; 62%
CuCN (10 mol%), r.t., overnight; 69%
1 n.u+
PhCHO, *CHO n_Budph sn_Bu$ *Buy+ 197. cis : trans (94 : 6) 196 199, 33%; cis : tmns (65:15) 199, 62%; cis : frans (90:10)
Scheme 47
Copper-catalyzed allylic substitution reactions of alkylchlorobis(cyclopentadienyl)zirconium(lV) complexes were investigated by Venanzi and Lipshutz. 17518 The SNP-substitution of allylic halides and phosphates occurred in good yields and provided terminal olefins as the major isomers (Scheme 48).
CICp& nn-CgH13 Ph hOP(0)(OEt)2 200 CuCN (10 mol%), Et20, 3 h; 65% w 201 + 93:7 Ph\//\,GH13 262
Scheme 48
complexes
12887
Epoxide openings and substitution of benzylic halides and vinyl triflates can be performed with organozirconocenes and copper complexes with non-transferable ligands such as thienyl cuprates Me(2_Th)Cu(CN)Li2, since the methyl substituent of mixed cuprates MeRCu(CN)Li2 is preferentially transferred from copper to the electrophile (Scheme 49). 183 Addition to unactivated primary halides required the use of the presumed mixed metal cuprate Me(2-Th)Cu(CN)LiMgCl.
\
R~ZfcppCI 203 THF, -78 to -20 OC I + is d
Cu(CN)Lip
204
205
207
205
Scheme 49
To circumvent the use of stoichiometric copper reagents and organolithiums in this scheme, Lipshutz and Wood developed a cyanocuprate-catalyzed 1,Caddition of vinylic zirconocenes using a zincate as an organolithium shuttle (Scheme 50). 184 A 3-component coupling (3-CC) version of this process included the regeneration of the cyanocuprate (Me2Cu(CN)Li2) with methyl anions provided from the zincate (Me3ZnLi) (Scheme 51). 1121185The zincate transported the elements of MeLi to copper(l). MeLi itself, or any hard carbanionic equivalents, could not be tolerated by the starting material. Attempts to use the zincate without cuprate to effect both the transmetalation and the subsequent Michael addition were not successful.
12888
P. WIF and H. JAHN F
CpgrHCl, THF, 30 min, rd.
1. MeLi, MegnLi, THF, -78 C, Me&u(CN)Li 2. -78 88% C; A (20 mol%); o 2,, h JdAyT= 212
Scheme 50
0
MeLi, Me$nLi, w 21PC R=alkyl hle&u(CN)Li2 (cat.), THF, -78 C b 214 Cu(CN)Lip Ihe 218 R
R oz
6
I
215 t
219, 88 - 71%
Scheme 51
Using spectroscopic evidence, a catalytic cycle for the cyanocuprate-catalyzed 3-component couplings was proposed.lm The zincate MegZnLi in the reaction mixture serves to transmetalate the initially formed copper enolate 216, thereby regenerating the catalyst. This ligand-exchange leads to the production of the reactive zinc enolate 217, which can undergo further C-C bond constructions, such as aldol and alkylation reactions leading to 216 and 219.187 Catalytic copper(l) is also useful for the functionalization of zirconacyclopentenes.l~llsQ17d
complexes
12889
D. Zirconium+Mercufy Erythro- and fhre~ alkylzirconocenes 220 and 222 were transmetalated by Budnik and Kochi to the mercury derivatives 221 and 223 with 90% retention of configuration (Scheme 52). 90 HgCh,
benzene or CHQ -&A D
D HgCl
221 90%
retention of configuration
HgCla benzene or CHC13 ZrCp&l -3\r D
D HgCl 223
+
D
222
Scheme 52
E. Zirconium+Nickel Nickel-catalyzed conjugate addition of alkenylzirconocenes is a useful transformation for prostaglandin synthesis.lsl In the presence of catalytic amounts of Ni(acac)p, rapid enone addition is achieved with terminal alkenylzirconocenes (Scheme 53). w Organometallics derived from internal alkynes give only modest yields, and no examples using alkylzirconocenes have been reported. Reduction of Ni(acac)p with one equivalent of DIBAL-H prior to reaction appears to give improved yieldssl~l~ A one-electron transfer mechanism was proposed for these reactions (Figure 8).1w*fs
234
235
236
237
Figure 8
12890
P. WIPF and H. JAHN
1.
t-B.i+
cp,zrHcl, 25 w f_Bu&ZrCP2CI C 224 benzene, 225
/ 7
O 226
Ni(acac)p, THF, -76 OC, then 6 h, 0 OC; 2.l+so+; >95%
227
cat. Ni(acac)2, DIBAL-H (1 2. Ifso+; 52%
: 1)
OTBS
CppZrHCI,
OTBS cat. Ni(acac)z,
C5H11 benzene, 25 OC 230
231
Scheme 53
Hauske et al. applied a Ni(ll)-catalyzed conjugate addition to both cyclic and acyclic Michael acceptors in their investigations to convert amino aldehydes directly into substituted chiral ally1 amines via the intemediacy of propargylic amines. Propargylic amine, prepared in one step from the amino aldehyde by exposure to dimethyl diazophosphonate, underwent hydrozirconation to the trans vinyl zirconium intermediate. Subsequent Ni(ll)-catalyzed conjugate addition led to the desired chainextended ketone 241 (Scheme 54). 196 This group also reported the synthesis of novel FKBP inhibitors by this methodology. Q7
BocHN
x
236
(Me0)2P(O)CHN2 KO t-Bu 239
Cp2ZrCl&iEt3BH 246
CHO
w cat. Ni(acac)2, DIBAL-H (1 : 1) 2. HsO+; 51%
24
2:l mixtureof diastereomers
Scheme 54
12891
Negishi et al. discovered the nickel-catalyzed coupling of aryl halides and alkenylzirconium reagents. Arylnickel(ll) species were formed by oxidative addition of halides to in situ generated Ni(PPh3)4 (Scheme 55). The transmetalation of internal alkenyl units proceeded very slowly in this cross-coupling [email protected]~ Addition of ZnClp facilitated coupling with di- and trisubstituted alkeny1zirconocenes.m CppZrHCI, benzene,
EtO+ 242 2 h, r.t. * Eto&z~P2cI 243 Phi, THF. 12 h, r.t., * Ni(PPh& (cat.); 99% EtobPh 244
Scheme 55
F. Zirconium+Palladium The first observation of a Zr-Pd-transmetalation in alkene homocoupling reactions was reported by Schwartz et al. in 1977. 12s Negishi and coworkers investigated the palladium(O)catalyzed regio- and stereoselective synthesis of conjugated dienes from alkenylzirconocenes and alkenyl halides (Scheme 56).tw,at This method was also applied for the preparation of (e-5alkenylP -deoxyuridines.202 The Pd-catalyzed coupling reaction of alkenyl- and aryltirconium compounds with allylic halides, acetates, and alcohol derivatives containing OAIR2, OPO(OR2), and OSiR3 groups gave the corresponding cross-coupled products in the following order of reactivity: halogen, OAc > OAIR2 > OPO(OR)2 > OSiR3.~~~
- 245 ZICp2GI
246 * w 247
Pd(PPh& (5 mol%). THF, 1 h, r.t.; 91%
Scheme 56 Schwartz and coworkers described the reactions between (rc-allylic)Pd(ll) halide species and alkenylzirconium complexes which gave rise to 1,4-dienes in high yield. This methodology was used for the synthesis of 25-hydroxycholesterol and (20R)-cholestan-3-one (Scheme 57).205,m Palladium was replaced with retention of configuration, The use of additives such as maleic anhydride had a profound effect on the regiochemistry of the couplings.~7~~
12892
P. WIPF and H. JAHN
Cp&rHCI (2 equiv). Maleic anhydride, THF AOH 240 t uene~ 45% * C~(Ci)+JGZr(Cl)Cp, t -78+r.t., overnight
AcO
Scheme 57 In the palladium-catalyzed coupling of vinyl halides, the use of disubstituted and trisubstituted alkenylzirconocenes is unsatisfactory due to a slow Zr+Pd transmetalation. Negishi and coworkers discovered that the kinetics of this step can be improved by the addition of ZnCl2 which has an electronegativity between Zr and Pd and low steric requirements. The use of 0.5 equiv of the ZnCl2 shuttle induced the formation of 254 in 85% yield after 1 h at room temperature, whereas ~2% product was formed in the absence of ZnCI2 (Scheme 58). 200 In model studies toward the synthesis of hennoxazole A, this method was used tor the formation of 1,4-diene 257 from zirconocene 255 and the n-ally1 palladium complex derived from 256.m.210
CO&e
Br
y
Pd(PPh& (5 mol%). THF. ZnC12(50 mol%), 1 h, r.t.; 65%
Br ~CO*Me 256 TBSO~ZrCp&I 255 Pdp(dba)pCHCla, THF, ZnClp, 12 h, r.t. * TBSO
~CO$Ae 257
Scheme 56
A nice comparison of the efficiency of various Zr+Pd transmetalation protocols was recently reported by Barrett et al.211 Conversion of the alkenylzirconocene obtained in situ by hydrozirconation of alkyne 256 to the vinyl iodide, followed by Stille coupling gave the desired dienoate 259 in ~30% yield (Scheme 59). In contrast, transmetalation to zinc chloride or direct use of the vinyl zirconocene, followed by palladium-catalyzed addition to bromoacrylate, increased the yield
Organochlorozirconocenecomplexes
12893
to 64% and 62%, respectively. This efficient synthesis of the sensitive tetraene ester 259 was an important step toward the total synthesis of papulacandin D by these authors.
1. Cp$r(H)CI, THF 2. 12 * 3. (E))-Bu$nCH=CHC02Me, (CH3CN)2PdC12.THF
OR
OR
258
259,
<30%
1. Cp&(H)CI, 2. ZnC12 258
THF w 259, 64%
3. (E)-BtCH=CHCO&Ie, (PhsP)dPd, THF
1. Cp2Zr(H)CI, THF 2. (E)-BrCH=CHC02Me, [(Ph3P)2PdC12,DIBAI-H] 258 e 259, 82%
Scheme 59
G. Zirconium+Tin Conversion of organozirconocenes to stannanes has not yet been extensively investigated. A Zr+Sn-transmetalation was used for the synthesis of n-octyltin(lV) trichloride. [($%jH6)2Zr(nOct)CI], prepared in situ from l-, 2-, or 3-octene and Cp2ZrHCI, reacted with stannic chloride in by the moderate yields to give nC6H17SnCl3. 212 Fryzuk et al. prepared 1,Sdienylstannanes selective hydrozirconation of 1,3-enynes and transmetalation with tributyltin chloride?ls Recently, Kim and Kim developed a new efficient procedure for the synthesis of simple and bicyclic organostannanes by transmetalation of organotirconocenes with organotin alkoxides (Scheme 60). The hydrozirconation product of trimethylsilyl acetylene reacted very effectively with tributyltin ethoxide, whereas the transmetalation with tributyltin chloride, bis(tributyltin) oxide, tributyltin thiophenoxide or N,N-diethyltributylstannazane was very slow.214
TMSE 260
cp2zrHcI, TMS,+ZrCp2CI
THF 261
Bu3SnX, THF _ 40 OC, 15 h
TMS+SnBu3 262
X = Cl (24%); X = NE12(36%); X = SPh (5%); X = OSnBuB (8%); X = OEt (85%)
Scheme 50
12894
P. WIPF and H. JAHN
Hydrozirconation of triallylamine followed by in situ metal exchange with SnCl4 was used by Vedejs et al. for the preparation of the 1-aza&stannabicycloundecane 263 (Figure 9).2 This s compound was subsequently applied as an internally activated stannane for palladium-catalyzed cross-coupling reactions.
dl
263
Figure 9
H. Zirconium+Zinc The first indications of the feasibility of zirconocene-zinc ligand exchange reactions were revealed by Negishi and coworkers who found that many of the Pd- or Ni-catalyzed reactions of alkenylaluminum or -zirconium compounds with alkenyl, aryl, or alkynyl halides could be significantly accelerated by the addition of ZnCl2. 200 An organozinc species was postulated as an intermediate, and Hartner and Schwartz were indeed able to prepare dineohexenylzinc from the corresponding chrorozirconocene.lm A synthetically useful variant of this transmetalation reaction was reported by Wipf and Xu in 1994.*1sl*17Transmetalation of alkenyl zirconocenes to the corresponding organozinc compounds occurred rapidly and at low temperatures in the presence of commercially available dimethyl- or diethylzinc (Scheme 61). Subsequent addition of aldehydes provided an in situ protocol for the conversion of alkynes into allylic alcohols.
cp&-lcl n-81.1264 C&Cl,, r.t. *
/)B&
ZrCPnCl 265
Me$Zn, -65 C )
Bnoh,
269
;:g$;:g+3. H11C5CH0, 0 C, 2 h 72%
,.,+
270 OH
Scheme 61
complexes
12895
In the presence of 8 mol% of chiral amino alcohol 271, this process led to the formation of optically active allylic alcohol 272 (Scheme 62). 21s The unexpectedly low level of enantiomeric excess for the product (38% ee) is probably due to the presence of zirconocene complex that catalyzes the racemic addition reaction.
1. Cp2Zr(H)CI. CH2C12. rt. 2. Me2Zn, -65 C p 264 272 36% ee OH
*Ph
4. PhCHO, -20 C, 6 h
Scheme 62
The zirconium+zinc transmetalation combines the ease of preparation of functionalized organometallics from alkynes via hydrozirconation with the broad range of reactivity of organozinc reagent@ and is therefore an attractive protocol in natural product total synthesis. For the synthesis of the curacin A segment 279, Wipf and Xu performed a hydrozirconation of alkyne 273 followed by addition of the in situ obtalned organozinc reagent to aldehyde 275 (Scheme 63).8z The crossconjugated dienone 277 was obtained in 85% yield after oxidation of bis-allylic alcohol 276 with manganese dioxide. Regio- and stereoselective enolization of the dienone, followed by Stillereduction of the enoltriflate 276 gave Gene 279 en route to curacin A. CGWIFI,
BDPSOy\ 273 CH2C12,21 / BDPSO-Zr(CI)Cp2 274
1. Et2Zn (1.1 equiv), -60 C
2.0 C, 6 h
275
BDPSO+ 276 OH
BDPSO+ 277 0
1. KHMDSA, THF. -78 C b 2. Tf2NPh, -7&O C, 12 h, 276, R =OTf 279, R = H, 71% 3. Bu3SnH, Pdp(dba)&HC& LiCI, PPh3, THF ?L, 4 h BDPSO+ R
Scheme 63
12896
Another application of this methodology was used for the preparation of the Clg-side chain of the antibiotic manumycin (Scheme 64).21sA key step was the hydrozirconation of the TBS-protected alkyne 94, followed by an in situ Zr+Zn-transmetalation and addition to (R)Q-methyl-hexanal. After trifluoroacetylation of the allylic alcohol, the silyl ether was converted to the carboxylic acid under elimination of the trifluoroacetate and formation of the conjugated diene moiety to give 282.
1. Cp$3(H)CI, CH$&, r.!.; 2. Me.& -60-10 OC; 3
//
OH TBS 281
TBSO
94 /v-+HO 49% s 280
1. TFAA. pyridine, DMAP, 0 OC, 91%; 2. TsOH, MeOH/Et,O, 99% 3. Dess-Martin Periodinane; (i_PrhNEt, THF; 79%; 4. NaC102, NaHsPO,, THF/Hp 2-methyl-2-butene, r.t.; 61%
282 (5:1),
Scheme 54
Zheng and Srebnik have recently reported the acceleration of the 1,2-addition of alkyl- and alkenylzirconocene chlorides to aliphatic and aromatic aldehydes by catalytic amounts of ZnBr2.a ZnCl2 was found to be ineffective in dilute solutions, but could also catalyze the reaction, though less efficiently than ZnBr2, in more concentrated mixtures. Treatment of the alkylzirconocene chloride 283 with benzaldehyde in the presence of catalytic amounts of ZnBr2 afforded after aqueous workup the secondary alcohol 285 or the Oppenauer oxidation product 288, depending on the ratio of reagents to benzaldehyde (Scheme 65).
TMS/C.Z;~CI
PhCHO ZnBr2 (20 mol%), THF, 3 h, 25 C PhCy
-TMSJF 1
I 284 jH20: 69% TMSdPh 285
TMSJPh 285
Scheme 65
12897
Lipshutz and Wood reported a related process involving the use of a mixed zincate in the transmetalation of an intermediate vinyl zirconocene, but the yields were highly variable and dependent on the nature of the R substituent in the I-alkyne 287 (Scheme 66).zt
0
Me$!nLi, 1. R-_= 287 2. MeLi, -78 C
0 R+ ZnMe2Li 289 c) I
CpgrHCI;
w R+ 266 ZrCppMe p
THF, -78 C
Scheme 88
It can be expected that further advances, especially in the asymmetric catalysis of the nucleophilic addition, will continue to broaden the scope of the zirconium-zinc transmetalation.
10. Cationic Zirconocene
Complexes
The use of cationic zirconocenes as Ziegler-Natta polymerization catalysts abounds,s$sllc but there are still surprisingly few applications of cationic organometallics derived from organochlorobis(cyclopentadienyl)zirconium(lV) complexes. 222323 In 1968, Suzuki et al. observed an acceleration effect in the C-glycosidation of phenols by treatment of glycosyl fluorides with a mixture of Cp2MCl2 (M = Ti, Zr, H9 and AgCl04. 2%?2.%~ In this process, the initially formed 0-glycoside rearranged to the C-congener. Further studies of this group demonstrated the remarkable rate acceleration effect of AgCl04 on the Grignard-type addition of alkenyl- and alkylzirconocenes to aldehydes, offering a new possibility for C-C bond formation (Scheme 67).m
Cp2ZrHCI, CH2C12, r.t., 10 min /&n-B 264 CICp2Zr~n-Bu 266
1
1
PhCHO, cat. AgC104, 10 min, 92% * PhLn-Bu 291
Cp2ZrtlCI,CH2C12,
r.t., 10 min &rrBu 292
;;CMHOj cat. AgCl04,
* PhLmBu
294
Scheme 67
12898
Wipf and Xu reported a highly efficient tandem epoxide rearrangement-carbonyl addition sequence with alkyl- and alkenylzirconocenes. Whereas the copper(l)-catalyzed addition of in situ prepared (E)-[tert-butyl-dimethylsilyl)oxy]zirconocene 296 in the presence of AI(OEt)3 to the vinyl epoxide 297 resulted in a 23% yield of a 1:l (E) : (z) mixture of diene 296, the addition of 5 mol% of AgCl04 to a mixture of zirconocene 296 and epoxide 297 led to a rapid conversion to the secondary alcohol 299 in 92% yield (Scheme 68) ? Key features of this new methodology are (1) a rapid opening of the epoxide ring followed by a [1,2]-hydride shift in the presence of in situ prepared cationic organozirconocene complexes: (2) CC-bond formation via transfer of the alkenyl or alkyl ligand from the zirconocene to the aldehyde intermediate; (3) the use of highly functionalized (ester, alkene, silyl ether) Lewis acid-sensitive substrates and catalytic amounts of Ag( I) salt (Figure 10). The cationic zirconocene complex 302 is regenerated by chloride abstraction from 301 by alkoxy zirconocene 307 at the completion of a catalytic cycle.
CppZrHCI. CH2C12, 20 OC, 20 min
296
TBDMSOdoH 266 (E:Z= 1:l)
TI3DMSO- +
b n-C4Hg 262
1. Cp2ZrHCI, CH2C12 m 2. AgC104, 0 *Ph
RC4HgxPh 300
75%
Scheme 66
complexes
12899
FR
OZrRCpP 305 I \
[1 SW \
AgC104 Cp$tZr-Cl 301
I
Cp2RZr 302 ! e
+
d* cp;zP
R 306 R
R Y OZrCppCl 308 +b 301
J 307
Figure 10
Intramolecular neighboring group participation of a Lewis-basic moiety attached to the epoxide can be used to suppress the [1,2]-hydrogen shift. Treatment of epoxy ester 309 with hexenyl zirconocene 266 in the presence of 5 mol% of silver perchlorate led to the isolation of acetal 312 in 49% yield (Scheme 69).= Only a single isomer was formed as a consequence of the suprafacial transfer of the alkenyl ligand in the dialkoxycarbenium intermediate 311. Acetal 312 represents the kinetic product since treatment with small amounts of HCI in the NMR tube led to an approximately equimolar mixture of five- and six-membered acetals 313 and 314 with no diastereocontrol. Upon hydrolysis, keto ester 315 was isolated quantitatively. The overall transformation from diester 309 to ketoester 315 including the alkyne hydrozirconation can be performed in one pot and represents a chemoselective nucleophilic ester addition of an organometallic reagent that is free from subsequent carbonyl addition products. The intermediate dialkoxycarbenium ion 311 can also be used as a reactive Diels-Alder dienophile in substrates with an a,&unsaturated epoxy ester moiety.230
12!mo
P. WPF and H. JAHN
HCI, CDC13
Scheme 69
Maeta and Suzuki described a new method for 1,Sdiene synthesis based on a three-carbon elongation of aldehydes with in situ prepared cationic zirconocenes~l 3-Trimethylsilyl-lpropenylzirconocene chloride, generated from 3-trimethylsilyl-1-propyne and Cp2ZrHCI, reacted with aldehyde in the presence of catalytic amounts of AgCl04, and subsequent 1,Celimination gave 1,3dienes with excellent (E)-selectivities (Scheme 70). 0
CICp$r~SiMe~ 316 + cat. AgCIO.+, CH2C12, r.t., 20 min, then reflux, 4 h; 73% -0 316
CT
H 317
Scheme 70
In a variant of this process, two- and four-carbon homologation of aldehydes was achieved by AgClOq-catalyzed addition of alkoxyalkenylzirconocene chloride .m Treatment of 1-ethoxyacetylene or (Z)-1-methoxy-1-buten-3-yne with Cp2ZrHCI, followed by addition of aldehyde and catalytic amounts of AgC104 afforded the corresponding (Q-unsaturated aldehydes 320 or 321 after acid hydrolysis (Scheme 71). More recently Suzuki and coworkers reported that AgAsF6 serves as a safe and often more efficient alternative to the potentially explosive AgClO4.m
complexes
12901
-CHO
319
1. CICpnZr &OEt
AgCl04 (5 mol%); CH2Cl2, r.t., 30 min: 2. H30+; 90% 1 -CHO 320 \CHO 321 I
1. cicppzr AgC104 (5 mol%); OMe CH2C12,rd., 30 min; 2. H30+; 89%
Scheme 71
11. Concluding Remarks Since the preparation of the first organochlorobis(cyclopentadienyl)zirconium(lV) complex by Wailes, W&gold and Bell 25 years ago, ~4 the application of these organometallics for carbon-carbon and carbon-heteroatom bond formations has become an integral part of synthetic strategy and tactics. Nonetheless, we hope it becomes clear from this review that the chemistry of organozirconocenes is very much an emerging field, with many opportunities for further expansion into uncharted territory. The use of zirconium complexes in asymmetric or even diastereocontrolled transformations has just begun, and many more manifolds are open for transmetalation schemes and for the direct functionalization of organic molecules. A deeper understanding of reaction mechanisms ranging from hydrozirconation to ligand transfer reactions is clearly necessary and will assist in the development of catalytic processes that can take advantage of more elaborate zirconium complexes. As the widespread use of palladium complexes has shown, the fine-tuning of ligands can lead to considerable variation in reactivity and scope. 2% Therefore, the versatility that the parent organochlorobis(cyclopentadienyl)zirconium(lV) complexes have already demonstrated is quite remarkable.
Acknowledgment. Financial support for our studies in organozirconocene and natural products chemistry was generously provided by NSF, NIH, the American Cancer Society, the Sloan and the Dreyfus Foundations, and by Lilly, Upjohn, Merck, and Zeneca. We would also like to acknowledge the many contributions of other members of the Wipf group, especially Jackie Smitrovich, Wenjing Xu, Hongyong Kim, Hidenori Takahashi, Philip Coish, Seth Ribe and Nian Zhuang who have been involved at various stages in zirconocene-based projects. Special thanks go to Professors C. Merlic (UCLA), J. Schwartz (Princeton U.), and G. Posner (Johns Hopkins U.) for their helpful comments and review of this manuscript.
12902
P. WIPF and H. JAHN
12. References and Notes 1. (a) Labinger, J. A. In Comprehensive Organic Synthesis; B. M. Trost and I. Fleming, Eds.; Pergamon: Oxford, 1991; Vol. 8; pp 667. (b) Schwartz, J.; Labinger, J. A. Angew. Chem. Int. Ed. Engl. 1976, 15,333. Annby, U.; Karlsson, S.; Gronowitz, S.; Hallberg, A.; Alvhall, J.; Svenson, R. Acta Chem. Stand. 199347,425. Negishi, E.; Takahashi, T. Aldrichim. Acta 1965, 78, 31. Negishi, E.; Takahashi, T. Synthesis 1988, 1. Takacs, J. M. in Comp. Organomet. Chem. II (Abel, E. W.; Stone, F.-G. A.; Wilkinson, G.; Hegedus, L. S., Eds.); Pergamon 1995, Volume 12, Chapter 3.1., pp. 39. (a) Dzhemilev, U., M.; Sultanov, R. M.; Gaimaldinov, R. G. J. Organomet. Chem. 1995, 497, 1. (b) Kondakov, D. Y.; Negishi, E.-l. J. Am. Chem. Sot. 1996, 778, 1577. (c) Hoveyda, A. H.; Morken, J. P. Angew. Chem. Int, Ed. Engl. 1996, 35, 1262. (d) Lewis, D. P.; Whitby, R. J.; Jones, Ft. V. H. Tetrahedron 1995, 57, 4541. (e) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633. (a) Negishi, E.-l.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1966, 27, 2829. (b) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.; Dixon, D. A.; Harlow, R. L. J. Am. Chem. Sot. 1994, 776, 9457. (cj Knight, K. S.; Wang, D.; Waymouth, R. M.; Ziller, J. J. Am. Chem. Sot. 1994, 776, 1845. (d) Takahashi, T.; Ham, R.; Nishihara, Y.; Kotora, M. J. Am. Chem. Sot. 1996, 778, 5154, and references cited therein. (a) Jordan, R. F. Adv. Organomet, Chem. 1991, 32,325. (b) Guram, A. S.; Guo, Z.; Jordan, R. F. J. Am. Chem. Sot. 1993, 7 75, 4902. (c) Shaughnessy, K. H.; Waymouth, R. M. J. Am. Chem. Sot. 1995, 777,5873. (d) Grubbs, R. H.; Coates, G. W. Act. Chem. Res. 1996,29,85. (a) Brintzinger, H. H.; Fischer, D.; Miilhaupt, R.; Rieger, D.; Waymouth, R. M. Angew. Chem. Int. Ed. Engl. 1995, 34, 1143. (b) Sinn, H.; Kaminsky, W.; Vollmer, H.-J.; Woldt, R. Angew. Chem. Int. Ed. Engl. 1980, 79, 390. (a) Yang, X.; Stem, C. L.; Marks, T. J. J. Am. Chem. Sot. 1991, 773, 3623. (b) Yang, X. M.; Stem, C. L.; Marks, T. J. Angew Chem Int Ed 1992, 37, 1375. (c) Yang, X. M.; Stern, C. L.; Marks, T. J. J.Am. Chem. Sot. 1994, 776,10015. Negishi, E.-l.; Takahashi, T. Act. Chem. Res. 1994, 27, 124. (a) Broene, R. D.; Buchwald, S. L. Science 1993, 267, 1696. (b) Erker, G. Pure Appl. Chem. 1992, 64, 393. (c) Buchwald, S. L.; Nielsen, R. 8. Chem. Rev. 1988, 88, 1047. For a recent symposium on zirconocene chemistry, see: Recent advances in the chemistry of zirconocene and related compounds. Tetrahedron Symposia-in-print No. 57 (Negishi, E.-l., Ed.), Tetrahedron 1995, 57 (15) 42554570. Zirconium is ca. 106 times more abundant than palladium, and on a molar basis presently ca. 20 times cheaper. The most readily available zirconocene, bis(cyclopentadienyl)zirconium dichloride, sells at $0.5-1.5/g. Wilkinson, G.; Pauson, P. L.; Birmingham, J. M.; Cotton, F. A. J. Am. Chem. Sot. 1953, 75, 1011. For an extensive overview of organozirconium and -hafnium chemistry, see: (a) Cardin, D. J.; Lappert, M. F.; Raston, C. L. Chemistry of organo-zirconium and -hafnium compounds; Wiley: New York, 1986. (b) Wailes, P. C.; Coutts, Ft. S. P.; Weigold, H. Organometallic chemistry of titanium, zirconium, and hafnium; Academic Press, New York, 1974.
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23. 24. 25. 28.
27. 28. 29.

30.
31. 32. 33. 34. 35. 38. 37.
38.
39. 40.
41. 42. 43. 44. 45. 48.
12904
P. WJPF and H. JAHN
47.
48.
49.
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55. 56. 57.
56. 59. 60. 61. 82. 88. 84. 85. 88. 87. 88. 69. 70.
71. 72 78. 74. 75. 78.
complexes
12905
77. 78.
79.
(a) Wipf, P.; Takahashi, Pittsburgh, 1995.
H. unpublished
results.
(b) Kim, H.-Y., Thesis,
University
of
80. 81. 82. 83. 84.
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12906
P. WIPF and H. JAHN
111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143.
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12907
144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156.
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12908
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complexes
12909
215. 216. 217. 216. 219. 220. 221. 222.

223.
Vedejs, E.; Haight, A. R.; Moss, W. 0. J. Am. Chem. Sot. 1992, 714,6556. Wipf, P.; Xu, W. Tetrahedron Lett.1994, 35,5197. Wipf, P.; Xu, W. Org. Synth. 1996, 74, in press. Knochel, P.; Singer, Ft. D. Chem. Rev. 1993, 93,2117. Wipf, P.; Xu, W.; Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure A@. Chem., in press. Zheng, B.; Srebnik, M. J. Org. Chem. 1995, SO,3278. Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Sac, 1994, 776,11689. Review: Guram, A. S.; Jordan, R. F. in Camp. Oganomet. Chem. /I (Abel, E. W.; Stone, F.-G. A.; Wilkinson, G.; Hegedus, L. S., Eds.); Pergamon 1995, Volume 12, Chapter 12, pp. 589. For representative examples for the use of other cationic derivatives of zirconocenes, see: (a) Guram, A. S.; Jordan, R. F. J. Org. Chem. 1992, 57, 5994. (b) Hollis, T. K.; Odenkirk, W.; Robinson, N. P.; Whelan, J.; Bosnich, B. Tetrahedron 1993, 49 5415. (c) Jaquith, J. B.; Guan, J.; Wang, S.; Collins, S. Organometallics 1995, 74, 1079. Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Left, 1988, 29,6935. Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Sot. 1992, 774, 3568. Review: Suzuki, K. Pure A@. Chem. 1994, 66,1557. Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron L&t. 1992, 33, 5965. Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825. Wipf, P.; Xu, W. J. Org. Chem. 1993, S&5880. Wipf, P.; Xu, W. Tetrahedron 1995, 57,455l. Maeta, H.; Suzuki, K. Tetrahedron Lett. 1992, 33, 5969. Maeta, H.; Suzuki, K. Tetrahedron Lett. 1993, 34, 341. Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba, S. Tetrahedron 1995, 57,4483. Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27, 373. Review: Tsuji, J. Palladium reagents and catalysts; Wiley: Chichester, 1995.
224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235.
(Received 26 June 1996)
12910
P. WIPF and H. JAHN
Biographical
Sketch
Peter Wipf
Heike Jahn
Peter Wipr received his Diploma in 1984 and his PhD in 1987 from the University of Zurich under the direction of Prof. Heinz Heimgartner. He continued his scientific eduction as a Swiss NSF Postdoctoral Fellow at the University of Virginia with Prof. Robert E. Ireland, where he worked on the total synthesis of FK-506 and studied the ester enolate Claisen rearrangement. In 1990, he joined the faculty at the University of Pittsburgh as an Assistant Professor, and was promoted to Associate Professor in 1995. His current research interests focus on the total synthesis of natural products, heterocyclic and organometallic chemistry. Peter Wipf has been named an NSF Presidential Faculty Fellow and a Lilly Grantee. He has received a Camille Dreyfus Teacher-Scholar Award, an Alfred P. Sloan Foundation Fellowship, an American Cancer Society Junior Faculty Award, the ETH Ruzicka Award, an American Cyanamid Young Faculty Award, the Merck Young Investigator Award, and the Zeneca Award for Excellence in Chemistry.
Heike Jahn received her Diploma in 1988 and her Ph.D in 1991 from the MartinLuther-University Halle-Wittenberg under the direction of Professor H.-J. Deutscher in the field of liquid crystals. After working for the Beilstein Information System, she conducted postdoctoral studies in P. Wipf group at the University of Pittsburgh on s the total synthesis of Manumycin-type antibiotics and combinatorial synthesis from 1994 to 1995.

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What are organozirconocenes and what are their applications in organic synthesis?

What are organozirconocenes and what are their applications in organic synthesis?

What are some common reactions of organozirconocenes discussed in the paper?

What are some common reactions of organozirconocenes discussed in the paper?

PII: S0040-4020(96)00754-5

TETRAHEDRON REPORT NUMBER 406

Cationic Zirconocene Complexes Concluding Remarks

P. WIPF and H. JAI-IN

\z(+C chemoselectivity, regioselectivity,

Figure 1. Summary of typical preparation and reactions of organozirconocenes.

P. WIPF and H. JAHN

L.iiIH,, THF CPnZrfJ2 b

P. WIPF and H. JAHN

P. WIPF and H. JAHN

* ;.! ..__......_ .._1.. _. .._ ,..

CH2 A.. :I CH2

i................. reaction coordinate +

Group Compatibility of Hydrozirconation

0 TIPS TIPS 1. Cp2ZrHCI, THF, r.t. 2. H20; 63%

P. WPF and H. JAI-IN

2. Me&u(CN)Li2, THF, -78 C

13 1. -78 86%, C, ? 0 2. n-Bu4NF, 93% 1 CHO

WTMS 15 m THF, r.t.; 80% cp2zrwCTMS 16

CO, benzene, r.t., 90 min; 80%

Cp;jrHCI, THF, 40 C 20 min 20

CuBr*SMez (catJ -hOH

2. Cp2ZrHCI, 40 C, -9 1. C(l). PhCOCl THF

P. WIPF and H. JAHN

THF, 60 C 85% (29+30)/N s 12 : 1 &* iPh + +Ph +$-

CHBCH2COCl CuBr . SMe2

cP2z(-_r K~oTBDp_?__________ cp2z+ cp2RoTBDpft Cp>r&OTBDPS

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38% D 1. Cp$HCl (2 equiv), dioxane, 40 20 h; k, * 2. D20

1. n-BuLi, THF, -78 C

* 2. Cp2ZrC12,-78+20 C Cp2(C )Zr--&o 74%

Cp&Clp, CH~(0kle)~, -5 C /\ ) CpdCI)Zr--0 34% 72

1. Cp~ri-lCI, dioxane, r *.;;;0C.2 h: -a ) &+

I 2. dioxane,45 20 h; 1.2 eq. Cp*CpZrnCl, D20 C,

P. WIPF and H. JAHN

Cp2ZrHCl (0.93 equivj benzene, 2 h, r.t. w cp2(c,)zr2 55 + dr(c,)cp2 b:::::;t. 89 + *

Cp2ZrHCl (0.93 equiv) benzene, 2 h, r.t. + cp2(c,)Zr)$+ 84 &c,)cp2 bLE:9t.64 + 65 >98 : 2

BFBOEtB (or CF$OOH), 10 min; 92% M n-C1oH21 114, E:Z

-35 1 h; 97% Br, CHPCIP, C,

Br ~COMe 256 TBSO~ZrCp&I 255 Pdp(dba)pCHCla, THF, ZnClp, 12 h, r.t. TBSO