Table Of ContentTopics Organomet Chem (2004) 8:1–25
DOI 10.1007/b13144
© Springer-Verlag Berlin Heidelberg 2004
Hydrozirconation and Its Applications
Peter Wipf( ) · Christopher Kendall
University ofPittsburgh,Department ofChemistry,Pittsburgh PA 15260,USA
[email protected]
1 Introduction and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Preparation ofCpZrHCl and Related Reagents . . . . . . . . . . . . . . . . 3
2
3 Functional Group Compatibility ofHydrozirconation . . . . . . . . . . . . 4
4 Alternative Methods for Generating Organozirconocenes . . . . . . . . . . 5
5 Hydrozirconation Followed by Halogenation . . . . . . . . . . . . . . . . . 5
6 Hydrogenation and Reduction . . . . . . . . . . . . . . . . . . . . . . . . . 7
7 Hydrozirconation Followed by C–C Bond Formation . . . . . . . . . . . . 9
7.1 Silver-Catalyzed Ligand Abstraction . . . . . . . . . . . . . . . . . . . . . . 10
7.2 Transmetalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.2.1 Zirconium Æ Palladium and Zirconium Æ Nickel . . . . . . . . . . . . . . 12
7.2.2 Zirconium Æ Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
7.2.3 Zirconium Æ Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
8 Miscellaneous Reactions ofOrganozirconocenes . . . . . . . . . . . . . . . 18
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Abstract Next to hydroboration and hydrostannylation,hydrozirconation is among the few
general methods available for the stoichiometric conversion ofreadily available alkenes and
alkynes into stable,strongly nucleophilic synthetic intermediates.More significantly,the
sterically shielded carbon–zirconium bond oforganozirconocenes can participate in trans-
metalation schemes that link zirconium chemistry with many other elements in the periodic
table,in particular with the highly functional group tolerant late transition metals.The in
situ conversion ofalkenes and alkynes into chain-extended synthetic building blocks by se-
quential hydrozirconation and further metal-catalyzed or metal-mediated condensations
with electrophiles is thus characterized by experimental convenience and considerable
strategic flexibility. In addition, the number of synthetic protocols that use organozir-
conocenes directly for intra- or intermolecular carbon–carbon and carbon–heteroatom
bond formations is steadily increasing.As an extension ofour comprehensive treatment of
the topic in 1996,this review concentrates on the developments in hydrozirconation and its
applications in synthesis from 1996 through mid-2002.
Keywords Zirconocenes · Transmetalation · Cationic complexes · Alkenes · Alkynes
2 P.Wipf· C.Kendall
1
Introduction and Scope
The hydrozirconation of alkenes and alkynes with Cp ZrHCl,a.k.a.Schwartz
2
reagent [1],is one of two common methods for forming organozirconocenes
(Scheme1).According to the Pauling electronegativity scale,the ionic charac-
ter ofthe C–Zr bond (26%) is almost equivalent to the C–Mg bond (27%),but
organozirconocene complexes are intrinsically considerably weaker nucle-
ophiles than Grignard reagents due to steric shielding at the metal atom by the
two cyclopentadienyl ligands.While the preparations ofGrignard and organo-
lithium reagents mainly originate from the corresponding halides,the oppor-
tunity to use the more readily available, synthetically versatile alkenes and
alkynes as starting materials is a great asset ofzirconocene chemistry.Subse-
quent activation of the C–Zr bond by addition of catalytic or stoichiometric
metal salts benefits from the ease offormation ofbridged bimetallic complexes
of early transition metals such as zirconium and the broad functional group
compatibility and extraordinary synthetic utility oflate transition metals.Fig-
ure1 illustrates the ability ofzirconocene to participate in mixed-metallic com-
plex formation,often assisted by bridging chloride or oxygen atoms [2,3].
Scheme1 Formation ofalkyl- and alkenylzirconium reagents by the hydrozirconation of
alkenes and alkynes
Organozirconocene complexes can also be activated by ligand substitution
or abstraction.In addition,small electrophiles such as halogens,dioxygen,pro-
tons,and isonitriles can be directly added to the Zr–C bond.This review will
present a survey ofmany recent examples ofhydrozirconation in organic syn-
thesis,mostly focusing on material published since our last comprehensive
review [4] on this subject [5–7].The majority ofexamples for synthetic appli-
cations utilize alkenylzirconocenes, since the reaction of Cp ZrHCl with
2
alkynes is fast,regioselective,and quite functional group tolerant.Alkenes are
not as reactive as alkynes,and furthermore internal alkenes are rapidly iso-
merized into terminal alkylzirconocenes [8–10],thus limiting the usefulness
of this transformation.Some recent reactions of alkylzirconocenes are also
covered.
Cp ZrHCl was first prepared in 1970 [11] and used to hydrozirconate alkenes
2
[12] and alkynes [13] by Wailes and coworkers. Subseqently, Schwartz and
coworkers treated the resulting alkylzirconocene [14] and alkenylzirconocene
Hydrozirconation and Its Applications 3
Fig.1 Crystal structures of two zirconocene complexes with heteroatoms and carbon
bridges to alanes
[15] products with inorganic electrophiles and used transmetalation from Zr
to Al in order to increase reactivity towards organic electrophiles [16].Due to
these pioneering synthetic applications,Cp ZrHCl is commonly referred to as
2
“Schwartz reagent”.
2
Preparation of Cp ZrHCl and Related Reagents
2
The commercially available reagent is typically prepared by reduction of
Cp ZrCl with an aluminum hydride.Wailes and Weigold originally used one
2 2
equivalent ofLiAl(Ot-Bu) H as the reducing agent in THF [11].The insoluble
3
zirconocene hydrochloride was isolated in 90% yield. The more practical
LiAlH was at first not recommended as a reducing agent since it could lead
4
to formation of significant quantities of Cp ZrH , a much more insoluble
2 2
(and thus less reactive) complex than Cp ZrHCl. For a solubilized version
2
of zirconocene dihydride, see [17]. Schwartz and coworkers used
Na[AlH (OCH CH OCH ) ] (Red-Al) as the reducing agent in THF;however,
2 2 2 3 2
this protocol contaminated the Cp ZrHCl with ca.30% NaCl [14].Buchwald and
2
coworkers discovered that the reaction,first reported by Wailes and Weigold
[11],of Cp ZrH with CH Cl (forming Cp ZrHCl and CH Cl) was very rapid
2 2 2 2 2 3
at room temperature,whereas the analogous reaction between Cp ZrHCl and
2
CH Cl was slower [18].Thus,by adding a CH Cl wash to the workup of the
2 2 2 2
LiAlH reduction of Cp ZrCl ,the problem of over-reducing to Cp ZrH was
4 2 2 2 2
minimized.An important practical aspect ofthis process is the use ofa filtered
Et O solution ofLiAlH ,which is slowly added to the solution ofzirconocene.
2 4
The reaction ofCp ZrCl with one equivalent oft-BuLi in toluene can also be
2 2
used to prepare Cp ZrHCl [19].Since the reagent does not have a very long
2
shelf-life,methods for its in situ generation have been developed,including
the treatment of Cp ZrCl with t-BuMgCl in benzene/Et O which forms
2 2 2
i-BuZrCp Cl,a Cp ZrHCl equivalent [20,21],and reduction of Cp ZrCl with
2 2 2 2
LiEt BH in THF which forms the Schwartz reagent, Et B and LiCl, two by-
3 3
4 P.Wipf· C.Kendall
products that do not interfere with hydrozirconation [22] but can be a problem
for further transmetalation.Bu ZrCl ,prepared by treatment ofZrCl with two
2 2 4
equivalents of BuLi,can also serve as a hydrozirconating agent in hexane or
toluene,but not in THF [23].Many cyclopentadiene ring-substituted deriva-
tives ofCp ZrHCl have been prepared and tested in hydrozirconation schemes
2
[24,25].
Cp ZrHCl is a moderately air-,moisture-,and light-sensitive amorphous col-
2
orless solid that can be handled and weighed on a balance without special pre-
cautions.In our hands,storage in a polyethylene bottle under N extends the
2
shelflife ofthe reagent to at least 20days without significant decrease in reac-
tivity.The hydrozirconation ofterminal alkynes and alkenes proceeds rapidly
(5–15min) at room temperature in CH Cl or THF,and much more slowly in
2 2
benzene or toluene [8].The reaction is also very easily monitored visually since
the colorless Cp ZrHCl is insoluble in most common organic solvents whereas
2
the colored organozirconocenes are highly soluble.Ifthe reaction is performed
under kinetic control with a slight excess ofalkyne,the regioselectivity ofhy-
drozirconation is actually quite low.However,ifexcess Schwartz reagent is em-
ployed,thermodynamic equilibration via double hydrozirconation-b-elimina-
tion leads to the highly regioselective formation ofthe terminal,sterically less
hindered vinyl organometallic.
Procedure:Schwartz Reagent [26]
To a dry,1 L Schlenk flask equipped with a magnetic stirring bar Cp ZrCl
2 2
(100g,0.342mol) is added under argon,followed by dry THF (650mL).Dis-
solution ofthe solid is accomplished by gentle heating.To the solution is added
dropwise, over a 45 min period, a filtered, clear solution of LiAlH (3.6 g,
4
94mmol) in Et O (100mL).The resulting suspension is stirred at room tem-
2
perature for 90 min,then Schlenk-filtered under argon using a “D”frit.The
white solid is washed with THF (4¥75mL),CH Cl (2¥100mL with stirring and
2 2
a contact time of no greater than 10 min per wash), and then with Et O
2
(4¥50mL),and dried in the dark under reduced pressure to yield 66g (75%)
ofCp ZrHCl as a white powder.
2
3
Functional Group Compatibility of Hydrozirconation
True to its nature as an early transition metal,zirconium displays considerable
Lewis acidity and binds to hard Lewis bases such as carbonyl groups,thus fa-
cilitating hydride transfer and reduction.In general,amides,ketones,aldehy-
des,and nitriles are not compatible with alkene and alkyne hydrozirconation
conditions.Alkynes are selectively hydrozirconated in the presence of esters,
but only sterically hindered triisopropylsilylesters survive the slower hy-
drozirconation of alkenes.Acylsilanes are also readily tolerated in hydrozir-
conation,and carbamates,acetals,epoxides,silylethers,alkyl- and phenylethers,
Hydrozirconation and Its Applications 5
Scheme2 Hydrozirconation ofan electrophilic and easily deprotonated substrate
halides, and sulfides are recovered unchanged after exposure to Schwartz
reagent.Alcohols and sulfonamides undergo an acid-base reaction with one
equivalent ofzirconocene hydrochloride but otherwise do not significantly in-
terfere with alkene and alkyne hydrozirconation.An example for the consid-
erable functional group compatibility and low basicity ofhydrozirconation is
shown in Scheme2.
4
Alternative Methods for Generating Organozirconocenes
Other widely used reagents for the formation oforganozirconium complexes
are Cp ZrEt and Cp ZrBu . These “Cp Zr(II)” equivalents can react with
2 2 2 2 2
alkenes and alkynes to form zirconacyclopentanes,-cyclopentenes,and -cy-
clopentadienes,which react very similarly to the acyclic organozirconocenes
formed by hydrozirconation.For a recent review,see [27] and references cited
therein.Cp ZrR reagents can also be inserted into vinyl halides [28],2,2-di-
2 2
fluorovinyltosylate [29],methoxy enol ethers [30],enolsilanes [31],and vinyl
sulfides,sulfoxides,and sulfones [32] to form internal and terminal as well as
cyclic alkenylzirconocenes.
5
Hydrozirconation Followed by Halogenation
One ofthe most widely used applications in organozirconium chemistry is the
preparation of(E)-vinyl halides via hydrozirconation and halogenation.Recent
applications of this method in natural product synthesis include (+)-am-
phidinolide J [33],tedonolide [34,35],and the CP-molecules (CP-263,114 and
CP-225,917) [36].For a fragment needed for (+)-acutiphycin,hydrozirconation
ofalkyne5followed by bromination afforded bromides6and7as a 94:6 mix-
ture ofregioisomers [37] (Scheme3).Vinyl bromide6was then converted in 3
steps into Grignard reagent8,and added to aldehyde9,installing all carbons
necessary for completion ofthe total synthesis.
6 P.Wipf· C.Kendall
Scheme3 Synthesis ofthe (+)-acutiphycin precursor (E)-vinyl bromide6by the hydrozir-
conation and bromination ofalkyne5
Procedure:Hydrozirconation,bromination ofinternal alkynes [37]
A solution of alkyne5(1.51g,5.50mmol) in benzene (36.7mL) was treated
with Cp ZrHCl (4.30g,16.5mmol) in one portion,warmed to 40°C for 1h,
2
and cooled to room temperature.NBS (1.96g,11.0mmol) was then added,and
the reaction mixture was stirred for 15 min and quenched with saturated
NaHCO .The biphasic mixture was stirred vigorously for 5min and extracted
3
with hexane/ethyl acetate (9:1).The combined organic extracts were wash-
ed with brine, dried (MgSO ), filtered through a pad of SiO , and washed
4 2
with hexane/ethyl acetate (4:1).Concentration and chromatography on SiO
2
(hexanes/ethyl acetate,95:5) afforded a 16.4:1 mixture of 6 to 7 as a color-
less oil.
(Z)-Vinyl halides can also be prepared from terminal alkynes via the hy-
drozirconation ofstannylacetylenes [38].In their total synthesis ofmyxalamide
A (Scheme4),Mapp and Heathcock reduced the triple bond ofstannylacetyl-
ene12with Cp ZrHCl [39].Due to the higher reactivity ofthe zirconocene sub-
2
stituent over the stannyl group,aqueous workup and TBDMS-deprotection af-
forded (Z)-vinylstannane14.Replacement ofthe tributyltin group with iodine
led to iodotriene15,which was isolated as a 15:1 ratio ofZ/Eisomers at the ter-
minal alkene.The strategy ofusing both stoichiometric zirconium and tin was
Hydrozirconation and Its Applications 7
Scheme4 Synthesis ofa (Z)-vinyl iodide intermediate in the total synthesis ofmyxalamide A
preferred because Wittig olefination ofaldehyde17afforded15with aZ/Era-
tio of5:1 (which could not be improved by purification).
Panek and coworkers used a similar difference in the reactivity of gem-
bimetallic alkenes for the stereoselective synthesis oftrisubstituted alkenes [40]
(Scheme 5). Silylacetylenes react with Schwartz reagent much like stanny-
lacetylenes,and again the zirconium moiety is selectively transformed first
when quenched with inorganic electrophiles [41]. Thus, iodosilane 20 was
formed after treatment of zirconocene19with I .Negishi coupling of20and
2
EtZnCl was very high yielding and was followed by iododesilylation to install
the second vinyl iodide. Stille coupling with vinylstannane 23 afforded the
trisubstituted alkene24,a potential synthetic intermediate for the C1–C12 frag-
ment ofcallystatin A.
6
Hydrogenation and Reduction
Regiospecific deuterium labeling can be achieved by quenching organozir-
conocenes with D O or by using Cp ZrDCl for hydrozirconation.A nice demon-
2 2
stration of this concept is the synthesis of three deuterium-substituted ana-
logues of dimethyl hept-1,6-dienyl-4,4-dicarboxylate [42] (Scheme 6).These
compounds were used for the study ofthe mechanism ofthe transition metal-
8 P.Wipf· C.Kendall
Scheme5 Rapid stereoselective synthesis oftrisustituted alkenes from silylacetylenes
Scheme6 Regiospecific 2H-labelling using hydrozirconation
Hydrozirconation and Its Applications 9
catalyzed 1,6-diene cycloisomerization.Diyne 25 was treated with sufficient
Cp ZrHCl to reduce both triple bonds,and quenched with D O to afford 1,7-
2 2
(E,E)-bisdeuterodiene26.A second regioisomer,2,6-2H -diene27,was synthe-
2
sized using Cp ZrDCl for the hydrozirconation and quenching with H O.The
2 2
third regioisomer in this series,1,7-(Z,Z)-2H -diene29,was prepared by a for-
2
mal hydrogenation (hydrozirconation and H O quench) ofbisdeuterodiyne28.
2
A tritiated version ofthe Schwartz reagent has also been used for regioselec-
tively labeling olefins with tritium [43].
In some cases,hydrozirconation and quenching with water is more selective
and more efficient than catalytic hydrogenation protocols.For example,this
strategy has been used for the hydrogenation ofbuckminsterfullerene C en
60
route to organofullerenes [44].
Cp ZrHCl has been used as a reducing agent by Ganem and coworkers for
2
the deoxygenation ofb-ketoesters toa,b-unsaturated esters [45],and for the re-
duction ofamides to give imines [46].Similarly,Schwartz reagent reducesN,N-
disubstituted amides to aldehydes [47].This reagent has also been used by Ma-
joral and coworkers for reducing phosphine oxides into phosphines [48] and
dicyanophosphines into cyanophosphanes [49].Trauner and Danishefsky used
the Ganem reduction protocol in their synthesis ofthe spiroquinolizidine sub-
unit ofhalichlorine [50] (Scheme7).
Scheme7 Deoxygenation ofthe lithium enolate of30using CpZrHCl in the synthesis ofa
2
halichlorine fragment
7
Hydrozirconation Followed by C–C Bond Formation
With the exception of direct insertion into CO and isocyanides [51], car-
bon–carbon bond formation from organozirconocenes requires the use of
metal salts for transmetalation or (chloride) ligand abstraction.The former
protocol has been successfully applied for many carbonyl additions and cross-
couplings,whereas the latter strategy is particularly useful for conversions with
electrophiles such as epoxides and aldehydes.
10 P.Wipf· C.Kendall
7.1
Silver-Catalyzed Ligand Abstraction
One way to increase alkenylzirconocene reactivity towards organic elec-
trophiles is to reduce the steric congestion about zirconium by ligand (chloride)
abstraction.Maeta et al.reported that cationic zirconocenes prepared in situ re-
acted rapidly with aldehydes to generate 1,2-addition products [52].For ex-
ample,when the product ofthe hydrozirconation of1-hexyne was treated with
hydrocinnamaldehyde in the presence of5mol% ofAgClO ,alcohol33was iso-
4
lated in 90% yield after a 10min reaction time (Scheme8).In the absence ofthe
Ag(I) salt,only 17% conversion was observed after 2h.AgAsF can also catalyze
6
this transformation [53]; however,other Ag(I) salts such as AgOTf,AgSbF ,
6
AgPF ,and AgBF were less effective.Wipf and Xu have shown that epoxides
6 4
are rapidly activated by the cationic zirconocene obtained from treatment of
the hydrozirconation product with catalytic amounts of AgClO [54]. After
4
the cationic zirconocene-promoted epoxide rearrangement/[1,2]-H shift,
carbon–ligand transfer to the resulting aldehyde provides access to secondary
alcohols.
Scheme8 Alkenylzirconocene addition to aldehydes catalyzed by AgClO
4
Procedure:AgClO -catalyzed alkenylzirconocene addition to aldehydes [52].
4
A mixture of Cp ZrHCl (401 mg, 1.55 mmol) and 1-hexyne (132 mg,
2
1.61mmol) in CH Cl (4.0mL) was stirred at room temperature for 10min.To
2 2
the resulting solution was added 3-phenylpropanal (174 mg,1.30 mmol) in
CH Cl (4.0mL) followed by AgClO (13mg,63 mmol,5mol%).The reaction
2 2 4
mixture gradually turned dark brown.After stirring for 10 min,the mixture
was poured into saturated NaHCO .Extractive workup (EtOAc) followed by pu-
3
rification by preparative TLC (hexane/EtOAc,80:20) gave allylic alcohol33as
a colorless oil (255mg,90%).
When epoxy ester35was subjected to these reaction conditions,acetal36
was formed as a single diastereomer [55].Hydrolysis ofthe acetal afforded an
enone,thus the net transformation represented a new conversion of an ester
into ana,b-unsaturated ketone.Wipfand Methot used this reaction in a syn-
thesis of pyridazinones [56] (Scheme 9).The optimized conditions included
addition of 5 mol% of triphenyl phosphite to the reaction mixture and ad-
sorbing AgClO onto Celite to improve the stability and simplify the handling
4
ofthe reagent.Conjugate addition to36followed by hydrolysis formed enone
37.A second cuprate addition,followed by cyclization using hydrazine and sub-
sequent oxidation afforded pyridazinone38in 86% yield from36.
