Organometallics in Organic Synthesis

1. So who cares (i.e., why?)

-Pattern of reactivity of organic compounds is imposed on molecule by existing functional groups OMe O δ+ δ− δ− δ+ δ− OMe δ− - By default, this limits what you can do with the compound

- Coordination of a metal fragment can change this completely i.e., can render – an electrophilic species nucleophilic - a nucleophilic species electrophilic - can make a normally unstable molecule stable - can make a stable molecule reactive - can make impossible reactions possible 1 The (Very) Basics of Organometallics

-The 18 Electron Rule

Most (middle) transition metal complexes prefer having 18 valence electrons (2s + 6p + 10d)

For transition metal complexes in the 0 oxidation state

4e 5e 6e 7e 8e 9e 10e

Ti V Cr Mn Fe Co Ni

Zr Nb Mo Rc Ru Rh Pd

Hf Ta W Re Os Ir Pt 2 -The 18 e rule is followed most closely in complexes of middle transition metals (Cr to Co)

-As for early transition metal complexes, it’s usually too difficult to get enough ligands around the metal to get it to 18 e (i.e., Ti)

Cl

Ti (16 e) (Cp2TiCl2) Cl

- As for late transition metal complexes (Ni, Pd, Pt), particularly

II the square planar M L4 complexes - tend to be very stable as 16 e- complexes

- energy gap to 9th orbital is quite big; molecule is quite willing not to fill that orbital 3 To count to 18 (or 16), need e-’s from ligands - I’ll adopt a ‘radical approach’ – not only valid one

A) Inorganic Ligands

1e- -X -H -R

- 2e R3P: (RO)3P: R-C≡N: R-N≡C:

R3N: R2S: R2O:

3e- NO (usually) nitrosyl complexes

4 Organic Ligands - Part 1

η1 ( 1 e-) -R (alkyls) -Ph (aryls) M (σ -allyls)

C C η2 ( 2 e-) M (alkenes) M (alkynes) C C R N - + R MCO MC M η1 (2e-) MCO N R R (carbonyl ligands) (carbenes, alkylidenes)

η3 (3e-) M (π -allyls)

1 - (carbynes) η (3e ) MCR 5 Organic Ligands, Cont'd.

(trimethylenemethanes) 4 - M = M η (4e ) (dienes) (TMM) M

η5 (5e-) (dienyls) (cyclopentadienyls) M M

η6 (6e-) (arenes, trienes) M

η7 (7e-) (trienyls)

M (cyclotetraenes) - rarely, usually η4 η8 (8e-) 6 So.....

The number of electrons on the free metal

+ sum of the η number of the hydrocarbon ligands + sum of the electrons donated by other ligands

+ any negative charge on the complex - positive charge on the complex

Should = 18 normally

Many exceptions with early or late transition metals ; works best with middle transition metals

+ Fe Cr Mo OC OC C N C O O O

6 (Cr) + 6 (Ph) + (3x2) = 18 e- 6 (Mo) + 5 (Cp) + 2 + 3 +3 -1 = 18 e- 8 (Fe) + (2x5) = 18e-

Cl Ph3P - - Pd 10 (Pd) + (2x2) + (2x1) = 16 e 8 + 4 (TMM) + (3x2) = 18 e Fe OC Ph3P Cl C C O O 7 Bonding of Hydrocarbon Ligands

- In its simplist form, bonding of the π- system to a transition metal fragment is based on the

Dewar-Chatt-Duncanson Model

C Consider M - There are two contributions to bonding C

C 1) Ligand to Metal Donation M Note: this is not a π- bond, but rather a σ- bond C

2) Metal to Ligand Back Donation

C Note: this is a π- bond M C

Dewar, M. J. S. Bull. Chim. Soc. Fr. 1951, C71. Chatt, J.; Duncanson, L. A. J. Chem. Soc. 1953, 2939.

For higher level descriptions:

8 η3, η4, η5 - see Yamamoto, A., p. 58-72 η6 - see Collman, Hegedus, Norton, Finke p. 43-47 Consequences of Bonding of Hydrocarbon Ligands

1) - In the alkene, the C=C bond is made weaker by complexation

2) - The ligand may be made more or less electron rich by complexation -depends on case

3) - The organic fragment often loses its only plane of symmetry -for example

and are the same compound

But......

These are not the same compound - the plane of symmetry is destroyed

Fe Fe No non-superimposable mirror images OC CO Enantiomers C C C O O C O O

mirror image 9 Other examples

+ + OMe MeO Ph Ph

Cr Cr OC CO Pd Pd C C Ph2P PPh Ph P PPh C O O C 2 2 2 O O

Same situation: Each pair is enantiomeric

10 Basic Organometallic Reactions

There are several additional fundamental types of reactions in organometallic chemistry

The more complex reactions are normally some combination of these fundamental ones

1) Lewis Acid Dissociation

- many transition metal compounds, especially hydrides, can lose as Lewis acid (i.e., deprotonate)

H+ + -Co(CO) H Co(CO)4 4

change in number of metal valence e-'s 0

change in formal metal oxidation state -2

change in coordination number at the metal -1

This may be a surprise, but many transition metal hydrides are quite acidic -notice that making the metal more electron rich decreases acidity

HCo(CO)4 (pKa = 8.3, CH3CN) H2Fe(CO)4 (11.4) HCo(CO)3PPh3 (15.4)

Winkler, J. R. et al (Gray, H. B.) J. Am. Chem Soc. 1986, 108, 2263.

SH OH O (pK = 10.3, a H O (32.0) (24.4) 11 (18.0) 2 H C CH CH3S(O)CH3) 3 3 2) Lewis Base Dissociation

Very, very, very...... common process

18e 16e Fe(CO)5 Fe(CO)4 + CO 16e 14e + Pd(PPh3)4 Pd(PPh3)3 PPh3

change in number of metal valence e-'s -2

change in formal metal oxidation state 0

change in coordination number at the metal -1

-Reverse reaction: Lewis base Association

Obvious application are in ligand substitution processes,

which may be dissociative ('SN1 like')

slow Ni(CO) L 4 Ni(CO)3 + CO LNi(CO)3 fast

st v = k [ Ni(CO)4] 1 order 12 Most common for 18 e- systems - Alternatively, this can be associative, i.e., "SN2 like" -more common fo 16 e-, d8 square planar complexes (i.e., NiII, PdII, PtII RhI, IrI)

Y Lc X Lc Pt + Y Pt X Lt Lc Lc X Lt Pt Lt Lc Y Lc square pyramidal trig. bipy rate v = 2nd order

Lc Y Lc Y X + Pt Lt Lc Lt Lc Pt

square pyramidal trig. bipy X

13 3) Oxidative Addition

- represented by

n+2 A n + LnM A-B Ln M B change in number of metal valence e-'s +2 (14 - 16 e)

change in formal metal oxidation state -+2 (0 - +2)

change in coordination number at the metal +2 for more details, see: R Yamamoto pp. 222-239 R Collman & Hegedus pp. 279-321

-Overall reaction is cleavage of the A-B bond with bonding to the metal O - Most common A-B is R C-X X = halogen or pseudohalogen 3 OSCF3 triflate O

-Classic 'organic' example is Grignard reagent formation

II Br MgBr o + Mg 14 - Most common example in this course will be of the following type:

0 Br II Br Pd(PPh ) 2 PPh Pd(PPh ) + 3 4 3 + 3 2 Pd Ph3P PPh3 - the 2nd step is the oxidative addition

Therefore, system needs: a) 2 available oxidation states i.e., Pdo/PdII , Feo/FeII, IrI/IrIII

b) open coordination site

- Reverse reaction: Reductive Elimination Mechanism

- Most is known about late transition metals (such as Ir, Ni groups)

A) If the R of R-X is alkyl (especially 1o or 2o), the reaction is believed to (usually) occur

via an SN2 substitution +

CH3 CH3 Cl fast .. PPh3 rds PPh Ir Cl 3 Ir Cl PPh Ir Ph P 3 Ph P CO 3 CO CH3-I Ph P 3 3 CO I - Inversion at alkyl carbon has been observed

- Kinetics are overall 2nd order v = k [IrI] [CH I] 3 15 B) Vinyl (and perhaps aryl) halides go via π - complex formation, with ultimate direct insertion

slow Ph P PPh 3 3 Ph P Pt fast 3 X "Pt(PPh3)2" X X Pt PPh3

- Goes with retention of configuration of C=C configuration

- Also believed to be mechanism for addition of H2

B') Aryl halides go via direct insertion into C-X bond (clearly related to B)

i.e., P P M Could result in retention of Pd C configuration in some cases X X

C) - Now defrocked - Nucleophilic Aromatic Substiution - was an old proposal for aryl cases, to rationalized that cases with electron withdrawing groups "always" go faster

X X rds PdL2X + "L2Pd" EWG - PdL2 EWG 16 EWG + C)' - much more likely and often detected in calculations is initial formation of an η2-benzene complex

R R N R N Cl N Pd N Cl Pd N R Cl R Pd N R R Pd N + N R N Cl N R R

transition state

Green, J. C. J. Organomet. Chem. 2005, 690, 6054.

D) - Electron transfer, radical mechanisms do exist (Ni, Mg)

rds + -. i.e. Ln + RX [ LnM RX ] X [ L M+ RX-.] n LnM R

17 H Rh + Rh Me P Me P 3 3 H

Bi, S. Chem. Phys. Lett. 2006, 431, 385.

Aside: One electron oxidative additions also exist I I o + 2 LnM + A-B LnM-A LnM-B

Conventional organic example - Lithium-Halogen exchange

Br Li + 2 Li LiBr +

Many new opinions on these matters:

R Hartwig, J. F. Synlett 2006, 1283. R Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed. Engl. 2004, 43, 4704. R Jutand, A. Eur. J. Inorg. Chem. 2003, 2017. Alcazar-Roman, L. M.; Luis, M.; Hartwig, J.F.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A.

J. Am. Chem. Soc. 2000, 122, 4618. (chelate PR3)

Hartwig, J. F.; Paul, P. J. Am. Chem. Soc. 1995, 117, 5373 (monodentate PR3) R Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. Lersh,M.; Tilset, M. J. Am. Chem. Soc. 2005, 127, 2471 (C-H activation). 18 4) Reductive Elimination - reverse of oxidative addition

II A o + LnM LnM A-B B

change in number of metal valence e-'s -2 (16e - 14e)

change in formal metal oxidation state -2 (+2 - 0)

change in coordination number at the metal -2

Ph3P Pt Ph3P Pt Ph P + "Pt(PPh3)2" 3 Ph3P

transition state -not an intermediate 19 In 'normal' cases, the reaction goes by a concerted mechanism -and, importantly for organic chemists......

CH Ph 3 Ph retention of configuration Pd PPh at carbon H 3 H CH3

D PPh3 D

Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981

Note: Whether the precursor is square planar or trigonal bipyramidal, it's the cis groups which reductively eliminate

- Again, need two accessible oxidation states

- Other notes on reductive elimination: - Non 18 e situations must be accessible - Ni group (Ni, Pd, Pt) are the usual synthetic choices

Since metal becomes more electron rich during the reaction, the reaction is sometimes accelerated by addition of a ligand which is electron withdrawing

R R R N R Ni O O O N R R R R More details in general: Yamamoto, pp. 240-5 20 Collman, Hegedus pp 322-33 5) Insertion (Migration) -There is more than one type possible

M A AB M-R is a B R Metal-C or M R Metal-H bond or

M R* M A R* A B B

AB is R'2CCR'2 R'2CO R'2C NR'

:A B is :C O :C NR' :CR'2

Most common :A-B is CO

21 -The reaction is a concerted migration of R*, with retention of configuration at R* and the metal, if they are chiral

H C CH CH 3 L 3 3 L OC CO rds OC C O OC O Mn Mn Mn OC CO OC CO OC CO CO CO CO

Change in # of valence electron at the metal -2 (18 to 16e)

Change in metal oxidation state 0 (+1 to +1)

Change in coordination number -1 (6 to 5)

22 Note: Reverse reaction is deinsertion

Most common A=B in this case are alkenes or alkynes -for example, the intermediate step in hydrogenation

O O insertion H O H Ni O Ni Ph P deinsertion Ph2P PPh 2 PPh2 2

- The reverse reaction in this case (β-elimination) is one of the most common reactions of alkylmetals - main mode of decomposition

-again, if inserting group is alkyl, generally there is retention of configuration at R*

see R Cross, R. J., in "Chemistry of the Metal-Carbon Bond", Hartley and Patai, 1982, V.2

R Yamamoto, p. 246-272 23 6) Oxidative Coupling

Oxidative coupling occurs when two 'π-bound' ligands on the metal react with each other to form (usually) a C-C σ bond

L M L M

One of the best known examples is....

R R

III I empty coordination site ultimately Co Co filled by a ligand R R

-This has become increasingly important with a variety of metals and transformations

Change in number of valence electrons at metal -2 (18 to 16e)

Change in metal oxidation state +2 (+1 to +3)

Change in metal coordination number 0 ('3' to '3') 24 Note: There are several other fundamental mechanisms, but they have a close 'organic' analogy η2-Olefin/Acetylene Complexes a) Preparation

i) -most common method - ligand exchange (with CO, CH3CN, alkenes)

i.e., with Feo it is almost always as follows

CO Et CO2Et hν 2 + CO + Fe(CO)5 Fe(CO)4

CO Et ether solvents 2 CO2Et + Fe(CO)5 + Fe2(CO)9 Fe(CO)4 Weiss et al Helv. Chim. Acta. 1963, 46, 288

Note: The departing ligand doesn't need to be CO - some other examples

60oC Fe+ + + OC + OC Fe OC R OC or R R R 25 -sterically hindered alkene Cutler, M. et al (M. Rosenblum) J. Am. Chem. Soc. 1976, 98, 3495 R Co + 2 R R Co R + C H R 2 4

R -volatile alkenes Jonas, K. et al Angew. Chem. Int. Ed. Engl. 1983, 22, 716.

R R R OPr-i OPr-i OPr-i Ti + Ti Ti OPr-i R OPr-i OPr-i R R R Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343, 759. ii) Synthesis by Displacement of Halide Cl- may be displaced by an alkene, either on its own or with an assisting Lewis acid

(SN1 like reactivity)

Cl Pd + 2- - PdCl4 2 Cl + Cl

PPh + 3 R Ag PPh3 Pt + AgCl(s) + Pt Cl R Schultz, R. G. J. Organomet. Chem. 1966, 8, 435 26 Davies, S. G. et al J. Organomet. Chem. 1986, 188, C41. iii) -by hydride abstraction (also called σ-bond metathesis) - this type is common for the preparation of alkene and alkyne early transition metal complexes

Cp Cp -CH Cp Cp Zr 4(g) Zr CH3 Zr H Cp Cp accessible from the organolithium benzyne complex

iPrO β-elimination iPrO i Ti Ti + Ti(O Pr)4 + 2 BrMg iPrO Lewis base iPrO H H dissociation

iPrO CH iPrO CH 3 3 H reductive elimination Ti Ti + H iPrO iPrO Lewis base association

Buchwald, S.L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047. see also Sato review

iv) - By intramolecular nucleophilic substitution 27 -often for alkyne complexes, with a wider variey of metals than hydride abstraction Br Na Na/Hg PR PR 3 PR 3 PR 3 Ni 3 Ni Ni PR Ni PR Cl 3 PR 3 PR Cl 3 3

R Bennett, M. A. Chem. Ber./Receuil 1997, 130, 1029. R Bennett, M. A. Pure Appl. Chem. 1989, 61, 1695. R Bennett, M. A. Angew. Chem. Int. Ed. Engl. 1989, 28, 1296. b) Getting Rid of Them (Decomplexation) -most organic chemists want the metal removed from the organic 'ligand' at the end of the process

i) Competitive ligand association

R R (CO) Fe + 4 L: (CO)4Fe L +

most common L include another alkene or alkyne, R3P, CO, N + Cp Cp Fe CO I- Cp Cp + Fe CO I 28 ii) oxidation of the metal -very often, if one oxidizes the metal, it no longer bond very well to the organic ligand, and it simply falls off -several very common oxidants include..... +4 FeCl3, Ce ((H4N)2Ce(NO3)6), others + - Me3N -O (trimethylamine N-oxide, N-methylmorpholine N-oxide) Shvo, Y.; Hazum, E. J. Chem. Soc., Chem. Commun. 1974, 336 (for iron diene compelxes)

O O

Me3NO

Fe(CO)4 acetone-CH2Cl2 CO2Et CO2Et Green, J. R.; Carroll, M. K. Tetrahedron Lett. 1991, 32, 1141.

O O Co2(CO)6 Me3NO SiMe 3 SiMe3 R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.

c) Uses of η2- Metal Complexes i) as a protecting group

-recall the intro.....that olefin coordination changes the electron density of 29 that alkene -can make the alkene more or less reactive than the uncomplexes alkene, depending upon the case

Consider...... O O C C CO2H Fe CO2H C Fe(CO)4 O C O -therefore, very slightly overall electron donating (essentially the same)

but + charge on complex almost unboubtedly renders η2-complex less electron rich OC Fe OC -as a result, the alkene is less reactive to attack by E+, and to hydrogenation -but(!), the alkene is more reative to attack by Nu- Note:

+ + OC Fe = Fp OC 30 +

Fp - + + BF4 Fp Fp H2, Pd/C

CF3CO2H

+

Fp - BF4

Fp+ Fp+

Hg(OAc) + Br Br2 + 2 + Fp Fp Fp HgOAc

90% 82% Br OAc

OH OH OH OH OMe OMe Br OMe NaI, acetone Br OMe Br2

CH2Cl2, 90% 80%

+ + Fp Fp

31 -Fp+ alkene complexes are air stable, water stable, and you can store them at 0oC Alkynes -many alkyne complexes known PR3 Ph P PPh3 Cp Cp Ni PR Fp + 3 Pt Mo 3 R R R R R R

But Co complexes are especially robust Co2(CO)6 -2CO R R not real structure, of course Co2(CO)8 + R R R Co OC CO 2 2 2 OC Co Co CO or -bonding is called μ−η (μ -η ) OC CO Co R -these are in general very stable complexes -since p- bonds are used in bonding to metals as well, they are not available to electrophiles, like most other alkynes are

Co2(CO)6 H-N=N-H

Co2(CO)6 Co2(CO)8 Co (CO) 1) BH3 2 6

2) H2O2 32 R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. η2-Complexes as Electrophiles

a) Cationic Complexes (Fp+)

-just as the '+' charge, nominally on Fe, ultimately withdraws electron density from the alkene and reduces its reactivity to electrophiles (E+)....

-so it by contrast increased reactivity of alkenes to nucleophiles (Nu-)

The stoichiometric chemistry is dominated by chemistry of + + OC Fe = Fp OC Thus, Cp Nu: Cp + Fe Fe OC or OC Nu OC Nu- OC -list of Nu- 's hat do this is pretty large OLi - OSiMe3 Carbon based R' - R2CuLi or R' + F EtO2C CO2Et R R in some cases Cp Cp enamines OC Fe OC Fe R2N OC OC + 33 R2N O

Heteroatom based RnNH3-n ; ROH (+Na2CO3); RSH (+Na2CO3); R3P (amines) (alcohols) (thiols) (phosphines)

Stereochemistry of Addition

- -The addition of Nu: or Nu is stereospecifically trans to the metal. So.....

H + H Ph NH + Bn [Fe] Fe 2 OC CH3 NH2 H Me OC Nu: OC Fe H OC H H Me CH3 NH Bn + 2

+ H [Fe] Fe H + Bn OC Ph NH2 Me H NH OC Nu: Fe 2 OC H Me H OC H NH Bn + 2 Regiochemistry If you draw various resonance forms of the Fp+-alkene cation complex, the nucleophile ends up attacking the carbon atom where the 'traditional' organic 34 cation would be most highly stabilized (i.e., 'SN1 like') reactivity + + Fp Fe Fp CH3 OC CH3 OC CH + 2 more contributing resonance form

Li(CH(CO Et) 2 2 Li(CH(CO2Et)2

CH Fp 3 EtO2C CO2Et major EtO2C minor Fp CH3 CO2Et

Note: Unfortunately, with simple alkyl substutuents (like above), the regioselectivity is pretty poor. However, with strong cation stabilizing or detsabilizing (electron withdrawing) groups, the outcome is much more decisive

+ EtO2C CO2Et Fp + LiCH(CO2Et)2 Ph Fp Ph Fp Ph

δ+ β Fp + Fe(CO)2Cp α + O 35 OLi O O So what do you do with the products? -there are very few natural products with covalent Fe-C bonds in them, so it's generally desired to turn these into something 'all organic'

1) -the alkyl-Fp compounds may be transformed into several functional groups, i.e....

I 2 Br2 Fp R RI Fp R RBr CS2 -normally, this occurs with inversion of configuration at the carbon being attacked.

But......

HCl or Fp R RH with retention of configuration CF CO H 3 2 at the carbon attacked! HgCl 2 } Fp R RHgCl if a good Nu- is present (I-, Br-) R-Nu Why this dichotomy? +

SN2 attack on R + E+ Fe Fe OC OC OC R OC (Lewis acid, E - R if no strong Nu present or electrophile) R-E reductive elimination of ER 36 (retention of configuration) 2) Oxidation

In the presence of an oxidant, migratory insertion of CO occurs before the metal is lost. The 17 e- species does this very rapidly IV III II -common oxidants are Ce , Fe , Cu , O2

This is most often done in methanol solvent, so that the final product is a methyl ester. + Cp O D [O] D Cp D D O L Cp Fe Fe +. III t-Bu CO t-Bu t-Bu Fe t-Bu OMe CO MeOH CO D CO D CO D L D

17e- 17e- notice the retention of configuration

This includes Br2 and Cl2 as oxidants

O O Br Cl Fp-R 2 R Fp-R 2 R MeOH OMe Cl

notice difference when solvent is CS2

3) Elimination

If the is a H atom b- to the iron, which can assume an antiperiplanar conformation, - + 37 it can be abstracted as H , usually by Ph3C R + Ph C+ Fp Fp 3 H H R

Rules for abstraction: -if there is a choice between forming a terminal alkene and an internal one, one normally gets the terminal alkene - probably a steric accessibility argument

+ Fp + Fp + + Fp Ph3C BF4 CH3 H H CH2Cl2

-if internal alkenes must be made, one gets mostly the (Z)- isomer -no one really knows why....perhaps a greater stability of the complex

+ + Fp Ph3C BF4 major Fp+

References: R Pearson, A. J. 'Iron Compounds in Organic Synthesis', 1994, Ch.2 R Rosenblum, M. J. Organomet. Chem. 1986, 300, 191. R Rosenblum, M. Pure Appl. Chem. 1984, 56, 129. R Rosenblum, M. Acc. Chem. Res. 1974, 7, 122. R Green, J.R.; Donaldson, W. A. in 'Encyclopedia of Inorganic Chemistry' 1994, V. 2, p.1735. Enantiomerically pure versions 38 Turnbull, M. M.; Foxman, B.M.; Rosenblum, M. Organometallics 1988, 7, 200. Begum, M. K. et al (Rosenblum) J. Am. Chem. Soc. 1989, 111, 5252. -some similar chemistry is known for the corresponding alkyne complexes, i.e.,

Fp+ It is not nearly as well explored R R see Reger, D.L. Organometallics 1984, 3, 135 & 1759.

Use in synthesis (M. Rosenblum) Cp O +. O + 1) Cl2 reduct. Fp Ph NH2 OC Fe Fp NHBn Me N HBnN elim? N 3 Bn

+ Fp O NH3 + :NH R Fp Fp R R N N NaBH 4 Fp R

H Fp Ag2O O Δ N Fe N N O R 72% Cp CO R CO migration R Wong, P. K. (Rosenblum) J. Am. Chem. Soc. 1977, 99, 2823. 39 Berryhill, S. R. (Rosenblum) J. Org. Chem. 1980, 45, 1984; 1983, 48, 158. Synthesis of stereochemically defined alkenes from enol ethers

MeO OMe MeO OMe EtOH + EtO OEt Fp + + Fp Fp + R2CuLi (anti to Fe)

OEt OEt R HBF anti EtO H R 4 R Fp Fp EtO + O Fp departure of Fp Et O + (-EtOH) OEt EtOH R H Et

This can be repeated, using other ether function, with modification to get either alkene isomer

R 1) Nu- Nu R I- Nu R EtO + Fp 2) HBF4 Fp +

Δ

1) Nu- R R EtO R I- + 2) HBF4 Nu Fp Nu 40 Fp + PdII Complexes of Alkenes -probably the other major choice in alkene-TM complexes

Early Chemistry -Pd II forms comlexes with alkenes; an amine ligand is usually added to break up dimer and make a more reactive species R R R Li PdCl Cl R' N 2 4 Cl 3 Cl or + Pd Pd Pd Cl (MeCN)2PdCl2 Cl Cl NR'3 R -susceptible to attack by nucleophiles on the more substituted C -can sometimes reduce Pd off at low T, but mostly get β-H elimination O O O Nu:/Nu- = R NH, H O (ROH), - ) amines, water, alcohols, 2 2 R ( R - R enolates

R Nu- R Nu o Cl -L R Nu L -HCl, -Pd R Nu Pd or L Pd Pd H Cl NR'3 Nu: Cl 41 Cl NR'3 BUT...... This is stoichiometric in Pd, and PdCl2 1g, $102; 25g, $1155

see, R Hegedus p.188-201 R Handbook of Organopalladium Chemistry for Organic Synthesis V2, Ch V3 Holton, R.A. J. Am. Chem. Soc. 1985, 107, 2127 (chelating amines/sulphides)

However, if one has a stoichiometric oxidant present to oxidize the Pdo back to PdII, the could in principle be catalytic

II - this can work: oxidant is most often O2 or benzoquinone (BQ), or Cu

Earliest Successes

- is with oxygen based nucleophiles (H2O, ROH) -perhaps because oxygen nucleophiles don't displace the alkene ligand R O Pd and ROPd are not tremendously strong interactions R'

-traditional version, with water as nucleophile, is called the Wacker process

OAc OAc PdCl2(cat) OH O OAc

CuCl(cat)

O2, H2O actually not true 42 species -reaction is selective for terminal alkenes; in fact intermolecular reactions for internal alkenes work poorly in most cases (except strong EWG substituted ones)

-Markovnikov addition - Nu: attacks most substituted side of the alkene normally -this can be overridden by coordinating groups within the substrate

o II I II -CuCl2 oxidizes Pd back to Pd ; O2 oxidizes Cu back to Cu

Alcohols and phenols can do this type of chemistry too, usually as an intramolecular addition

PdCl2 isomerization DMSO, H O O OH 2 O KHCO3, air

-normal tendency is to form 5- membered ring over 6- membered ring; this tendency can be overriden in some cases

II - first work was with PdCl2 as the Pd source, but now it is often replaced with other PdII salts - -Reason - with Cl salts, attack of Nu is anti to Pd; whereas with Pd(OAc)2, Pd(OCOCF2)2, attack is syn to Pd 43 -syn attack allows/forces β-H elimination away from ring R R H H H R H R R R R R PdCl 2 anti O Pd Cl R O R OH R OH R H or R R

R O H R H H R R R R R PdX syn O H R OH 2 R O H Pd X R

usually

Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.

( )n ( )n 5 mol% Pd(OAc) 2 90-96% HO O DMSO, O2, rt -this even allows asymmetric synthesis at the newly formed chiral centre ligand 10 mol% Pd(OCOCF3)2 O 20mol% ligand O N OH BQ, MeOH, 60o N 75%, 96% ee O 44 Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071 N Nucleophiles -sometimes called aza-Wacker

-problem with amine ligands - these are generally too basic/nucleophilic; tend to displace alkene as ligand

-as a result, in the vast majority of successful cases, the lone pair on N is deactivated

H H O H H N N N N { { S = { Tsor even { Ar O O

- with this restriction, this has become an increasingly important way of making heterocycles; especially possible for indole type systems OTBDMS OTBDMS 10% PdCl2(MeCN)2 77% 1.5 equiv BQ CH3 NH N 3 equiv K2CO3, THF, rt CH3 CH3 Ts 5 mol% Pd(OAc)2 N NH Ts O2, 2 equiv NaOAc, DMSO, rt 45 R Minatti, A.; Munoz, K. Chem. Soc. Rev. 2007, 36, 1142. Carbon Nucleophiles -success in these nucleophilic attack reactions has even been extended to carbon based nucleophiles such as silyl enol ethers, enolizable β-dicarbonyls, electron rich aromatics and heterocycles - there are even some intermolecular cases

10mol% Pd(OAc)2 MeO O R' 1 equiv BQ MeO O R' 54-77% 20 mol% ethyl nicotinate OMe t-AmOH-AcOH, 20 mol% NaOAc OMe

10mol% Pd(OAc)2 O2 82% 40 mol% ethyl nicotinate N t-AmOH-AcOH, 80o N

Ferreira, E. M.; Stoltz, B. M.* J. Am. Chem. Soc. 2003, 125, 9578.

7 mol% Pd(OAc)2, S OEt 1 mol% H4PMo11VO40 CO Et + S 2 86% O 7 mol% acetylacetone, 4 mol% NaOAc, EtCO2H, O2

O O O O OH O 5 mol% PdCl (MeCN) R 2 2 R R 64-97% 2.5 equiv CuCl2, CuCl2, rt 46 even organometallics, i.e., Ar-HgOAc (ancient history), ArB(OH)2, ArSnR'3 dmphen= i.e. O O Pd(OAc)2, B(OH)2 + OBu-n OBu-n dmphen(cat) N N NMM, MeCN, o O2, 50

exhaustive review R Becalli, E. M.; Broggini, G.; Martinelli, M.; Sottocomola, S. Chem. Rev. 2007, 107, 5318.

We have been hiding an important point for a bit now, though

Some of these (the organometallics, syn attack cases) are probably going through a different intermediate than has been presented L L L L H Pd X Pd X Pd R 'insertion' X R X Pd H β-elimin. R A H R A reaction H H A H H A A Nu bound to metal R

A -much more common way to get at the intermediates A -by oxidative addition of Pdo to organic halides/triflates -called Heck reaction 47 Reveiws - many

R Heck, R.F. Org, React. 1982, 27, 345; Acc. Chem. Res. 1979, 12, 146. R Larock, Adv. Met-Org. Chem. 1994, 3, 97. R Jefery, T. Adv. Met. Org. Chem. 1996, 5, ch.4. R Crisp, G. T. Chem. Soc. rev. 1998, 27, 427. (mechansitic detail) R Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31 mechanistic detail R De Vries, J. G. Dalt. Trans. 2006, 421 (mechanistic discussion) R lonso, F.; Beletskaya, I. P.; Yus, M.. Tetrahedron 2005, 61, 11771. R Miyaura, N. Adv. Synth. Catal. 2004, 346, 1522. R Jutand, A. Pure Appl. Chem. 2004, 76, 565 (mechanistic detail) R Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945 (asymmetric synthesis) R Link, J. T. Org. React. 2002, 60 157 (intramolecular rxns)

I

Pd(OAc)2 + Br CO Me CO Me 2 2 CO2Me Et3NPd(OAc)2, Br 68% 63% P(o-tol)3, Et3N

So now we need Pdo, but we added PdII Not a typo; PdII complexes often used and reduced in situ

H AcO + + "Pdo" Pd(OAc)2 + HOAc

X " " -HX β-elim XPdH "Pdo" X2Pd + NEt XPd NEt2 3 -X- n picked up + by NEt3 H H + Et n N 48 Et Regiochemistry -somewhat different than intermolecular cases -some tendency to go away from EWG's and towards EDG's, but sterics now (apparently) dominates -Nu: goes 'towards' the less substituted site 100 4 H C Ph i.e. 3 O CO Me N CO2Me 2 96 93 7 100 40

60

Stereochemistry -resulting alkene is usually the most thermodynamically stable one, meaning trans ...... all else being equal

Nature of the Organic Halide R-X (usually) can't have β-hydrogens on an sp3 carbon atom, because of β-elimination

H o R H Br "Pd " H H L L β-elimination Pd H-Br + Pdo + R R Br 49 β-elimination takes place before any coupling can occur

X Thus X X X (aryl) (vinyl) (allyl) (benzyl)

Halides -Br is most common choice

-I faster at oxidative addn, but more side rxns (sometimes better, sometimes worse) O -triflates are excellent pseudohalides {SCF3 O

-Cl historically sluggish, but coming along nicely with new catalysts, including sterically hindered phosphines, carbenes as ligands, and ortho- metallated palladacycles O PPr-i O O 2 i.e., t P Bu3 N N Pd Cl .. Cy2P O PPr-i2

R Whitcome, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449. R Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. Engl. 2002, 41, 4176. 50 R Christmann, U.; Vilar, R.* Angew. Chem. Int. Ed. 2005, 44, 366 A cute but increasingly irrelevant variation - acid chlorides -aryl chlorides are very reactive to oxidative addition, and may be accessibe when the halides are not

L O o O migratory "Pd " (Pd(OAc)2) Cl Br Br Br Pd Cl Cl Pd deinsertion Ph NMe L 2 Cl L -CO

Br X -can occur under very mild conds, in some cases - being made obsolete by improvements to aryl chloride Heck reactions Spenser, A. J. Organomet. Chem. 1983, 247, 113; 1984, 265, 273. Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287. Tetrahedron Lett. 1985, 26 2667.

The Alkene R R R' R R 3 1 R R' 3 1 > and >> >>> R R4 R2 X R2 monosub disubst. trisubst tetrasubst. -forget it 51 only practical ones -ligands generally stabilize palladium intermediates, but are't always added -inorganic base is often used (instead of amine) to consume H-X O O

I PdCl2(MeCN)2

O HCOOH O O O Br O Note what happens to Pd(OAc)2 + β-elimination process S OH S Et OSi Et OSi 3 H 3 H Pd(dba) 2 CO2Me OTf + CO Me N 2 K PO N O 3 4 O CO PMP 2 CO2PMP

In some cases, other things can be done to the alkylpalladium

Pdo R' R-X + R' R PdX 52 a) Trap with organometallics

Ph

I 10% Pd(OAc)2 + PhZnCl 20% PPh 60% N 3 N H Et2O-THF, rt

Grigg, R. et al Tetrahedron Lett. 1990, 31, 6573 & refs therein

b) Further cyclopalladation

3% Pd(PPh3)4, EtO2C EtO2C EtO2C 76% EtO2C Et3N, CH3CN,Δ I Yang, Y. et al (E.-i. Negishi) J. Am. Chem. Soc. 1990, 112, 8590.

For still more reviews, see...

R Handbook of Organopalldium Chemistry for Organic Synthesis V1, Ch IV 2.4-2.6 R Naso, F.; Marchese, G., in The Chemistry of Halides, Pseudo Halides, and Azides; Patai, S; Rappoport, Z. eds Ch. 26, Wiley 1983, R Green, J. R. in The Chemistry of Halides, Pseudo Halides, and Azides, Supplement D2, Ch 25, Wiley 1995 R Shibasaki, M. Soden, C. D. Kojima, A. Tetrahedron 1997, 53, 7371 R Balme, G. Bouyssi, D.; Lomberget, T. Monteiri, N. Synthesis 2003, 2115 53 η3- Hydrocarbon Metal Complexes

i.e. type complexes Note: We will discuss these here, too; MLn even though they're Fe OC η1 OC Preparation of η3-allyl Complexes i) From olefins (alkenes) with allylic leaving groups

Na PdCl Cl 2 4 + CO2 +2 HCl + 2 NaCl CO, H2O, MeOH Pd (Pdo generated in situ) Cl 2 I Fe(CO) or Fe (CO) I 5 2 9 Fe CO CO Δ, -CO C O + Fe(CO) (CO)4Fe 4 - Fe (CO) HBF4 BF 2 9 OH 4 OH Et2O, -H2O OR Ni(cod)2 OR Ni + 2 PPh 3 PPh3 54 R = Ph, Ac Cp Cp hν - Cl Fe CO CpFe (CO)2 + Fe CO CO -CO 3 η1 η Fish, R. W. et al (Rosenblum) J. Organomet. Chem. 1976, 105, 101.

- O O O Fe(CO) C O 5 + O C Fe(CO)3 Fe(CO)3

ii) From Metal-Diene Complexes + + Fe(CO) Fe(CO)3 3 Fe(CO)4 - HBF4 BF - 4 BF4 CO Salzer, A.*; Hafner, A. Helv. Chem. Acta 1983, 66, 1774.

Y Cl + PdCl + Y- 2 Pd Pd Y- = Cl-, RO-, Cl AcO-, PhHgCl Y 55 Trost, B. Tetrahedron 1977, 33, 2615. iii) Activation of allylic C-H Bonds -most applicable for Pd complexes " " NaOAc -HCl + PdCl 2 H H HOAc Pd Cl Cl Pd Cl L i.e.,

PdCl2 Cl Trost, B. M. Tetrahedron Lett. 1974, 2603. Pd 2 Huttl, R. Chem. Ber. 1968, 101, 252.

CO2H CO2H PdCl2 Chrisope, D. R.; Beak, P.; Saunders, W. H., CO2H Cl J. A. Chem. Soc. 1988, 110, 230 CO2H AcOH Pd 2

iv) Propargyl (di)Co complexes

Co2(CO)6 Co (CO) + 2 6 Co2(CO)6 H (-ROH) or + R' CH2OR R' CH2OR R' CH - 2 56 BF3 (-ROBF3 ) Allyl/Propargyl η3- Complexes as Electrophiles

a) Cationic allyl tetracarbonyl complexes

Nu: R R Nu

+ Fe(CO)4 Fe(CO)4

-complexes react with a pretty wide range of nucleophiles to give η2-alkene complexes as immediate products

-these η2-alkene complexes are not all that stable, easily decomplexed by mild oxidant -allyl attack is presominantly at less substituted side of allyl unit (more later)

Nu: can be... R3N (amines), Ph3P (phosphines), R2Cd (RMgBr), RCu(CN)ZnI O O OSiMe electron rich arenes, H- (Et SiH), 3 M 3 , R' MeO OMe , R - R R (M = Me Si, Bu Sn, R B) O 3 3 2

R Pearson, A. J. "Iron Compounds in Organic Synthesis", Academic Press, 1994, Ch.3 R Green, J. R.; Donaldson, W. A., in "Encyclopedia of Inorganic Chemistry", Lukehart, C. M., ed., Wiley 1994, V 4, p. 1735. 57 Regiochemistry -Site of attack is normally at the less substituted end of the allyl unit

-C2 attack has never been observed

N Fe(CO) Fe(CO)3 3 HBF4 + CO N

PPh3 O O 1) O - OMe + O - + 2) HO , H PPh3 + 3) air 68% 17%

-Site of attack is away from electron withdrawing group

OSiMe3 Fe(CO)4 CO Et CO Et CO2Et 2 Me3NO 2 O O Fe(CO)4 + CH2Cl2

58 Green, J. R.*; Carroll, M. K. Tetrahedron Lett. 1991, 32, 1141. Why care? -allyl cations are very highly reactive; either too unstable to prepare or too reactive to be isolated or control their reactivity

-site γ-to carbonyl is normally nucleophilic; therefore this is umpolung reactivity

-iron allyls are geometrically stable

R de Koning, H.; Hiemstra, H.; Moolenar, M. J.; Speckamp, W. N. Eur. J. Org. Chem. 1998, 1729. R Enders, D.; Jandeleit, B.; von Berg, S. Synlett 1997, 421. b) AllylpalladiumII Complexes Hegedus, p. 245 start Tsuji, p. 116-168 -by FAR, the most widely used η3-allylmetals -like the Pd alkene complexes, the chloro- bridged dimers usually aren't reactive enough

-reactivity is enhanced in one of two ways + THF -AgCl - Pd BF4 AgBF4 Pd THF Pd Cl O Cl THF

2 + PPh3 -halide displacement by Cl- Pd good ligands Ph P 3 PPh3 59

-can also be activated by other ligands (esp. phosphines), dimethyl sulphoxide (DMSO), hexamethylphosphoric triamide (HMPA)

- once 'activated', these can undergo nucleophilic attack by several reagents O O O O OSnR'3 OLi OSiMe3 AcO-, R NH, 2 OR , Ph S , - OR R R R O - R" R" R" less reliable

-attack superficially similar to allylirons -i.e., normally at the less substituted allyl terminus -this can, however, be affected by choice of phosphine ligand

-rationale - more electron rich C-Pd bond shouold be the stronger one - this is the more substituted one - therefore the less substituted one is more weakly held, so Nu- attacks there

-BUT , with a bigger ligand (i.e., (o-tol)3P), there is a steric repulsion between PdL2 and the more substituted C - makes that bond weaker, more easily attacked

Consider..... 60 SO Me Pd Cl - 2 L, Me-SO -CH-CO Me 2 2 CO Me SO Me 2 2 2 + DMSO, RT CO2Me

L

PPh3 62 38

n-Bu3P 100 0 P 3 18 82

Trost, B. M. et al J. Am. Chem. Soc. 1978, 100, 3416.

-electron withdrawing groups direct attack to the end site remote to the group -electron donating groups direct attack to the end near the EDG

EtO C CO Et 2 2 CO2Et CO2Et -

Pd Cl EtO2C CO2Et 2

EtO2C CO2Et EtO2C CO2Et O OAc O - Cl NHAc O NAc Pd 2 61 -there are rare cases of attack at the central carbon of the allyl unit - C-2 attack

-usually observed for Nu- with high pKa's (20-30), or where the central carbon has a leaving group -C-2 attack has very limited use in synthetic organic chemistry so far

- -Pdo CO2Me + CO Et 2 CO2Et Pd+ Et3N NEt3

Pd(NEt3)2 -for a good discussion and lead refs, see... Aranyos, A., et al (Backvall, J. R.) Organometallics 1997, 16, 1058. Organ, M. et al J. Am. Chem. Soc. 1998, 120, 9283.

Stereochemistry of Attack

-recall - oxidative addition to for π- allyl is on a alkyl centre, and therefore goes with inversion of configuration Me OAc H PPh3 H o + "Pd (PPh3)2" Pd

PPh3 62 -now, nucleophilic attack on the allylpalladium normally occurs away from the palladium (it could be called backside attack, too), so overall there is a retention of configuration at carbon

SO2Ph O H C Me - 3 PPh Ph S CH-CO Me CO Me H 3 2 H 2 Pd + O

PPh3

Note: This is the normal (and ideal) situation non-stabilized carbanions are not usually good for attack on these species; when the do work, the mechanism is different....

- then, the initial attack step is on the metal, which is followed by reductive elimination to give retention for this step 2

Pd Cl reductive Pd CH3 CH3MgI CH3 elimination H MgX Nu- = MeMgX, SnBu3 PhMgBr ClCp2Zr a) b) c)

Tetrahedron Lett. 1979, 3221 J. Organomet. Chem. 1975, 102, 359 J. Chem. Soc., Chem. Commun. 1984, 107 a) J. Am. Chem. Soc. 1984, 106, 5028. 63 b) Organometallics, 1985, 4, 417 c) J. Am. Chem. Soc. 1982, 104, 1310 and 5028. -Acetate/carboxylate will attack with retention under special conditions, or if forced by the constraints of the molecule "PdCl" Larock, R.C. J. Org. Chem. 1984, 49, 3662. O ( )n OH ( )n O H O Cl H Cl

The best news is that many, many, many of these reactions can be done as catalytic reactions

for example, allylic oxidation McMurry, J. R.; Kocovsky, P. Tetrahedron Lett. 1984, 25, 4187. O O Pd(OC(O)CF ) O 3 2(cat) + HOAc, O (solvent) O O

O O OMe O O

or most commonly..... + L L Nu- - Nu X Pd X Pd X + L2Pd + L4Pd L L

O O O

X = -OAc, -OC-R -OC-OR -OPh, -OH, -SO2Ph, -NO2, 64 so......

OAc Godleski, S. A.;Valpey, R. S. 66% J. Org. Chem. 1982, 47, 381. NaH, THF, Δ CO2Et CO2Et CO2Et 7% Pd(PPh3)4 CO2Et

Me2NH, Pd(acac)2 Backvall, J. R. J. Org. Chem. 1981, 46, 3479. N dppe, THF NMe Ar OAc 2 Ar

(Ph3P)34Pd(cat) AcO O HN O dppb H N N (cat) 2 O N THF, Δ O HAcN HAcN Trost, B.M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881.

OH O o O 40 , Pd(PPh3)4 85% CH2(SO2Ph)2 + Pd PPh 3 SO Ph SO Ph Ph3P 2 2

65 Notes on that last one: 1) Allylic substituent, CHR-OH is electron withdrawing and sterically blocking 'proximal' attack - therefore, attack is on remote (distal) end of allyl unit

2) Oxidative addition goes with inversion Nucleophilic attack is from backside of Pd allyl = inversion so overall retention

Question: How about the other possible regiochemical outcome, i.e., attack at more substituted end?

If you instead use Co group catalysts, particularly RhI and IrI, and use less donating

ligands (phosphites, esp. P(OPh)3), it is clear that allyl more 'electrophilic', so location of '+' resonance for more critical - attack on more substituted end. n-Bu [Ir(cod)Cl2]2 n-Bu + n-Bu 90% OAc 4 P(OPh) , THF, RT 3 Nu Nu NaCH(CO2Et)2 97:3 R Takeuchi, R. Synlett 2002, 1954 (Ir)

RhCl(PPh ) ,P(OPh) + 89% 3 3 3 Nu OAc Nu NaCH(CO Me) , THF, 30o 2 2 >99:1 R Leahy, D. K.; Evans, P. A. Modern Rh-Catalyzed Organic Reactions, Ch. 10 -Other metal systems such as IrIII, MoII can do similar substitutions R Krska, S. W. et al (+Trost, B. M.); Pure Appl. Chem. 2004, 76, 625.(Mo) 66 Enantioselectivity -most of the work has been done on allyls with symmetrical substitution patterns, using a chiral ligand

H3C CH3 - Nu H C CH H3C CH3 3 3 + + Pd Nu H H Nu L* L* - - Most recent reviews Nu = CH(CO2Et)2 especially R Trost, B. M. J. Org. Chem. 2004, 69, 5813. R Trost, B. M. Chem. Rev. 2003, 103, 2921. R Graening, T.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2003, 42, 2580.

This still can be a very tricky process, as there are many isomerization processes possible OAc L* OAc Pd + L* k Nu PdL * Pd 1 2 + L* L*

A OAc OAc L* + Nu * Pd Pd PdL2 L* k + L* L* 2 B 1) Under normal reaction conditions (high phosphine to Pd ratios), nucleophilic displacement is slow relative to π-allyl interconversion 67 -therefore, the product can depend of stabilities of A and B 2) Acyclic systems can racemize by an η3 - η1 - η3 mechanism Y X X Pd H H Pd Y X Pd X Pd Y Y -same process can also result in anti / syn- isomerization of allyl Pd's

Pd Pd X Pd X Y X Y Y syn,syn- syn,anti- anti,anti-

Nevertheless, there has been considerable success in this enantioselective transformation, especially using ......

O O where O O X X HX XH N N most common H H is a symmetrical diol PPh2 Ph2P P P diamine Ph Ph2 2 DPPBA ligands

see Trost reviews listed on last page R Trost. B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. 68 Other successful ligands

H Me Me i t X = R = Pr, Bu X N OH MeO O PPh2 Fe PPh2 OH Me Ph2P N PPh 2 N OH R MOP (Monophosphine OH ligands) ( )n BPPF-X N OH R Hayashi, T. J. Organomet. N N Chem. 1999, 576, 195. R R BOX (Bis-oxazoline ligands) R Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.

NaCH(EWG)2 Ar Ar Ar * Ar up to 96% ee with (R)- or (S)- BPPFX o CH(EWG) OAc (π-C3H5)PdCl/L*, 40 2 Hayashi, T. et al Tetrahedron Lett. 1986, 27, 191.

O PdCl/ Bz O 2 BzO conduramine A-1 benzamide O O

O O TMSN3, DPPBA pancratistatin Bz O N3 = OBz O 83% yield, >98% ee from Trost (1996) review 69 π-Allylnickel Halides

Preparation R X Hegedus, p.278 R benzene Ni Ni X R + Ni(cod)2 X or Ni(CO) X = Br 4 usually

-These are isostructural, isoelectronic with the corresponding allylpalladium compounds -Reactivity can be different, however

These can behave as if they are nucleophiles themselves, and will allylate organic halides (X = Br, usually)

R Br DMF Ni + R'X R' + NiBrX o R 2 25 -ketones and aldehydes are often tolerated (i.e., they survive this rxn at RT) -esters are tolerated well

Regiochemistry - reaction occurs at less substituted allyl terminus

Br I DMF Ni α-santelene 70 + 25o 2 So who cares?

Look carefully at the above; the centre that's being attacked is neopentyl (i.e., R3C-CH2-X)

-neopentyl centres are normally forbidden for nuceophilic (SN2) substitution -works just fine here

-Generally true - rxn works well in cases where SN2 is impossible (i.e., aryl halides) OAc OAc O Br HMPA + Ni Br 2 OAc OAc O and if you want to do... vitamin K analogue O Br -this is very tough directly - + CH 2 O

But.. O O O Br + MeO DMF H3O OMe OMe Ni OMe + 2 N N Br N O CH OMe 3 Hegedus, L. S.; Stiverson, R. K. J. Am. Chem. Soc. 1974, 96, 3250. Hegedus, L. S. et al J. Org. Chem. 1977, 42, 1329. 71 Works with aryl, vinyl, 1o, 2o, 3o alkyl bromides and iodides However, allyl halides 'scramble'

Br Br Br + Ni + + Br Ni + 2 2 Other points -like allylPd's the allyl fragment loses its stereochemical integrity

Br 1) Ni(cod)2 R + R 2) R-X

-chiral (and enantiomerically pure) 2o alkyl halides racemize MeO Br CH3 Ni CH 1) 3 racemic I H 2 H 2) H O+ 3 O -while vinyl (alkenyl) halides retain their stereochemical integrity

O OEt Br OEt O DMF O O I + Ni 2

Hegedus believes that this is all due to the interventional of NiI and NiIII as well as NiII

Hegedus, L. S.; Thompson, D.H.P. J. Am. Chem. Soc. 1985, 107, 5663. 72 Initiation

hν or Δ III Br I II Br II I III allyl Ni Ni allyl allyl Ni Ni allyl allyl-Ni +allyl-Ni Br Br ? Oxidative addition/reductive elimination R I III I allyl-Ni + R-X allyl Ni allyl-R + Ni -X Br

Scarmbling of R * III R I III R III R allyl-Ni allyl Ni allyl Ni + allyl-NiII-Br allyl-NiII-Br + allyl Ni * Br * Br * Br + allyl-NiI Chain carrying step

NiI-X + allyl-NiII-Br NiIIBrX + allyl-NiI

Scrambling of R goes with inversion, i.e., SN2 like - therefore occurs with alkyls, but not alkenyls

The rest is like you expect - for alkyls, oxidative addition is with inversion, reductive elimination with retention - for alkenyls, oxidative addition with retention, 73 reductive elimination with retention Other electrophiles -although organic halides react preferentially, these allylnickel species will react with aldehydes and the more reactive ketones at ca. 50oC -ordinary acyclic aliphatic and α,β-unsaturated ketones only react sluggishly Br O DMF R Ni + R R' R' 50o OH 2 -example of use in spirocyclic α-methylene-γ-butyrolactones

O Br O OH O EtO Ni + ( )n O O ( )n 2 ( )n OEt Billington, D. C. Chem. Soc. Rev. 1985, 14, 93.

π-Allylnickels as Electrophiles PPh + 3 With two phosphine ligands Ni does pretty much the same chemistry

PPh3 as α π-allylpalladium complexes -what's unusual? - successful coupling of Grignard reagents, i.e.,

X o II + Ni (or Ni ) + RMgX + 2 PR'3 R

-large variety of X, including -Br, -Cl, -Oalkyl, -OAr, -OSiR3, -OH, -OTHP, -SR -the R of RMgX is suprising....R = Ar, or 2o or 1o alkyl -β-hydride elimination is apparently a lesser problem in alkyl-Ni 74 β-elimination step for R = alkyls is often slow enough that one can get reasonable amounts of C-C bond formation

PhMgBr 95% PhS OMe PhS Cl2Ni(dppp)(cat), o benzene, 0 Sugimura, H.; Takei, H. Chem. Lett. 1984, 351 ( )6 MgBr OEt EtO ( ) 74% 7 CH Cl Ni(dppp) , 3 OEt 2 (cat) THF, 0o Hayashi, T., et al J. Organomet. Chem. 1985, 285, 259. for work with chiral phosphine ligands, see: Cansiglio, G., et al Tetrahedron 1986, 42, 2043. -Work in this area has slowed drastically since the mid 1980's

π-Allyliron Tetracarbonyl Lactone Complexes -this area is almost entirely the work of S. V. Ley -recall.... O O O C O O hν, Fe(CO)5 Fe(CO) 90% Fe(CO)3 3 benzene

75 hν, Fe(CO)5 O Fe(CO) 3 + Fe(CO)3 benzene O O O syn, 64% O anti, 11% -Note: Photochemical conditions usually give retention (completely) - in above case, one can actually separate the diastereomers chromatographically

-when one attempts the typical oxidative metallation, it causes reductive elimination and therefore C-C bond formation - with two possible outcomes

CAN O O CAN O O β-lactone δ-lactone Fe(CO) 3 [(NH ) Ce(NO ) ], (major) O high T or 4 2 3 6 O under CO CH3CN, RT

Note: The stereochemical nature of the reductive elimination step is retention retention of configuration CAN O Fe(CO) 3 51%+ 29% O O O O CH3CN, RT O H 76 while, conversely CAN likely because the trans fused Fe(CO) 3 β-lactone would be impossibly CH CN, RT O 3 O O strained O Examples of the use of this in the synthesis of δ-lactones O O Fe (CO) 195o, 60 atm CO 2 9 O parasorbic acid Fe(CO)3 THF benzene, 73% lactone (racemic) O O -naturally occurring lactone from sorbus acucupara carpenter bee malyngolide O O pheromone O O OH Ley, S.V. et al J. Organomet. Chem. 1985, 285, C17. The two routes to C-C brond formation

O O O O O [O] reductive CO Fe(CO) +. 3 O ? Fe(CO)3 elimin. O O

Fe(CO)3 ? [O] reductive O [O] O O CO, Δ, O O elimin. high O Fe(CO)3 Fe(CO) O +. 3 77 π-Allyltricarbonyl Lactam Complexes -these have had a larger impact than the corresponding lactone complexes Preparation - less common O Δ (CO) Fe (CO) Fe hν, 3 3 N-CO2Me N-CO2Me RT, CO N-CO2Me Fe(CO)5 -but, vinyl aziridines aren't all that readily accessible, so....

-can be made more readily from the lactone complexes, through Lewis acid mediated substitution 1 Ph 1 RT, Al2O3, PhH N O 2 Fe(CO) or 3 PhNH 2 3 + 2 Fe(CO) O ZnCl2, RT, Et2O 3 3 4 O 4 -this goes with transposition of the allylic fragment via the following mechanism (E = Lewis acid) Ph H PhN+ H N+ + - .. 2 2 O-E intramolecular H2NPh - Fe(CO)3 Fe(CO) O 3 Fe O + E- + oxidative addition O O O E- (CO) 3 Ph Ph + - + HN: O-E -H , N O -H O +H+ 2 OH Fe(CO)3 Fe -E 78 (CO)3 -when these compounds are oxidized, the reductive elimination is more highly selective for the β-lactam

O o β-lactam (CO) Fe -30 - RT 3 (azetidinone) Ph N CAN, EtOH, 72% N O Ph

-these 3-alkenyl-2-azetidinones are not so readily accessible for other methods -example of synthetic use (+)-thienamycin CH3 NH2 OCH Ph O 3 hν, Fe(CO) O H ZnCl2-TMEDA, 5 Fe(CO)3 OCH Et O/THF OCH benzene, RT 3 2 3 O OCH3

O (CO) Fe 3 Ph O Fe(CO)3 -can separate the two diastereomers N CH3 H C chromatographically 3 H H + N Ph H OCH3

OCH H3CO OCH3 3 79 O (CO)3Fe Ph OCH CAN, MeOH 3 N CH 3 OCH H H -30o - RT N 3 O Ph OCH 3 H CH3

OCH3

O Fe(CO) O 3 OCH3 OCH CAN, MeOH o 3 H C 1) O3, -78 3 N OCH o N 3 OCH3 Ph -30 - RT Ph N H O 2) Me2S O Ph H CH3 H CH3 H3CO OCH3

spontaneous epimerization OH NH + R Ley, S.V. Cox, L. R. Chem. Rev. 1996, 96, 423 2 R Ley, S. V. Pure Appl. Chem. 1994, 66, 1416. S R Cox, L.R.; Ley, S.V. Chem. Soc. Rev. 1998, 27, 301 N O CO2- 80 (+)-thienamycin Propargyl Cation-Dicobalt Hexacarbonyl Complexes

R Green, J. R. Curr. Org. Chem. 2001, 5, 809. R Caffyn, A.J.M.; Nicholas, K. M. in Comprehensive Organo- R Teobald, B. J. Tetrahedron 2002, 58, 4133. metallic Chemistry II, 1995, V.12, Ch. 7.1 R Nicholas, K. M. Acc. Chem. Res. 1987, 20, 208.

(Di)Cobalt alkyne complexes form cations at the propargylic site very easily

HO " " OH + R2 HBF4 or R' R' R2 R' R R 2 R3 3 R3 HPF6 (CO) Co (CO)6Co2 6 2 (CO)3Co Co(CO)3

thermally stable, dark red/beet/brown structure is a lie solids

-as cations go, these are very stable Consider KR+ R+ + 2 H O + 2 ROH + H3O -log KR+ = pKR+ i.e., the less negative (more positive) the number, the more stable

+ pK + = -6.8 - -7.4 Consider Ph3C = R or -5.5 + R2 R' depending on reference + R3 + (CO) Co 81 pKR = -6.6 6 2 meaning, about the same -best estimation of structure Schreiber, S. L.; et al J. Am. Chem. Soc. 1987, 109, 5749. -X-Ray of cation Melikyan, G. G. et al Angew. Chem. Int. Ed. Engl. 1998, 37, 161.

R 2 R2 R -both antarafacial and supra- 3 R3 facial migrations going on, Co(CO) (CO)3Co 3 (CO) Co Co(CO) along with epimerization + 3 + 3 R' R' -actually pretty complicated

R3 R2 R2 R2 (CO)3Co Co(CO) (CO) Co Co(CO) + 3 3 + 3 R' R'

-these are much more electrophilic than allylpalladiums, so they are electrophilic enough to react with several types of nucleophiles 82 X electron rich -arene needs one or more activating groups, i.e., aromatics

-OCH3, -OH, -NMe2 O O O O O-SiMe SiMe 3 O-BR'2 O 3 OMe R SnBu R R 3 β-dicarbonyls silyl enol ethers enol borinates enol allylsilanes or silyl ketene acetals acetates allyltins

NaBH4 R2NH Et AlCN R Al R Cu(CN)ZnI ??? or 2 3 2 Et3SiH + CF3COOH amines cyanation alkylation

reduction

A couple of examples

CH Cl OSiMe 2 2 pretty high syn 3 R' O + R' o stereoselection Ph + -78 (CO)6Co2 Ph Co2(CO)6 83 -the cations can be generated in several related ways, such as from ethers or acetates, halides, alkenes, epoxides, etc.

OCH3 BF3 AgBF4 Cl R' R' + R' o CH2Cl2, -78 o (CO) Co (CO) Co CH2Cl2, -20 6 2 6 2 (CO)6Co2

O O R Cl + R' RCO R' R AlCl + 3 (CO) Co (CO)6Co2 6 2

( )n ( )n + + H R' R Smit, W.A.; Caple, R.; Smoliakova, I.P. R' Chem. Rev. 1994, 94, 2359. O (CO) Co (CO) Co 6 2 OH 6 2

-intramolecular variants of this reation are certainly viable

R R BF3-OEt2

Me3Si CH Cl Co (CO) Co2(CO)6 2 2 2 6 OMe 84 OMe OMe OMe BF3-OEt2 OMe MeO MeO iPr NEt, MeO MeO MeO Co (CO) 2 MeO 2 6 CH Cl 2 2 NHAc MeO Co2(CO)6 AcO 70% MeO NSC 51046 -notice stabilization of 7 membered ring alkyne

+4 +3 + - in general, the cobalt carbonyl unit can be removed as before (Ce , Fe , Me3N -O )

Importance - in traditional organic chemistry, SN2' reactions are a major competitive problem in substitutions of propargyl-X

SN2' R i.e., R allenes C CH2 X Nu- Nu

-this never, ever, ever happens with Co propargyl cations (Nicholas reactions)

Other Nucleophilic Allyls 1 -η -allyl Fp [CpFe(CO)2] complexes

X or Fe + Fe Fp OC OC CO CO 85 -behave as modestly reactive nucleophiles to a pretty wide range of E+

E+ + Fp E Fp E Fp + O + HgCl + R Cl O 2 Fp Fp Fp Fp HgCl AgSbF6 R

+ + + + Me3O Fp H CH Fp Fp 3 Fp HBF4 CH O 3 + R R' OH Br + Fp 2 Fp Fp R Fp Br BF3 R'

R Rosenblum, M. J. Organomet. Chem. 1986, 300, 191.

-even Fp+-alkene complexes will react with these η1-Fp-allyls H+ + H + Fp Fp' Fp' + Fp+ Fp' NaI Fp 86 η1-propargyls do analogous chemistry H Fp

η1-allyls react with electron poor alkenes by initial nucleophilic attack, followed by electrophilic attack back onto the iron containing unit - this is ultimately a 3+2 cycloaddition resulting E R + Fp R Br2 Br R Fp + Fp R E - E E E CS2 E E E Ce+4 E = CO2R, CN (normally need 2) EtOH EtO2C R E E -to be sufficiently reactive, the alkene usually needs two electron withdrawing

groups, although some cyclic alkenones work with a Lewis acid added (AlBr3) O AlBr3 O + Fp Fp

-several more obscure electron deficient X=X systems do this [3+2] cycloaddition, but they aren't as important so we'll just list them δ− δ+ δ− δ+ δ+ δ− Ts NCO MeO2C NSO2 H2CSO2

-one further [3+2] cycloaddition partner that is interesting enough to show is specialized; cycloheptadienyl iron cation with an included alkene 87 R R R + + Fp Fp Fp + + (CO)3Fe (CO)3Fe (CO)3Fe if R = O-SiMe O 3 -"SiMe +" functionalized Rosenblum, M. J. Am. Chem. Soc. 3 Fp hydoazulene 1990, 112, 6316 and refs therein. ring system + (CO)3Fe

R Ruck-Braun, K.; Mikulas, M/; Amrhein, P. Synthesis 1999, 727.

η3 (?), η4 (?) Complexes - The Iron Oxyallys some magical species which Noyori proposed O Fe (CO) has never been isolated R R 2 9 R Noyori, R. Acc. Chem. Res. 1979, 12, 61. OFeLn Br Br R Noyori, R. Org. React. 1983, 29, 163. R R R Mann, J. Tetrahedron 1986, 42, 4611. +

But....the following have been isolated at various times OR O O (CO)3Fe S M(PPh ) Fe(CO)3 O Fe(CO)3 3 2 Fe(CO)3X Fe(CO)3 M = Pd, Pt see later Frey,M.; Jenny X = Br, Cl Ando, W. Organometallics 1990, R = H, TMS Albright, T.A. Organometallics J. Am. Chem. Soc. 1989, 8, 199. 9, 1806. J. Organomet. Chem. 1990, 112, 4574. 1991, 421, 257. Emerson, G.I. J. Am. Chem. Soc. 1966, 88, 3172. 88 -therefore, the most likely structures for these iron oxyallyls are....

or perhaps a dimer O O or η3 or O η4 + Fe(CO)3 Fe(CO) called oxyallyl cations 3 Fe(CO) L Br 3

-the iron oxyallys react with simple alkenes to give either [3+2] cycloaddition products or ene reaction products O O O O R R PhH, Δ R R R R R R + Fe (CO) + 2 9 R' R' + CH Br Br FeLn 3 R' CH3

-the [3+2] cycloadditions work best when the alkene has some carbocation stabilizingg groups O OFeLn O Fe2(CO)9 65% 60o, PhH via + Br Br Ph Ph Ph -i.e., with enamines O O O Fe2(CO)9 RT - 30o 83% Br Br N N O O 89

OFeLn O O Fe (CO) 2 9 51% O RT, O O Br Br NMe2 NMe2

-nitriles also react in a few cases

Regiochemistry -on the oxyallyl - the major product results from initial reaction at the least substituted end of the allyl (to give the most substituted Fe enolate)

-on the alkene - the major product is the one that goes through the most stable carbo- cationic intermediate O O O OFeLn Fe (CO) 2 9 major product Br Br FeLn + + Ph Ph

Stereochemistry - normally, one gets retention of stereochemistry about the alkene -does not mean concertedness; apparently, the intermediate cation is (very) short-lived -not enough time for bond rotation O O Fe (CO) O (D) 2 9 + (D) D Br Br benzene, 90 Ph D Ph D 55% -reaction is certainly not restricted to intermolecular cases; intramolecular ones work as well + Fe (CO) Br 2 9 + other products 110o, PhH O O OFeLn Br Camphor (major) 4+3 Cycloadditions -probably more imortantly than the [3+2] cycloadditions, these oxyallyl cations react with dienes ti give 7- membered rings

O O O Fe2(CO)9 R R R R 1 3 1 3 R R R 4 2 R4 2 Br Br +FeLn

-a couple of examples O o ca. 60 80% O + Fe2(CO)9 + Br Br

O O O 32o + + Fe2(CO)9 35% O 91 excess Limitations on Reagents in [4+3] - on the dibromoalkene

O O O O O Br Br R Br R R Br Br Br Br Br R Br Br Br Br can't use Br Br unsubstituted used tribromo used (except R = Ph) is even used one instead instead of.... sometimes

O O O Fe2(CO)9 Br Br Zn-Cu Br Br 63% O O O Br Br

-in cases with pyrroles, N-alkyl cases give electrophilic aromatic substitution N-acyl cases usually give the [4+3]

O Fe (CO) O 2 9 O N CO Me N CH + + 2 3 N Br Br N works, though CH 3 CH Mechanism 3 -allyl cation is a 3C, 2π electron system; diene is a 4π electron system -could this be a concerted [4π + 2π] cycloaddition? -Noyori thinks yes -Hoffmann thinks only sometimes, but mostly no 92 (Angew. Chem. Int. Ed. Engl. 1984, 23, 1) Regiochemistry -behaves as if it is a concerted reaction -therefore, it is controlled by HOMO-LUMO interactions

Consider O if we leave out the iron O LUMO Ph Ph +FeLn larger smaller orbital coefficients and EtO C O 2 O EtO2C HOMO

-frontier molecular orbital arguments require that atoms with larger orbital coefficients, and smaller with smaller O -therefore, frontier molecular orbital (FMO) arguments would predict Ph O EtO C -but if stepwise, one would predict.... 2 OFeLn OFeLn O Ph Ph Ph + O would be + O CO Et O EtO2C bad good 2 CO2Et favoured

O O Ph Ph -the actual result is.... O O 90 : 10 CO Et EtO2C 2 93 Stereochemical consequences -ordinary dienes O O Fe2(CO)9 + + O Br Br + O FeLn presumed usually major usually minor configuration (endo) (exo) -aromatic dienes O X X X Fe (CO) + 2 9 X O O Br Br O X = O, N-EWG pretty much a random mixture -it is the presence of these types of products that makes Hoffmann think that the reaction is not concerted

-use - pretty good way of making 7-membered ring containing natural products O O O O O i.e., FSOH Pd/C, H2 DDQ O O O NH4Cl, PhH CH2Cl2 nezukone

-also, in tropane alkaloid synthesis... 94 O H C i-Bu AlH H3C 3 E 2 N N N THF, -78o + 6,7-dihydrotropone OH

E = CO2Me HO H3C N 1-hyoscyamine H C 3 H C N 3 Ph N O O HO teloidine HO OH H HO H O H H HO many other natural product syntheses for reviews, see R Noyori, R. Acc. Chem. Res. 1979, 12, 61. R Noyori, R. Org. React. 1983, 29, 162. R Mann, J. Tetrahedron 1986, 42, 4611. part of R Rigby, J. H. Pigge, F. C. Org. React. 1997, 51, 351 R Harmata, M. Tetrahedron 1997, 53, 6235

η4- Complexes η4-Trimethylenemethane Complexes

-predominantly used with palladium, due to use of metal in catalytic amounts -iron also known and used some, but it is stoichiometric

-consider the following substrate that looks like a precursor to an η3-allylpalladium 95 - SiMe AcO 3 PdoL n SiMe3 - O CH3 i.e., O CH3 Pd(PPh ) O 3 4 + PdL PdL + O 2 2 PdL2

- in these cases, the Pd is coordinated to all 4 carbon atoms - this is a trimethylenemethane complex -excellent reagent for 3+2 cycloaddition reactions O SiMe o 3 Pd Ln EWG EWG = -CO2R, -CN, -SO2R, R OAc EWG -mechanism EWG - EWG + + EWG L Pd - 2 L2Pd

-stereochemical considerations -about alkene - get mostly retention of configuration, but not perfectly so

Pd(PPh3)4(cat), Δ CO2Me ( )5 OAc ( )5 CO2Me 96 SiMe3 Pd(PPh3)4(cat), Δ major minor Ph CO2Me + OAc Ph CO Me Ph CO2Me 2 SiMe3

-intramolecular reactions also work well + PdL2 SiMe3 Pd(dppe)2 H - CO2Me CO2Me OAc MeO2C H

-other aspects of the stereochemistry (i.e., diastereoselectivity) have been well established, but are beyond the course's scope Regiochemistry OAc R OAc OAc R = alkyl R or or R electron withdrawing electron donating SiMe 3 SiMe3 SiMe3 -regardless, it doesn't matter (much), -the produc is as if...... + + - EWG L2Pd L Pd EWG R EWG 2 - R R

97 -no real mechanistic explanation for this result -example of use in synthesis - loganin H O H O CO2Me Pd(OAc)2 SiMe3 1) O3 + + OAc (iPrO) P 2) MeOH, H 3 H H 1:1 ratio 3) NaOMe

H CO2Me H CO2Me racemic loganin O (key intermediate in alkaloid biosynthesis) O O H H O-beta-D-glu OCH3

-there is some work on reacting TMM-Pd complexes with C=O and C=N-EWG in the

presence of R3Sn-X co-catalysts -see Trost, B. M. et al J. Am. Chem. Soc. 1990, 112, 408. Trost, B. M. et al J. Am. Chem. Soc. 1993, 115, 6636. For reviews in the area see: Trost R Angew. Chem. Int. Ed. Engl. 1986, 25, 1. R Pure Appl. Chem. 1988, 60, 1615. R 'Comprehensive Organic Synthesis' V. 5, p. 271 (1991) R Org. React. 2002, 61, 1.

Iron tricarbonyl - trimethylenemethane complexes also known see Donaldson, W.A. J. Org. Chem. 1995, 60, 1611. 98 Frank-Neumann, M. Tetrahedron: Asymm. 1996, 7, 3193. Fe(CO)3 R Green, J. R.; Donaldson, W.A. 'Encyclopedia of Inorganic Chemistry, Vol. 4, 1994 η4-Diene Complexes Fe(CO) -absolutely dominated by iron tricarbonyl complexes 3 Preparation

Me NO or Δ + 3 + Fe(CO) Fe2(CO)9 5 hν, or Δ Fe(CO)3 -more subtle reagents (CO) Fe Δ low T + 3 Ph Fe(CO)3 2 Fe(CO) O 3 Fleckner, H.; Grevels, F.W.; Hess, D. J. Am. Chem. Soc. 1984, 106, 2027.

Me3NO mediated transfer Shvo, Y.; Hazum, E. J. Chem. Soc. Chem. Commun. 1975, 829

-the Fe(CO)3 unit is unusually stable; even in cases where it could lose more CO ligands, it normally does not

Ph Ph (CO)3Fe Ph Ph Ph Fe (CO) R O O R O 2 9 R R Δ (CO) Fe Fe(CO)3 3 Note: esters, amides only form η2-Fe(CO) complexes Reviews 4 R Pearson, A.J. 'Iron Compounds in Organic Synthesis, Ch. 4, 1994. R Green., J. R,; Donaldson, W. A. 'Encyclopedia of Inorganic Chemistry, 1994, Vol. 4 R Gree, R. Lellouche, J. P. Adv. Met.-Org. Chem. 1995, 4, Ch.4 R King, R.B. 'The Organic Chemistry of Iron', Vol. 1, 1978. 99 Rare/specialty methods

Agar, J.; Kaplan, F.; Roberts, B. W. J. Org. Chem. 1974, 39, 3451. O Fe(CO)5 hν, -CO Very stable complex R O 2 R -by contrast, free cyclobutadiene is not at all stable Fe(CO)3

MeO2C Fe2(CO)9 rare: ring opening is actually stereospecific Fe(CO) MeO C 3 Whitesides, T.H. J. Organomet. Chem. 1974, 67, 99. 2 MeO2C CO2Me

Molybdenum dienes complexes + + - CpMo(CO) CpMo(CO)2 Ph C BF 2 Na[(CO)3MoCp] hν 3 4 Br (CO) Mo or 3 + + NO PF6 + CpMo(CO) Br BrMo(CO) (MeCN) 2 CpMo(CO) Mo(CO)3(MeCN)3 2 2 2

+ - + Δ Na Cp Ph3C

R + R Mo(CO) (MeCN) Green, M. et al + 2 2 J. Chem. Soc., Chem. - Commun. 1985, 18. BF4 + (CO)2Mo

R Comprehensive Organometallic Chemistry, V.3, Ch 27.2 R Pearson, A. J. Adv. Met-Org. Chem. 1989, 1, 1. 100 Early Transition Metal Complexes R Cp2MCl2 + Cp M Cp2M 2 * Mg C C n * M = Ti, Zr H2 H2

R Yasuda, H.; Nakamura, A. Angew. Chem. Int. Ed. Engl. 1987, 26, 723. Cp2M 2. Decomplexation of η4-Diene Complexes a) Oxidation of Iron-Diene Complexes CH(CO Et) 2 2 CH(CO2Et)2 Me3NO FeCl3 OMe OMe RO RO Fe(CO)3 Fe(CO) Shvo, Y.; Hazum, E. J. Chem. Soc., Chem. Commun. 3 1974, 336.

IV I Other oxidants such as Ce , CuCl2, Ag work also

b) Early Transition Metal Dienes -have reactivity like..... (D) - H and therefore H2O Cp2Zr Cp Zr (D O) 2 2 101H(D) - notice regiochemistry 3. Use as Protecting/Stabilizing Groups

a) Protection of Dienes

-although coordination of a diene by Fe(CO)3 is inductively a slight electron donor, the reactivity of dienes to electrophiles is reduced

therefore 1) "BH " FeCl 3 3 OH OH 2) H O 2 2 Fe(CO)3 Fe(CO)3 OH

a b HO

RO RO RO Fe(CO) 3 b. i.,OsO a. i., H2, PtO2, PhCH2SiMe2H 4 ii., FeCl ii., FeCl3 3

-Carbenes - normally prefer to add to conjugated dienes over isolated C=C 's, but.... Cl Cl

Cl II Cl CHCl3 Cu tBuO- Cl Fe(CO) Fe(CO) 3 :C 3 102 Cl -and acylation* O

H3C Cl Fe(CO) Fe(CO)3 o H C(O)C 3 AlCl3, -78 3

* - diene-Fe(CO)3 complexes will also react, but more slowly -one can even do cycloadditions on free double bonds in the presence of

Fe(CO)3 complexes O O [4+2] PtO N N 2 N-CH3 CH N-CH3 N 3 N H Fe(CO) (CO) Fe N Fe(CO) 2 3 O 3 O O 3 O N N H H Me + N Me H N H Me NO H N N Δ H 3 O O O 84% O >90% (CO) Fe 75% 3 (CO) Fe (CO)3Fe 3

-also stable to Wittig reaction, aldol condensations, osmylation (dihydroxylation)

-exception (sort of) - let's say 'controlled' reactivity O consider v. non-selective reaction/oligomerization Cl 103 a mess AlCl3 -conversely,.. O + Fe(CO)3 (CO) Fe O -H+ 3 O (CO)3Fe (CO) Fe Cl CH + 3 3 CH AlCl3 O 3 CH3 stabilized intermediate depending upon conditions

-the reactivity is lower, but much more controlled PPh 3 PPh3 + O (CO) Fe Fe(CO)2PPh3 o 2 1) AlCl , -78 (CO)2Fe 3 O O Cl 96% CH3 + -H CH3 2) H2O H H

b) Stabilization of (overly) Reactive Species i) consider cyclobutane Fe(CO) Fe(CO) -classic antiaromatic compound 3 3 -'cannot' be isolated -very stable compounds R O hν Cl Fe2(CO)9 Fe(CO) O 5 R Fe(CO)3 Cl -stable enough to allow standard aromatic functionalization reactions - behaves pretty104 much like benzene -these cyclobutadiene-Fe(CO)3 complexes are stable enough to allow standard aromatic functionalization reaction - they behave pretty much like benzene

OH O O O H

Cl Fe(CO)3 Fe(CO)3 NaBH Fe(CO)3 4 AlCl3 POCl 3 O D Ph D+ N H

CH3 HO

Fe(CO)3 Fe(CO) CH O, 3 CH O, 2 2 Fe(CO) HCl 3 Me NH Hg(OAc) , Me2N 2 2 NaCl Cl

Fe(CO)3 ClHg Fe(CO)3

Fe(CO)3 Rosenblim, M.; et al J. Am. Chem. Soc. 1972, 94, 1239 Emerson, G.F.; Pettit, R., et al J. Am. Chem. Soc. 1975, 97, 3255. 105 R Green, J. R.; Donaldson, W.A. 'Encyclopedia of Inorganic Chemistry', Vol. 4, 1735, 1994. Note: Decomplexation of Fe leads to free cyclobutadiene, which can be trapped by other reagents

CeIV, FeIII, R R' R Δ R or Me NO 3 R' Fe(CO)3 R'

Pettit, R. J. Am. Chem. Soc. 1965, 87, 3253. Snapper, M.

ii) Dienols H not unstable R OH R O per se, but...

Fe(CO)3 coordinates more strongly to the π-system of a C=C relative to a C=O, so.... Fe (CO) 1) MeLi R O 2 9 R O R OH does not CH tautomerize CH3 3 2) H O 2 to aldehyde O (CO)3Fe O (CO)3Fe

HO R O R R OH Ph (CO)3Fe O

(CO)3Fe (CO)3Fe is similar, except it 106 isomerizes to.... iii) OMe O H2O OH

+ Fe(CO)3 Fe(CO)n Fe(CO)3 -almost nothing has been done with this, but it has much potential.... see Birch, A. J. Tetrahedron Lett. 1975, 119 (Org. Synth. VI, 996)

iv) Other examples (CO) Fe O 3 Landesberg, J.M.; Roth, W.R.; Neier, J.D. Sieczkowski, J. Tetrahedron Lett. 1967, 2053. J. Am. Chem. Soc. 1971, 93, 972

Fe(CO)3 4. η4 Diene Iron Complexes as Electrophiles -iron diene complexes will react with nucleophiles, although the pathways are a bit complex - - + - Nu Fe(CO) Nu H Nu Nu 3 A - thermod, kinetic, R R Fe(CO) o R 3 0 Fe(CO)3 -78o R Nu H+ CO Et Nucleophiles are restricted CN - 2 - to things like...... - Ph Ph SS - Semmelhack, M.F. J. Am. Chem. Soc. 1984, 106, 2715. R Nu107 -in cyclohexadiene complexes, species like A do further chemistry

CF CO H R 3 2 + R- R R R + + Fe(CO) - 3 Fe(CO) 3 major E O CO E+ R R

O - E = H, OH (O2), or ROSO2R Fe(CO)3 -see R Pearson, A.J. 'Iron Compounds in Organic Synthesis, p. 67-97. in acyclic dienes, get related but more complicated reaction pathway -see Semmelhack, M. F. Organometallics 1983, 2 1385 ; J. Am. Chem. Soc. 1985, 107, 1455. Yeh, M.C.P.; Hwu, C.C. J. Organometal. Chem. 1991, 419, 341. Chang, S. et al (M. Brookhart) J. Am. Chem. Soc. 1994, 116, 1869. b) Molybdenum Diene Complexes -these complexes are cationic, so that they obviously are a good choice for being more reactive as electrophiles

+ CpMo(CO) 2 - CpMo(CO) Nu 2 C-1 attack Nu 108 -range of nucleophiles should start looking familiar

-enamines - highly stabilized enolates CH(CO2Et)2 Grignards, or better NR2 still, cuprates

RMgBr, R2CuLi, R(CN)CuZnI

+ O Cp(CO)2Mo Mo(CO)2Cp 1) N O H 2) workup

+ O Mo(CO) Cp Mo(CO)2Cp 2 E, E' = -CO2Me, -SO2Ph, CH3 -CH(E)(E') E E' Note: Mo(CO) Cp Mo(CO) Cp 2 2 Na/Hg

CO2Me CO2Me SO Ph 2 109 + Mo(CO) Cp Mo(CO) Cp 2 MeMgBr 2

CH 3 CH3 H C CH Mo(CO) Cp 3 3 + 2 Note: Cp* = Mo(CO) Cp* 2 C5H11 H3C CH3 LiCu 2 C5H11 can be a ligand on Mo instead of Cp Stereochemistry -it is apparent from the above examples that the addition is routinely anti to Mo

Regiochemistry -the nucleophile's attack is generally at the less substituted end of the diene

+ Mo(CO) Ind O H C 2 1) N Ind(CO) Mo 3 2 O H3C 2) workup H H3C (CO)2Mo(MeCN)2 + η5-indenyl can be a ligand instead of Cp 110 Note; product allylMo has anti stereochemistry at addition site -tandem reactions are also feasible sterically available H + Ph3C CH MeMgBr CH MeMgX CH 3 3 H 3 CH (-H-) H H 3 H CpMo(CO) H CpMo(CO) 2 CpMo(CO)2 2 + CpMo(CO) + 2 not sterically available

Decomplexation Reactions of molybdenum Complexes -straight oxidative decomplexation does occur for diene complexes

Me NO C H 3 5 11 C5H11 MeCN (CO)2MoCp* +

-oxidative decomplexation of allylMo's with nucleophilic attack

Nu Nu I2 attack trans I Nu

H H to Mo H H CpMo(CO) CpMo(CO)2 2 +. 111 -oxidative decomplexation can occur with nucleophilic addition Mo(CO) Cp I 2 KOH Mo(CO) Cp 2 or 2 O NOPF6 O CO2Me CO2H -note stereochemistry R Pearson, A.J. Adv. Met. Org. Chem. 1989, 1, 1. R Backvall, J.-E. Adv. Met. Org. Chem. 1989, 1, 135. (mostly Pd catalyzed addns) asymmetric addns Pearson, A.J. et al Tetrahedron Lett. 1987, 28, 2459 c) we will not discuss this in detail, but PdII catalyzed additions to dienes is known

Nu- Nu R R R PdII, oxidant R Nu

- - Nucleophile is usually R2N or AcO ; oxidant is usually benzoquinone some cases of C-C bond formation -see Backvall review

112 η4-Diene Complexes as Nucleophiles

-early transition metal diene complexes don't really behave like dienes

-dominated by Cp2Zr complexes -

Cp Zr behaves like Cp Zr 2 2 -

-therefore, the zirconium dienes are reactive as nucleophiles, especially with oxygen containing electrophiles, where =O: coordination to Zr can increase the electrophilicity of C=O

1)E+ E Cp2Zr 2) workup

Regiochemistry -if a substituent is at the 2-position of the diene, the rxn occurs at the more substituted end O R R' + OH O H notice difference in R R' Cp Zr R R' product isomer Cp2Zr 2 dependence on acid vs. NH base cleavage or OH } NH R R' 113 -in acid, the allylZr cleaves via SE2' (remote end, much like allylsilanes) -in base, the product is the result of direct C-Zr bond cleavage

-other oxygen bearing E+'s include...... esters (or nitriles), and epoxides

O 1) 2) H+ R OR' R Cp Zr 2 or O 1) RCN 2) H+ Note: Rxn is at the more substituted O end of the epoxide - 1) R M M OH O O Cp Zr R + 2 2) H+ R R R = aryl, vinyl

-that is evidence of SN1 - type reactivity -further evidence is the loss of stereochemical integrity of the epoxide, i.e.,

O Ph Ph + Ph Me O O Cp2Zr O Cp Zr - Cp Zr or 2 2 Ph Me both epoxides give same isomeric mixture 114 α, β-unstaurated carbonyls -give high 1,2-addition R OR' 1) 1) Cp Zr O OH Cp Zr O 2 2 O 2) H+ 2) H+

Other electrophiles

CO2 H+ CO2 Cp*2Zr Cp* Zr Cp*2Zr O 2 O O O HO O But in many cases, further reaction can't be stopped Isocyanates NR

R-N=C=O O Cp Zr Cp2Zr 2

Photochemical Reactions

-with carbonyl compounds and alkenes/alkynes, a photochemical reaction occurs at o much lower T (-70 ) 115 -one big difference - the reaction now occurs away from a 2-substitutent carbonyls O R R R R C=O oxidative O R H+ R R 2 Cp Zr O 2 R Cp2Zr R HO Cp Zr 2 hν coupling Cp2Zr

alkenes/alkynes

R3

Cp2Zr hν Cp2Zr R3 Cp2Zr R3 Metal carbonyls M(CO) O O 6 M(CO)5 C Cp2Zr Cp2Zr M(CO) Cp2Zr M = Cr, W, Mo 5 Cp2Zr O M(CO)5

CpCo(CO)2 is similar Finally, at least for some products, the allylZr products themselves can be reacted with carbonyls R R O carbonyl, metal carbonyl adducts do this to R2C=O Cp2Zr -always get 9-membered ring with trans C=C Cp2Zr

see R Yasuda, H.; Nakamura, H. Angew. Chem. Int. Ed. Engl. 1987, 26, 723. R Taber, D. F. et al Curr. Org. Chem. 2000, 4, 809.

other Fe diene review R Gree, R. Synthesis 1989, 342. 116 η5-Dienyl Complexes

-dominated by and to a much lesser extent by R complexes - Cr(CO)3 (CO)3Fe+ we will cover this under η6- complexes

authors -dominated by A.J. Birch initially -more recently by A.J. Pearson (Case Western) W.A. Donaldson (Marquette) (acyclics)

Generation of η5-Cationic Complexes -most commonly made by hydride abstraction from diene complexes, normally by trityl cation

- Ph + Ph H source C BF4 Ph3C-H Ph triphenylmethyl (trityl) cation -thus.... + -works very well for cyclic dienes, Fe(CO)3 as adjacent substituent must Ph C+BF - 3 4 - be cis BF4 Fe(CO)3 117 -with acyclc dienes, one can normally abstract H- is the source is cis i.e.,

+ Ph3C + (CO)3Fe (CO)3Fe

-but, if the "H- source' can only be trans, the abstraction usually fails

+ - + PF - + Ph3C PF6 6 Ph3C Fe(CO) Fe(CO)3 3 (CO)3Fe no rxn

Regiochemistry of Hydride Abstraction -this abstraction s usually pretty selective, but not that readily predictable. It does not correspond to the most stable cation

-Pearson has made an orbital interaction based explanation - for those interested, see. Pearson, A.J. et al Organometallics 1984, 3, 1150.

-examples + MeO 1 OMe MeO Fe(CO) 2 3 + Hb Hb + Fe(CO)3 Fe(CO)3 Ha Ha R R R 3 H abstraction H abstraction 4 b a 118 RHb abstraction Ha abstraction

H 20 80 3-CH 3 0 100 4-CH 3 90 10 3-OCH 3 N O 56 44 4-morpholino 100 0 + 1 2 Fe(CO) Hb OMe 3 Hb OMe OMe Fe(CO)3 + Fe(CO) + 3 R Ha Ha R R 3 H abstraction H abstraction 4 a b R ro Ha abstraction Hb abstraction

H 90 10 1-CO2Me 0 100 4-CO2Me 100 0 4-CH3 100 0 4-OCH3 56 44

-the most common method for formation of acyclic pentadienyliron complexes is by protonation of an η4−dienyl alcohol complex by a strong acid 119 + Fe(CO)3 + + Fe(CO)3 H Fe(CO)3 HO R R R

see R Donaldson, W.A. Aldrichim. Acta 1997, 30, 17. also Magyar, E.S. et al Inorg. Chem. 1978, 17, 1775. Beihl, E.R. et al J. Organomet. Chem. 1979, 174, 297.

-there are related methods for preparation of dienylirons, from carbonyls, alkenes (trienes)

Fe(CO) o + 3 + + -28 Fe(CO)3 H Fe(CO)3 O HO R R H HO R H

Fe(CO) 3 +Fe(CO) HBF4 + 3 Fe(CO)3 R propionic anhydride R H3C R H3C

D CF3CO2D notice the stereochemistry of attack o D + D -78 , CH2Cl2 Fe(CO) J. Chem. Soc., Dalton Trans. 1977, 794120 and 2340 Fe(CO)3 3 -from alkoxy-substituted diene complexes and strong acid

OMe OMe OMe 1) H2SO4 Fe(CO)5 or + Fe(CO)3 + Fe(CO) Fe(CO) 3 2) NH PF 3 Fe2(CO)9 4 6 Birch redn 2:1

This goes via....

OMe MeO D MeO D + D + D2SO4 -H +H , -MeOH + Fe(CO) Fe(CO) 3 + 3 Fe(CO) H 3 Fe(CO)3 -and MeO H H OMe OMe -MeOH Fe(CO) Fe(CO) D D + 3 D 3 Fe(CO) + + 3 D SO Fe(CO) 2 4 H 3

-by cation rearrangement

OH H + H+ hydride + or Fe(CO) Fe(CO) 3 3 Fe(CO) 3 Fe(CO)3 transfer 121 Reactions as Electrophiles Nucleophilic Attack on η5-Complexes

-these cations readily react (normally) with nucleophiles to give C-C or C-heteroatom bond formation

-attack is from the exo- face (stereoselective, away from iron) -'normal' mode of attack is at C-1 terminus

Nucleophiles: C-C bonds O O enolates work OSiMe only 3 N - EtO C CO Et R' 2 2 R' enamines sometimes - R R stabilized enolates silyl enol ethers silyl ketene acetals

SiMe 3 allylsilanes RLi, RMgBr usually fail R Cd, R Zn, R CuLi, RCu(CN)ZnI usually better SnBu3 allyltins 2 2 2

C-X bonds

- R2NH (amines), H2O, MeO , R3P (phosphines), (RO)3P (phosphites), R3As (arsines)

NaBH4, Et3SiH, NaBH3CN (hydride sources)

Regiochemistry, part II -attack of the nucleophiles is at less substituted terminus -MeO as a substitutent is particularly powerful in this respect 122 OMe -enamine example OMe O + 1) N Fe(CO)3 -regiochem away from OMe Fe(CO)3 -sterochem exo (away from iron)

2) H2O O

CH NaCH(CO Me) 3 2 2 CH3

+ Fe(CO)3 MeO2C Fe(CO)3 MeO2C

CO2Me CO2Me + NaCH(CO2Me)2 Fe(CO) Fe(CO)3 3 MeO2C

MeO2C

MeO C + 2 Fe(CO) Fe(CO) NaCH(CO Me) 3 3 2 2 Fe(CO) MeO2C 3 + OMe OMe OMe MeO C CO Me 82:18 2 2 123 counterion dependent OMe OR OSiMe + 3 Fe(CO)3 Fe(CO)3 OMe CO2Me

R = Me, iPr see R Pearson, A.J., in Comprehensive Organometallic Chemistry, Vol. 8, p 939-1011 R Comprehensive Organic Synthesis, 1991, Vol. 4, p. 663-694 R Iron Compounds in Organic Synthesis, 1994, Ch.5 R Adv. Met-Org. Chem. 1989, 1, 1

R Harrington, P.J. Transition Metals in Total Synthesis, Ch. 4

The acyclic cases have also been studied fairly extensively

+ (CO)3Fe Fe(CO) R' CuLi2 R = Me, Ph, CO Me 3 3 2

o R Et2O/THF, -65 R R' (CO) Fe PhCH CH Cu(CN)ZnBr 3 2 2 Donaldson, W. A. et al Tetrahedron Lett. 1989, 30, 1339. R = Me H3C

- Also, RNH2, H2O, R2Cd, R'-CC-SiMe3 + F , NaBH3CN, 124 silyl enol ethers, allylsilanes (give trans products), and NaCH(CO2Et)2 in many cases There are, though, at least a few regiochemical exceptions.... + Fe(CO)3 CO2Me CeIV LiCH(CO2Et)2 (MeO2C)2CH MeO C RO C 2 MeOH 2 RO C RO C 2 2 H Fe(CO)3 C-2 attack see Donaldson reviews....most recent.. R Donaldson, W. A. Curr. Org. Chem. 2000, 4, 837 R Donaldson, W. A. Aldrichim. Acta 1997, 30, 17

-geometry of pentadienyl thermodynamically prefers a "U" shape, but if it's generated with an "S" shape, it will keep that conformation (configuration?) until about -30o

BF3-OEt2 Nu OAc R1 - o R R Nu , -78 1 1 (CO)3Fe R2 (CO)3Fe R2 (CO)3Fe R2 + -reacts before isomerization occurs, therefore retention Uemura, M. et al Tetrahedron Lett. 1987, 28, 641; Roush, W.R. et al Tetrahedron Lett. 1994, 35, 7347 and 7351. + + Fe(CO) Fe(CO) (P(OPh) 3 doesn't work; 2 3 Pearson's solution nucleophiles -see book deprotonate 125 instead Synthetic Utility -widely used by Pearson's and Knolker's groups R Synlett 1992, 371 R Chem. Soc. Rev. 1999, 28, 151. R Pearson, A.J. Acc. Chem. Res. 1980, 13, 463.

Example: as equivalent of cyclohexenone γ-cation O +

OMe - OMe OMe 1) HO OMe + - 1) Ph3C BF4 + Fe(CO)5 2) MeLi Fe(CO) Fe(CO)3 Fe(CO)3 3 Δ + - 3) NaH, 2) NH4 PF6 ( ) O 3 CO Me 2 ( )3 CO Me CO2Me CO2Me 2 MeO OMe O O O Et N, CH Cl OMe 3 2 2 1) Me NO Fe(CO)3 3 -78o 2) H O+ 3 (dilute) CO2Me CO2Me

O O

and OPr-i OPr-i 1) p-TsOH OPr-i + Ph C+BF - 3 4 Fe(CO)3 KH(CO2Me)2 Fe(CO)3 2) Fe (CO) , THF 2 9 CH2Cl2 o OMe OMe 30 OMe 126 OPr-i OPr-i OPr-i 1) KCN, DMSO, 1) p-TSCl, Fe(CO) Fe(CO) Fe(CO)3 3 Δ, -CO2 3 pyridine CO Me 2) iBu AlH, THF 2) NaCN, 2 2 OH CN -78o - RT HMPA CO Me MeO 2 MeO MeO major

OPr-i O 1)oxalic 1) Me NO 3 acid H H benzene (aq) O N

2) LiAlH4 2) NaHCO3 NH NH OMe MeO 2 MeO 2

N

OH (+/-)-limaspermine

N H

O

Other Pearson reviews: R Science 1984, 223, 895; R Pure Appl. Chem. 1983, 55, 1767; R Chem. Ind. 1982, 741; R Knolker, H.J. Chem. Soc. Rev. 1999, 28, 151. 127 Acyclics - synthesis of 5-HETE methyl ester + PF - (CO) Fe (CO)3Fe 6 H11C5 C Li 3 H2 H2, Lindlar cat.

MeO C o MeO2C + CuBr-Me2S, Et2O/THF, 2 90 >92%ee -45o 60% O (CO) Fe 1) CuLi2 (CO) Fe 3 O 3 1) DIBAL-H, 92% O 3 H 2)MnO , 65% MeO C 2 2) pTsOH, H2O/THF 2 O 3)MeOH, K2CO3

(CO)3Fe +4 (R)-HETE methyl ester H Ce H HO HO >93% ee 86%

MeO2C MeO2C 5-hydroxyeicosatrienoic acid (HETE) + diastereomer (S) enantiomer

Tao, C.; Donaldson, W.A. J. Org. Chem. 1993, 58, 2134.

For other metal pentadienyls, see:

R Ernst, R.D. Chem. Rev. 1988, 88, 1255. R Powell, P. Adv. Organomet. Chem. 1986, 26, 125. 128 η6-Triene Metal Complexes -dominated by h6-benzene metal complexes -very extensively developed; many, many complexes known Order of Utility

>>> > + 2+ Fe Mn + Fe Cr(CO)3 OCCO L

Preparation of Complexes Chromium a) Standard method - Arene + Cr(CO)6 + heat R R Bu O:THF (10:1) 2 + 3CO + Cr(CO)6 Δ Cr(CO)3

b) milder conditions - arene +L3Cr(CO)3 L = is often acetonitrile - requires only ca. 70o R R THF + (MeCN) Cr(CO) + 3 MeCN 3 6 Δ 129 Cr(CO)3 c) by arene exchange - one of the most weakly bound arenes is naphthalene, so R R Δ + +

Cr(CO)3 Cr(CO)3 equilibrium is well to the right, normally Kundig, E.P. et al J. Organomet.Chem. 1985, 286, 183.

d) Photolysis R R hν, RT + 3CO + Cr(CO)6

Cr(CO)3

e) last resort, from Cr(CO)(4-picoline)3 + Lewis acid R R often works in the most BF -OEt 3 2 sensitive cases + (CO)3Cr N 3 Cr(CO)3 Br I i.e., don't work at all under normal conditions, , due to oxidative addition

They do complex under these conditions, although the yields are poor 130 Ofele, K. Chem. Ber. 1966, 99, 1732. Complexes of Mn Cl 100o Cl (CO) MnBr + 5 + AlCl3 4h or Mn(CO) Cl +Mn(CO) 8 2 + HBF4/TFA 3 Cl Cl + TFA Mn2(CO)10 + HBF4 Δ + Mn(CO)3

+ Mn(CO)3

R Sun. S.; Dullaghan, C.A.; Sweigart, D. A. J. Chem. Soc., Dalton Trans. 1996, 4493.

Complexes of Iron a) Ligand exchange with ferrocene

2 AlCl H O HPF R 3 2 - 6 + - + - Fe + Cl Fe PF6 Fe + Fe AlCl4 Al R R R 131 b)using the metal Cp-halides AlCl R 3 + + AlCl - Fe Fe 4 OC Cl CO R

original prep, but not used much any more for Cp complexes -for Cp* complexes, though, it's the default way R Astruc, D.Tetrahedron 1983, 39, 4027. R Kündig, E.P. Top. Organomet. Chem. 2004, 7, 3. AlCl R 3 + + AlCl - Fe Fe 4 OC ca. 90o Br R CO

Electronic Effects in η6-Complexes

-complexation of the arene by Cr(CO)3 clearly results in a net withdrawal of π-electron density

is a weaker base than NH2 NH2

Cr(CO)3

and CO H pK 4.77 pK 5.52 pK 5.68 2 a CO2H a CO2H a

Cr(CO)3 (MeO)3PCr(CO)2 132 Consider O N CO H 2 2 pKa 4.48

Therefore, is often considered electronically O2N equal to......

Cr(CO)3 -this inductive lectron withdrawing ability, as well as resonance electron donating and

resonance electron withdrawing ability, contributes to the reactions that arene-Cr(CO)3 will undergo -we will discuss these as we encounter them

Nucleophilic Additions to Arene-M R Pape, A.; Kaliappan, K.P.; Kundig, E.P. Chem. Rev. 2000, 100, 2917. R Top. Organometal. Chem. 2004, 7, Ch.4 background Nu - H + Nu -

is not normally a commonly feasible reaction, unless the arene has some strongly electron withdrawing group(s) on it...

But.... Nu H + Nu- further reaction - Cr(CO)3 Cr(CO)3 133 is absolutely viable A -in 'normal' cases, nucleophiles which work in this process are limited to ones whose + conjugate acid (i.e., Nu-H ) has a pKa > 20 -therefore, successful nucelophiles include...

LiCH CO R, LiCH CN, KCH CO tBu, LiCHCN(OR), LiCH SPh, PhLi, 2 2 2 2 2 2 SS, Li H Li R , Li , tBuLi

Unsuccessful ones.. R LiCH(CO R) , R 2 2 Li , Grignards, Me2CuLi O O Li Note: nBuLi, MeLi, sBuLi do different reactions

So what does one do with the reaction intermediates, i.e., A ? Chem. Eur. J. 1998, 4, 251; Helv. Chem. Acta 1997, 80, 2023. R I R H 2 R

Cr(CO)3 -Cr(CO) several instances 3 not that reliable 1) CF CO H E+ 3 2 O 2) I2 E R R in some cases 134 R Kundig, E.P.; Pape, A. Top. Organomet. Chem. 1994, 7, CH5 Regiochemistry of Nucleophilic Attack R Nu R R Nu- I2 R R H Nu Nu Cr(CO)3 - Nu Cr(CO)3 o- m- p-

-do get mixtures under these conditions, but the general rules are......

meta (major) R = electron donating (-OCH3, -CH3, -NMe2) t t R = electron donating and large (-SiMe3, - Bu, -CH( Bu)2) para (major)

R = electron withdrawing (i.e, CF3) para (major) R = electron withdrawing and coordinating ortho -considerable variation with size of nucleophile -sterically smaller nucleophiles, such as -CH SPh, 2 SS give substantial ortho substitution - -Note: these are under kinetic conditions (-78o) Why this regiochemistry? -best guess - a combination of charge and orbital control -charge control - charge induced by preferred M-CO conformation -arene C's eclipsed by Cr-CO are attacked preferentially EDG EWG Bulky

135 Frontier Orbital Control -attack occurs at the lowest unoccupied arene centred M.O. (LUMO)

EDG EWG LUMO coefficients

-the argument is that if there is a good energy match between the LUMO of the arene-Cr(CO)3 and the HOMO of the nucleophile, then orbital control is favoured -in the absence of this match, charge control operates see Semmelhack, M.F. et al Organometallics 1983, 2, 467.

Thermodynamic Control

-it was later realized that this addition to the arene-Cr(CO)3 is reversible in many cases; this has a couple of consequences

1) if there is a leaving group present, one should be able to.....

Nu Nu -X- X H Nu- Nu- X X Nu

- - Cr(CO)3 Cr(CO) Cr(CO)3 3 Cr(CO)3

-this is possible, especially for X = F X = F > Cl, OPh >> others 136 2) some nucleophiles which don't give noticeable amounts of additionin non-X bearing cases now work well

- - i.e, NaOMe,, R2NH, CN, CH(CO2Et)2 now work

thus -CH(CO Et) CO Et Cl 2 2 2 Semmelhack, M.F. et al J. Am. Chem. Soc. 1974, 96, 7091, 7092. 25o, 20h CO Et Cr(CO) 2 3 Cr(CO)3 -another consequence -difference in regiochemistry of addition at different T -apparent that methoxy still prefers to be meta- to nucleophile under thermodynamic conditions -other substituents are much less predictable CN Examples 1) LiC(Me) CN o 2 + -70 , 1 min 35:64 o NC -70 , 8.6 h 02:97 N 2) I2 N N (CO)3Cr

NC o 1) N -78 , THF 72:28 Li + 0o, THF 03:97 CN Cr(CO) 2) H+ 3 NC 3) I2 Semmelhack, M.F. et al J. Am. Chem. Soc. 1977, 99, 959; Ohlsson, B.; Ullenius, C. J. Organomet. Chem. 1984, 267137, C34 Note: A couple of nucleophiles that do add kinetically do not undergo reversible reaction

Kundig, E.P. et al J. Am. Chem. Soc. 1989, 111, 1804. - t SS, CH2SPh, PhLi, BuLi R Kundig, E.P. Pure Appl. Chem. 1985, 57, 1855. -

Reaction with protic workup

-if a careful work is done using a proton source instead of I2, one gets reduced arene complex which then loses Cr easily - since the transient complex is coordinatively unsaturated (16e-) Cr, hydride shifts occur readily and one gets diene rearrangement

CN CN 1) Li CN H+ H shift CN H H H 2) H+ Cr(CO) (CO) Cr H 3 - 3 (CO)3Cr Cr(CO)3

B I2 predominant substitution regiochemistry CN

-except NC same conds methoxy has very high preference OCH3 for 1-position

Cr(CO)3 OCH3 Alkylation of anionic intermediates

- t -if the incorporated Nu is one of the irreversible ones SS, PhLi, BuLi -then the anionic intermediate B can be alkylated with 1o alkyl,- allylic, benzylic, propargylic iodides, bromides, or sulphonates, 138 BUT(!), the reaction usually goes with CO insertion (there are exceptions) S SS S S 1) CH3I, CO - notice stereochemistry S E+ attacks from same H CH 2) I2 or PPh3 3 side as the metal Cr(CO)3 B O -therefore, trans addn - Cr(CO)3 -conversely, nucleophiles which add reversibly fail

CN Br CN H - CN + + - Cr(CO) Cr(CO) Cr(CO) 3 3 3

-another successful example MeO O CH MeO 3 Kundig, E.P. J. Org. Chem. 1994, 59, 4773. 1) PhLi Ph Top. Organomet. Chem. 2004, 7, ch 5 2) MeI, CO 3) I MeO Cr(CO) 2 3 MeO

Improving Reactivity - Other Metals

-definite limits on the nucelophilic attack on arene-Cr(CO)3 139 -therefore, there is some use for other, more electrophilic, M-arene complexes here The relative rates of reaction of many of the complexes are known

+ 2+ 2+ Fe Mn + Ru Fe Cr(CO)3 OCCO CO v. small 1 11,000 6 x 106 2 x 108

+ Consider arene-Mn (CO)3 Nu Nu- = MeLi, PhLi, RMgBr, H-, Nu- H NaCH(CO2Et)2, O O Mn + - Mn(CO) R R OCCO CO 3 - Note: CN and :PPh3 add, but are reversible -so what now? Nu Nu CF CO H CrO , H SO 3 2 H 3 2 4 Nu (MeCN) Mn+(CO) + 3 3 acetone MeCN

Mn(CO)3 -other chemistry is possible with the intermediate dienyls, but it's beyond the scope of the course

R Pike, R. D.; Sweigart, D.A. Synlett 1990, 565; J. Chem. Soc. Dalton Trans 1996, 4493. 140 -and if there is a leaving group on the arene, the concept is the same, but the reversible nucleophiles are a different group

Nu- X Nu -nucleophiles which can add reversibly and or NuH Mn + + therefore do this include Mn MeO-, PhO-, PhS-, N -, R NH OC CO 3 2 CO OCCO CO X = Cl, Br, F but not H-, R-, Ph-

-the regiochemistry of kinetic substitutions are not as thoroughly studied, but what's available shows the same general trends i.e., EWG directs ortho- attack (para is usually blocked in Mn studies) EDG directs meta- attack H H X = Cl 69:37 LiAlH 4 X + X X X = NMe2 3:97 Mn Mn Mn + OC CO CO OCCO CO OCCO CO

Pauson, P.L. et al J. Chem. Soc., Dalton Trans. 1975, 1677 and 1683 Kane-Maguire, L.A.P.; Sweigart, D.A. Inorg. Chem. 1979, 48, 700. Pearson, A.J. Tetrahedron 1992, 48, 7527 J. Org. Chem. 1991, 56, 7092. 141 And the Cp-Fe+-arenes? R DDQ H R + RLi O + Cl CN Fe Fe Cl CN O R = Me, Et, Ph, PhCH2MgBr

-here, there are more examples of successful examples of hydride abstraction to get back the complex R with the exception of benzyl H Ph C+ Ph 3 R Ph C+ + H 3 Fe Fe + PhCH2CPh3 + Fe Fe

R Astruc, D. Tetrahedron 1983, 39, 4027. R Adb-El Aziz, A.S.; Bernardin, S. Chem. Soc. Rev. 2000, 203, 219.

A similar reaction pattern for substitutions are observed with the haloarenes

X MeO- OMe

+ + - - - - Fe Fe Nu = PhO , RO , RS , R2NH, NaCH(EWG)2 142 -fairly analogous trend is seen in the kinetic regiochemistry EWG - ortho attack EDG - meta attack H H - H H H- MeO H CO2Me OMe + CO Me + Fe Fe 2 Fe Fe

McGreer, J . F.; Watts, W.E. J. Organomet. Chem. 1976, 110, 103 Clack, D.W.; Kane-Maguire, L.A.P. J. Organomet. Chem. 1979, 174, 199.

Reactions on are very similar 2+ -see Astruc review if interested Fe

Effect #2 of electron withdrawing effect of arene-Cr(CO)3 -enahanced acidity of arene ring protons reaction is feasible, but.....pK 's are 38-42 Consider Li a R v. strong base R the pKa's of arene-Cr(CO)3 are

6-7 pKa units more acidic

pKa = 31.1 pKa = 34.8 OMe pKa = 33.0 C(O)NPr-i2

Cr(CO)3 Cr(CO) Cr(CO)3 3

pKa = 41.2 OMe pKa = 39.0 C(O)NPr-i pKa = 37.8 2 143 pKa associated with LDA is 35.7; LiTMP 37.1, so these can now be used as bases

-excellent for ortho- functionalization of aromatics; and -one gets a change in some of the relative abilities to direct ortho- lithiation

for free arene -CONR2 > -SO2NR2 > -NHCOR > -CH2NR2 > -OMe > -NR2 = -F for Cr complexes -F > -C(O)NHR > -CH2NR2 = -OMe >> -CH2OMe > -NR2, -SR So

O O O O NHR NHR 1) 2 LDA, THF, -78o NHR 1) 2 BuLi, TMEDA Me3Si NHR F F 2) Me SiCl F 2) Me3SiCl F 3 Cr(CO) 3 SiMe3 (CO)3Cr DMG can be trapped by a wide to give Li range of E+ DMG DMG DMG Cr(CO) CH I, Me SiCl, CO , Ph PCl, 3 3 3 2 2 CH O 3 SiMe3 CO2H , R R' Br Br Cr(CO) 3 Cr(CO)3 Cr(CO)3 DMG DMG DMG OH

PPh2 Br R R' Cr(CO) (CO) Cr 3 3 Cr(CO)3 144 further OSi(i-Pr) OSi(i-Pr) 3 1) t-BuLi, THF, -78o 3

2) MeI H3C this meta metallation is unheard of Cr(CO) 3 Cr(CO)3 in chemistry of free arenes

NSi(i-Pr) 3 1) BuLi, THF NSi(i-Pr) Widdowson, D.A. J. Chem. Soc., Chem. Commun. 3 1983, 955. Fukui, M., et al Tetrahedron Lett. 1982, 23, 1605. 2) E+ E

Cr(CO)3 Cr(CO)3 most recent review: R Semmelhack, M. F.; Chlenov, A. Top. Organomet. Chem. 2004, 7, CH 3

Effect #3 of Cr(CO)3 on arenes

CH2R pKa ca. 40 benzylic site also has enhanced acidity relative to CH2R -so benzylic deprotonation is quite easy

Cr(CO)3 -never seen pKa measured by I guess it's about 25 -as a result, one can often do benzylic deprotonation reactions which fail with the free arene

R2 R2 t Jaouen, G. et al R3 KO Bu, DMSO R3 R1 R1 J. Chem. Soc. Chem. Commun. 1984, 602, 475 EtO OEt CO2Et J. Chem. Soc. Chem. Commun. 1981, 1264 HO J. Organomet. Chem. 1984, 102, C37. Cr(CO)3 O O (CO)3Cr

R1, R2, R3 not acidifying groups (i.e., H, simple alkyl) 145 R' R' R' E - - R + 2 E R R2 2

Cr(CO)3 Cr(CO) Cr(CO)3 3 O R2 = - CN - CO Bu-t 2 , nBu-, Ph-, + + SS E = H , CH3I, Ph Cl - Semmelhack, M. F. Seufert, W.; Keller, L. J. Am. Chem. Soc. 1980, 102, 6586. Uemura, M.;Minami, T.; Hayashi, Y. J. Chem. Soc., Chem. Commun. 1984, 1193. -appears to be both a kinetic and a thermodynamic effect R Davies, S. G. et al Adv. Met. Org. Chem. 1991, 2, 1.

Effect #4 Stabilization of Benzylic Cations

-recall our discussion of pKR+ values.... + + Ph CH+ -13.4 + -6.6 PhCH2 < -17.3 2 CH2 -11.8 Ph3C

less Cr(CO)3 more stable stable

Cl Cl also, the S 1 solvolyses of are 103 - 105 times faster than N and Ph the corresponding non-complexed arenes Cr(CO)3 Cr(CO)3 146 -makes the following reactions possible OH + NR HPF6 HNR2 2 Y Y CH2 Y CH2Cl2 Cr(CO) Cr(CO) Cr(CO)3 o 3 3 -20 H O OH N H2SO4 Y + RCN Y R

Cr(CO)3 Cr(CO)3 -this Ritter reaction only works with 3o benzylic halides R Davies, S.G. Synlett 1993, 323.

Other Effests in Cr(CO)3-Arene Complexes R -stereochemistry 1 σ- plane is gone R R 1 is flat, achiral 2 Chiral σ- plane of symmetry Cr(CO)3 R2

-so what is R- and what is S- ??

Consider O O H CH H CH 3 3 147 (CO)3Cr (CO)3Cr H O -at position 1 we have C H O C 4 CH counterclockwise Cr 2 3 Cr C C C C 3 -therefore, H H Cr (S)-enantiomer Cr Cr CH3 Cr 1

-at position 2 we have C CHO CH C 4 3 CH Cr 3 3 clockwise CH HOC C C C 3 2 Cr Cr -therfore, Cr H Cr Cr (R)-enantiomer 1

-this is (1S,2R)-2-methylbenzaldehyde chromium tricarbonyl Note: Davies just uses the label at position 1, as the 2-position is then defined automatically

-chiral centre (or plane); therfore should be able to do asymmetric reactions -will give a sampling, as this is a fairly new and developing area 1) base NaBH4 CO2Me H 2) R-X R CO Me Cr(CO)3 O Cr(CO) OH Cr(CO) 2 Cr(CO)3 3 3 O O CH3 1) NaH H

2) CH3I 148 Cr(CO)3 Cr(CO)3 Acyclic cases R R disfavoured R R'Li or R'MgBr O H R' rotamer or NaCH NO H 2 2 Cr(CO) H O Cr(CO) OH 3 Cr(CO)3 3

X X X R'MgBr R O R' OH R Cr(CO) O R Cr(CO)3 3 Cr(CO)3

X = CH3, OR2 R = Me, Et, alkyl

SiMe3 + TiCl4 CH H3C HO 3 (CO) Cr CH (CO)3Cr (CO)3Cr 3 3

OH H HNCOMe H H SO 1) MeCN 2 4 Me H Me Me 2) H2O + Cr(CO) 3 Cr(CO)3 Cr(CO)3 149 R R R Cr(CO) -naphthalene 3 OH H OH H OH OMe OMe OMe Cr(CO)3 Cr(CO)3 major because R H R H favoured disfavoured X O X O LnCr LnCr

R Solladie-Cavallo, A. Adv. Met.-Org. Chem. 1989, 1, 99. R Uemura, M. Adv. Met.-Org. Chem. 1991, 2, 99. R Davies, S. et al Adv. Met.-Org. Chem. 1991, 2, 1.

-many of these are done on racemic material -so how does one get enantiomerically pure complexes? O O R R * 1) R O H2N N hydrolyze O H Ph N-NH-} H H H Cr(CO) Cr(CO) 3 Cr(CO) 3 racemic 3 separate diastereomers enantomerically pure 150 Classical Resolution 2) kinetic resolution OH lipase OH O pseudomonas sp. O X X + O X O Cr(CO)3 Cr(CO)3 Cr(CO) 85-100% ee 3 84-98% ee Uemura, M. et al Tetrahedron Lett. 1990, 31, 3603; Jaouen, G. et al J. Chem. Soc., Chem. Commun. 1984, 1284.

3) chiral auxiliaries MeO MeO 1) 2 nBuLi, O -30o O H+ CHO O + OMe 2) E O OMe (E = Me) E E Cr(CO) Cr(CO) 3 Cr(CO)3 90% de 3 Kondo, Y.; Green, J.R.; Ho, J. J. Org. Chem. 1993, 58, 6182.

4) enantioselective functionalization MeO O OMe CONPr-i X X X = OMe 2 1) Ph N Ph O Li SiMe3 or Kundig,E.P. at al Tetrahedron Lett. 1994, 35, 3497 Cr(CO) Li Simpkins, N.S. et al J. Org. Chem. 1994, 59, 1961 3 N Cr(CO)3 Siwek, M.J.; Green, J.R. J. Chem. Soc., Chem. Commun, Ph up to >90%ee 1996, 2359.

2) Me3SiCl 151 6 Other η -Cycloalkatriene-Cr(CO)3 Complexes

X o X X = N-CO Me, C=O, SO , CH , CH(Me) Cr(CO)6, 100 2 2 2 6 or (MeCN) Cr(CO) , unlike Fe complexes, this is η 3 3 Cr(CO) THF, Δ 3

X 1) R R hν, RT 1 2 R [6+4] cycloaddition R1 2 X good yields H H Cr(CO)3 2) P(OMe)3 or O2

Notes: rates unchanged if R's = EWG or EDG -if there are substituents on remote sites of triene, regiochemistry is 1:1

Mechanism(?) - not concerted

oxid

hν, -CO coupling Cr(CO) Cr(CO)2 Cr(CO)2 2 Cr(CO)3

-this is stepwise in nature, so there is no 'concertedness' reason why the [6+2] should fail, so...

CO2Et CO Et + 2 1) hν, RT, hexanes H H 92% Cr(CO) 2) O 3 2 152 -both of these can be catalytic in Cr - often in the presence of Mgo

CO2Me MeO2C CO2Et N CO Et 9% (CO) Cr-naphth + 2 3 H N H 77% n o Bu2O, 150

R Rigby, J.H. Adv. Met-Org. Chem. 1985, 4, 89. R Rigby, J.H. Tetrahedron 1999, 55, 4251. R Rigby, J.H. Org. React. 1997, 49, 331.

Multistep Reactions The [2+2+2] Cycloaddition - important method of making six membered rings -also, many of the other multistep processes are based on this reaction

-consider 3 H H -feasible reaction -requires 400o; many side reactions -not synthetically useful as such -there are several transition metal fragments which allow this type of reaction to occur at much lower temperatures, including... R N FeCl (CpCo(CO) ) 3 + EtMgBr ; (Ph3P)3RhCl ; 2 ; (CpCo(ethene)2) N Co Co R Grigg, R. OC CO R Modern Rhodium Catalyzed Reactions Vollhardt, K.P.C. Ch 7.3.1 153 This reaction proceeds by a combination of fundamental steps we have seen before CO R hν or Δ CpCo(CO)2 + R R CpCo R R -CO CpCo R R R R R 16e R R oxidative L Cp L = solvent in many cases CpCo coupling Co L = PPh isolated often by R 3 L R Yamazaki group R R (Tetrahedron Lett. 1974, 4549; J. Organomet. Chem. 1977, 139, 157; -then J. Am. Chem. Soc. 1983, 105, 1907.) R R Cp R R R Cp R Co Co now comes uncertainty...... R -the next step is undecided between L R R R R two possibilities R Possibility #1 - concerted cycloaddition Cp R R Co Cp R concerted R - "Cp-Co" R R Co R R R 'Diels-Alder R R R R R like' R R R R

"CpCo" regenerated; therefore possible to be catalytic in Co 154 Possibility #2 - Alkyne insertion/reductive elimination

R R R Cp R R R insertion reductive R R Co + "CpCo" R' CpCo R R elimination R' R R R' R' R' R'

Personal opinion - there are instances where the concerted cycloaddition mechanism is operating - more often, it is the insertion/elimination mechanism that is operating

Regiochemistry -if one has R(big) R(small) , what happens?

Rb Rs Rb Rb Cp Rs Cp a minor Rs major Co + Co amount of this CpCo Rs product Rs L Rs L Rb Rb Rb -simply from sterics

Rb Rs Rs Rs Rb Rb fast CpCo CpCo no way CpCo Rs Rs slower Rb 155 Rb Rb Rs -if one has R(EDG) R(EWG) , what happens?

Rw Rw Rw Rd Cp Rd Cp a minor Rd major Co + Co amount of this CpCo Rd product Rd L Rw L Rd Rw Rw

-reason - oxidative coupling step proposed to operate under orbital control - HOMO of complex dominates, and it is domonated by the π* of the alkene

-therefore, C-C bond formation to give metallacycle occurs at the EWG EDG carbon β- to the EWG

-if sterics and electronic effects compete, the steric effect overwhelm

Ph Ph MeO2C CO Me Cp CO2Me Ph CpCo 2 Cp Ph Co 43% + Co 5% Ph P Ph Ph P Ph Ph 3 Ph 3 Ph -there is still a third alkyne to participate in 2+2+2, so often one gets further regiochemical mixtures

-reaction becomes synthetically useful when BTMSA Me3Si SiMe3 is used as the third alkyne, as it only reacts with itself very slowly 156 -particularly synthetically useful reaction when the two other alkynes are joined i.e., L H Me3Si SiMe3 SiMe ( )n ( )n Co 3 ( )n H Cp CpCo(CO)2, hν SiMe3 n = 0, 1, 2 A good yields

SiMe SiMe 3 3 SiMe3 ( )n SiMe SiMe 3 3 SiMe3

SiMe3 Note; in this case, the rxn goes through instead of A Co SiMe3 L Cp

H -fortunately, silyl groups are removable from arenes

+ H H SiMe3 H or ( )n ( )n ( )n F- SiMe H SiMe3 3

-reactions tolerate a pretty good range of substituents, such as... -CO2R, -CH2OH, -CH2OR', O N-OR' -NR'2, -SR', , R H -reaction may be carried out thermally or photochemically (or both) 157 -reaction is often (but not always) catalytic in cobalt examples xs BTMSA SiMe3 CF CO H 3 2 SiMe3

CpCo(CO)2(cat) 72% SiMe3 SiMe hν, Δ 96% 3 Berris, B.C.; Vollhardt, K.P.C. J. Chem. Soc., SiMe3 Chem. Commun. 1982, 953. Me3Si xs BTMSA SiMe 36% CpCo(CO) 3 2 Dierks, R.; Vollhardt, K.P.C. Δ J. Am. Chem. Soc. 1983, 39, 3150. SiMe3

Me3Si SiMe3

MeO Vollhardt, K.P.C. et al xs BTMSA N N MeO Tetrahedron 1983, 39, 905. MeO CpCo(CO)2(cat) MeO SiMe hν 3 96% SiMe Other cyclization partners 3 -the 'third alkyne' does not have to be an alkyne per se - for example, it can be an alkyne

1 equiv CpCo CpCo(CO) CuCl -Et N 2 H 2 3 H 0o, CH CN SiMe3 Δ, isooctane 3 SiMe SiMe 3 3 158 Sternberg, E.D.; Vollhardt, K.P.C. J. Org. Chem. 1984, 49, 1564. CpCo(CO) CoCp CuCl -Et N Me Me 2 2 3 hν, Δ, 0o, or silica gel m-xylene

60% 61% Vollahrdt, K.P.C. et al J. Org. Chem. 1984, 49, 5010; Angew. Chem. Int. Ed. Engl. 1981, 20, 802.

-in these cases, there must be at least one equivalent of Co -must subsequently decomplex the Co-diene complex -normally, the alkene is the 'third' partner

-the 'third' partner can also be a nitrile

H N N Vollhardt, K.P.C. et al Tetrahedron 1983, 39, 905. CpCo(CO)2 ( )n + ( )n R H R n = 1-3

-or an isocyanate CpCo(CO) R H R 2(cat) N ( )n NCO ( )n Earl, R.A.; Vollhardt, K.P.C. H xylene, hν, Δ O J. Org. Chem. 1984, 49, 4786. n = 1-2 R R R R "" R2 H ca. 45% + R2 R1 N N C O R1 O 159 -again, these are, in almost all circumstances, the 3rd partner in the cycloaddition

i.e. R2 R R RR R R R R R 2 R 1 1 R N Co not Co R Co N not Co R Cp Cp Cp Cp R R R R R R R R Use in estrone synthesis O O O Me Si Me Si BTMSA 3 Δ 3 Me Si CpCo(CO)2 Me3Si 3

O O O H 71% CF CO H Me Si H 3 2 3 Pb(OC(O)CF3)4 H H H H H Me3Si H H Me3Si HO estrone Funk, R.L.; Vollhardt, K.P.C. J. Am. Chem. Soc. 1977, 99, 5483; 1979, 101, 215; 1980, 102, 5253.

-using the CoI / CoIII systems are not the only transition metal complexes capable of these cycloaddition - certainly the most popular, especially in early days, but other systems have been used effectively 160 -a survey of literature, early 2000's

I III I III Rh /Rh 20 Rh(PPh3)3Cl, [RhCl(cod)2]2 Ir /Ir 2 o II II IV Pd /Pd 15 Pd(PPh3)4 Ti /Ti 2 o II o II Ni /Ni 14 Ni(cod)2, (+ PPh3) Fe /Fe 1 o II III V Co /Co 9 Co2(CO)8 Ta /Ta 1 RuII/RuIV 5 o II Mo /Mo 3 Mo(CO)6

O O OH OH 2% (Ph3P)3RhCl 86% EtOH, 25o, 12h HO HO MeO MeO OMe OMe MeO OMe SiMe3 81% Pd(PPh3)4 +

OTf CsF, CH3CN MeO MeO 93:7 Many, many reviews on this R Tanaka, K. Synlett 2007, 1977. (Rh catalysts) R Chopade, P.R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (all metals) R Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209 (Co) R Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741 (all metals, small) R Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901 (all metals) R Grotjahn, D.B. Comprehensive Organometallic Chemistry II, Vol12, p741, 1995 (library) R Boese, R.; Sickle, A.P.; Vollhardt, K.P.C. Synthesis 1994, 1374. (indoles) R Schore, N. Comprehensive Organic Synthesis, Vol 5, p 1129, 1991 R Vollhardt, K.P.C. Angew. Chem. Int. Ed. Engl. 1984, 23, 539. 161 3. Interrupting the 2+2+2 -there are a number of reactions that start to follow this 2+2+2 pathway, getting to the metallacyclopentdiene or metallacyclopentene, and then go differently -only a time to look at a couple, but there are many more in synthesis see: Topics in Organometallic Chemistry 2006, 19 entire issue

The Pauson-Khand Reaction -two of the side products from the 2+2+2 are:

R R R Cp Cp R Co O Co CoCp CO CO R R R R (Fe : Knolker, H.J.) -cyclopentadienones are not very stable compounds, but if one of the C=C's is reduced, you have very useful cyclopentenones

-this type of material is often obtained by using and alkyne, and alkene, and Co2(CO)6 (or an alkyne-Co2(CO)6 complex) O i.e., R Δ + Co (CO) R' R + R' 2 8

Intermolecular Cases -no particular constraints on the alkyne 162 -if you have an unsymmetrical alkyne, larger groups end up next to C=O, as in Alkene Partner

-simple alkenes don't work especially well, unless present in huge excess (Note: this is making progress) -strained alkenes, "non β-hydride" alkenes (bridged bicyclic akenes),

and alkenes with ligands attached (X = NR2, SR, O?) give better yield, high regioselectivity O Ph Ph Ph H + Ph 15% ordinary alkene Co (CO) 2 6 CH SMe 3 SMe O Ph H + coordinating substit. Ph 73% Co (CO) 2 6 (note: trans)

Krafft,M. et al J. Am. Chem. Soc. 1991, 113, 1693 CH3 NMe O arrow is where 2 NMe 2 R 1st C-C bond + O Ph 2 S R forms 1 Si 1 O Krafft Carretero Kerr Yoshida (with Ru3(CO)12) -also chiral -loses benzoate -loses Si

H H + Δ Co (CO) bridged bicyclic alkene 2 6 Ph O H (non β-hydride) Ph

high % 163 2 ( )n ( )n C 1 even n = normal with mild conditions PhMe2Si especially n = small "no β-H" Cazes (no β-H)

Reviews focussing on intermolecular reactions R Gibson, S.E. et al Angew. Chem. Int. Ed. 2005, 44, 3022. R Laschat, S. Synlett 2005, 2547. -except for sulphoxides, alkenes with EWG's rarely work

Intramolecular Cases -reaction works much better when alkene and alkyne are in the same molecule Co (CO) 2 6 O O +N (NMO) O 85% O O CH2Cl2, RT

Co2(CO)8 60% (old conds) 95% O

-often particularly good for all carbon bridges when there is a gem dialkyl in the bridge

Co2(CO)8 H gem dimethyl or Thorpe-Ingold effect Δ, 82% SiMe O 3 TBDMSO TBDMSO SiMe3 164 -there are subtle stereochemical matters which are beyond this course's scope -many recent advances have increased yields and allowed reactions under milder conditions

i.e., polar aprotic solvents (CH CN, DME ) 3 MeO OMe o n R Sugihara Chem, Eur. J. 2001, 7, 1589 -use of 1 amines (CyNH2) and mercaptans ( BuSMe)

-photolysis O o + - + -3 amine oxides (Me3N -O , TMANO), (NMO) O N and room temp

Catalysis -the new holy Grail - to use catalytic amounts of metal and CO gas (under as low a pressure as possible), or a CO substitute (some aldehydes)

MeO C Co (CO) (5 mol%) MeO C 2 2 8 2 O 83% MeO C 2 CO (1 atm), DME (60o) MeO2C

-other metals (other than Co) now are common, especially for catalytic chemistry; I think that RhI is gradually replacing Co

I II Rh 25 [RhCl(CO)2]2 Zr 4 o Feo, hν 4 Mo 12 Mo(CO)6 -allenes(Brummond) Ruo 8 Ru (CO) Co nanoparticles 2 3 12 CoI 1 IrI 4 W 1 TiII 7

Most recent reviews: R Shibata,T. Adv. Synth. Catal. 2006, 348, 2328. R Pérez-Castells, J. Top Organomet Chem 2006, 19, 207 R Strübing, D.; Beller, M. Top Organomet Chem 2006, 18, 165 165 Mechanism of Pauson-Khand -unnaturally complex looking, because presence of second metal, which is just 'along for the ride' OC CO Co Co(CO) (CO)3Co Co(CO)3 R 3 Rb Rs + R Rs Rb Co2(CO)6 Rs Rb oxidative +L (CO)3 coupling L Co(CO) 2 Co (CO)3 Co(CO) 3 insertion Co Rs Rb Rs Rb O CoCO +L Rs Rb LL Co (CO)2 R R O H L R same as L2Co(CO) Rs Rb Co(CO)3 Rs Rb + LnCo-CoLn O O R Reviews R R Chung, Y.K. et al Synlett 2005, 545 (Co nanoparticles) R Brummond, K. Tetrahedron 2000, 56, 3262 (allenes) R Krafft, M.E. Tetrahedron 2004, 66, 9795. (Interrupted P.-K.) R Geis, G.; Schmalz, H.-G. Angew. Chem. Int. Ed. Engl. R Alcaide, J.C.; Almendros, P. Eur. J. Org. Chem. 2004, 3377 (allenes) 1998, 37, 911 R Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32. R Schore, N.E. Comprehensive Organometal. Chem. II R Gibson, S.E. Angew. Chem. Int. Ed. Engl. 2003, 42, 1800 (catalytic) 1992, Vol 12, Ch 7.2 R Carretero, J.C. Eur. J. Org. Chem. 2002, 288 R Schore, N.E. Org. React. 1991, 40, 1. R Carretero, J.C. Synlett 2001, 26. R Schore, N.E. Chem. Rev. 1988, 88, 1081. 166 -so how about alkyne only cases, i.e. + + CO O -sort of - uses Feo and product is the iron complex

SiMe Fe(CO) 3 5 ( )n O ca. 80% R Knolker, H.-J. Chem. Soc. Rev. ( )n 1999, 28, 151 SiMe glyme, 140o 3 Fe(CO) n = 1,2 3 -decomplexation is not straight-forward, because cyclopentadienone is unstable (anti-aromatic)

The [2+2+????] Reactions of Zirconium Alkyne Complexes R -compounds like R ZrCp ZrCp2 2 R R -also react with alkynes, alkenes, nitriles, to form C-C bonds by oxidative coupling process, similar to the 'first half' of the 2+2+2 R R R -can be isolated as R R' R Cp PMe3 Cp the PMe adduct + ZrCp Zr 3 ZrCp2 2 PMe R R' R' 3 R' R' R' -the zirconocene alkyne complexes themselves are made differently than in Co case -most usual method Cp Cp R n R Zr Δ R Br BuLi R Li Cp2ZrCl(Me) CH3 ZrCp2 -CH R R R R 4

R cannot be H, Cp Zr Cp Zr ( )n also made this way 2 , 2 167 Reactions Encountered -many of them quite analogous to Co complexes R R R R' R ZrCp R ZrCp R ZrCp R' N 2 2 2 H + N H R' R' H R' R ZrCp2 R R H2C=CH2 O R R ZrCp 2 H R' R O ZrCp2 R' R and unlike Co R

R Cp2Zr

ZrCp2 R -are further reaction possible? - YES -most common is hydrolysis R R R R + + H3O H O R ZrCp R 3 R 2 R ZrCp 2 CH R' R' R' R' 3

R R R R + H O+ R R H3O R R 3 ZrCp2 ZrCp2 N O O OH 168 R' R' R' R' -due to electronegativity difference between C and Zr, there's a tendency for these to react like - - R' -other reactions -with sulphur monochloride or dichloride R'

R' R' SCl 2 S benzothiophenes Cp2Zr Cp2Zr R' R' R' R' R' N S2Cl2 S benzothiazoles Cp2Zr N N R' R' -reactions with iodine R R R R R tBuLi I2 Cp Zr I Li Cp2Zr 2 I I R I R R 2 H O+ Cp Zr 3 2 I I N I N O R' Cp2Zr R' R' 169

Regiochemistry in benzyne reactivity

R R R' R' Rs Rb ZrCp2 ZrCp ZrCp R' 2 2 ZrCp2 Rb R' analogous to cobalt Rs

Intramolecular cases - E.I. Negishi 2 nBuLi β-elimin reductive Cp ZrCl Cp Zr "Cp Zr" 2 2 Cp Zr 2 2 + butane 2 - H elimin

R R "Cp Zr" ( )n 2 CO ( )n ZrCp Pauson-Khand R 2 ( )n O

R ( )n "Cp2Zr" same reactions as R R' ( )n ZrCp 2 intermolecular cases R'

see R Negishi, E.; Takahashi, T. Bull. Chem. Soc. of Jpn. 1998, 71, 755. R Majoral, J.-P. et al Coord. Chem. Rev. 1998, 178-80, 145 (main group elements) R Negishi, E. Acc. Chem. Res. 1994, 27, 124. R Buchwald, S.L.; Nielsen, R.B. Science 1993, 261, 1696. R Buchwald, S.L. Chem. Rev. 1988, 88, 1047. 170 Carbenes

LnM=CH2 (carbenes or alkylidenes) -structurally discrete carnes 'officially' fall into two types, characterized by their reactivity -I will arbitrarily add a third class

Fischer Type Carbenes Schrock Type Carbenes Methesis Carbenes (alkylidenes) PCy3 OMe Ph δ− Cl (CO) Cr δ+ Ru 5 Ti CH Cl R 2

PCy3 -mostly Cr group (Cr, Mo, W), or Fe group -early transition metal - early development by Schrock, -stabilized by heteroatom (O here) -electron rich at carbon so often lumped in with Schrock -reactivity - electron poor at C carbenes for convenience -mid- or late transition metals -no great M-C bond polarity, so C electronically neutral -mostly cycloaddition processes Fischer Carbenes R de Meijere, A. et al Angew. Chem. Int. Ed. Engl. 2000, 39, 3964 R Barluenga, J. J. Organomet. Chem. 2005, 690, 539.

Bonding : R R R1 R1 1 1 LnM : C LnM C LnM C LnM C R R 2 R2 R 2 2 171 Preparation O O + OMe PhLi - Me3O W(CO) (CO) W C (CO) W C 6 5 5 (CO)5W C Ph Ph Ph -nucleophiles mostly alkyllithiums, but don't absolutely have to be C based Li(NiPr ) + - OEt 2 Et3O BF4 Cr(CO)6 (CO)5M C NPr2-i Reactions of Fischer Carbenes -for many reactions, it's useful to think of these carbenes as having parallel reactivity to carboxylic esters

OR CAN OR -can actually do the transformation with CeIV

(CO)5M C = O C R R

a) Nucleophilic Attack at Carbene Carbon -calculations show that the LUMO of these species is localized at the carbene carbon (Blick, T.F.; Fenske, R.F.; Casey, C.P. J. Am. Chem. Soc. 1976, 98, 143) -attack of nucleophile, orbital controlled, is at that site

OMe OMe - Nu Nu-Li+ - -MeO (CO) Cr C Nu (CO) Cr C (CO)5Cr C 5 5 R R R

nucleophiles include organolithiums amines mercaptans RSH 172 RLi R'2NH H OMe N (CO) Cr C + H N CO Me CO Me 5 2 2 (CO)5Cr C 2 Ph Ph

b) Generation of α-Anion and Electrophile capture

OMe very acidic O O O pK = 25 (CO) Cr C pKa = 10 a 5 pKa = 8 OEt H C OEt CH 3 3 H H

n o OMe OMe OMe BuLi, -78 OMe - E+ (CO) Cr C (CO)5Cr C (CO)5Cr C (CO)5Cr C 5 CH CH CH CH2 3 - 2 2 E

-anion is so stabilized that it's a fairly weak nucleophile; therefore only captures more reactive electrophiles O O O Br CO Et (Michael acceptor) 2 Cl OR R R' R X -epoxides give further reaction

OMe OMe O 1) nBuLi, -78o (CO)5Cr C (CO)5Cr C (CO) Cr C CH 5 3 2) O O Casey, C.P. et al J. Organomet. Chem. 1974, 73, C28.

-aldehydes and ketones don't eliminate immediately, but the alcohols can be made to eliminate 173 OMe OMe 1) nBuLi, -78o OMe pyridine (CO) Cr C (CO)5Cr C 5 (CO)5Cr C OH 2) PhCHO, TiCl4 Ph 3) workup Ph Wulff, W.D. et al J. Am. Chem. Soc. 1985, 107, 503. -can make the anion less stable, more reactive, by exchanging one CO ligand for a phosphine; the anion will then react with (less electrophilic) alkyl halides/triflates Wulff, W.D. et al J. Org. Chem. 1987, 52, 3263.

Michael Addition to Vinyl Carbenes -since the α-anions are so stabilized, it's not suprising that reactions that give such an anion go well...... OMe OLi OMe 1) (CO) Cr C R 5 2 (CO)5Cr C 2) workup Nakamura, E. J. Am. Chem. Soc. R1 O 1993, 115, 9015. R2 R1 -can be highly stereoselective Note: some anions add to carbene carbon, to give other products

Diels Alder Reaction of Vinyl Carbenes - due to the strongly EWG nature of carbene, vinyl carbenes are more reactive (104 x) more reactive as dienophiles in 4+2 cycloadditions

OMe Cr(CO)5 (CO) Cr C H endo exo 5 OMe Cr(CO)5 94:6 H MeO 174 OMe also Wulff, W.D. et al J. Am. Chem. Soc. 1983, 105, 6726 C partcicpate Dotz, K.H. et al Angew. Chem. int. Ed. Engl. 1986, 25, 812 (CO)5Cr Wulff, W.D. et al J. Am. Chem. Soc. 1984, 106, 756. H Cyclopropanation with Alkenes R' R' -typical reaction of carbenes in organic chemistry :CR + R 2 R' R' R -may also be done with discrete organometallic complexes, with either electron poor or electron rich alkenes - probably by two different mechanisms electron poor alkenes OMe L MeO Ph OMe ca. 100o [2+2] OMe reduct. (CO)4Cr C (CO)4Cr Ph (CO)5Cr C Ph elimin. RO2C Ph CO2R RO C RO2C 2 + "(CO)4Cr"

O O EWG EWG CN and disubstituted -works with NMe2 P (OMe) 2 cases, i.e., R R

R Reibig, H.-U. "Organometallics in Organic Synthesis", V2, 1987, p.31 R Dotz, K.H. Angew. Chem. Int. ed. Engl. 1984, 23, 587. R Wu, Y,-T., Kurahashi, T., De Meijere, A. J. Organomet. Chem. 2005, 690, 5900. R Barluenga, J.; Rodríguez, F.; Fañanás, F.J.; Flórez, J. Top. Organomet. Chem. 2004, 13, 59.

-with electron rich alkenes, rxns are at lower temperature, different mechanism 175 R CO + Ph reduct N N N (CO)5Cr C Ph OMe elimin Ph N - R (CO) Cr R (CO) Cr OMe 5 MeO R Ph 5 OMe

-reaction done under CO atmosphere to suppress alkene metathesis

R R N (CO)5Cr C + Ph OMe R N (CO)5Cr OMe Δ + H2 -with normal alkenes, it's more useful to use Fe CH OC 2 Fe C -see R Helquist, P. Adv. Met. Org. Chem. 1991, 2, 143 OC made OC OC +SMe2 in situ Carbene-Alkyne Cycloaddition -probably most important type of rxn of Fischer carbenes; many uses in organic synthesis -vinyl and aryl carbenes do a 2+2+1+1 cycloaddition reaction to give very specific types of arenes OH OMe ca. 45o R (CO)5Cr C + R R Cr(CO)3 R OMe reaction is essentially R R MeO Cr O MeO C: :C O 176 -this process also occurs on aryl substituted carbenes OH OMe R' + R' R' (CO)5Cr C R Cr(CO)3 R R' OMe

-mechanism is not obvious; it is generally accepted to be

OMe OMe Rb Rs [2+2] metathesis (CO)4Cr C (CO)5Cr C (CO)4Cr OMe Rb (CO)4Cr -CO OMe Rs Rb Rs Rb Rs CO insertion

Dotz HO tautomerism O electrocyclic O C rearrangement Rb OMe Rb OMe OMe Rs Cr(CO) Rs Rb Rs 3 Cr(CO)3 Cr(CO)3 -easy to decomplex Chromium from arene HO O HO Rb Rb sometimes get Rb FeCl3- DMF IV Rs Rs or Ce /H2O Rs OMe O OMe Cr(CO)3 177 -aromatic heterocycles participate as well OH OMe n-Pr H Pr-n X = O, S (CO)5Cr Cr(CO)3 X X OMe -use in daunomycinone synthesis R s H O III Rb O O OH Fe /DMF 45o O O + O 76% THF O (CO)5Cr 2 steps MeO O MeO OMe OMe (CO)3Cr O O OH O O OH O CH3 OH O MeO MeO O OMe OMe daunomycinone -many, many other synthetic examples -see R Wulff, W.D. Adv. Met. Org. Chem. 1989, 1, 209. R Minatti, A.; Dötz, K.H. Topics Organomet Chem 2004, 13, 123.

-other major ring formation reactions of Fischer carbenes is β-lactam synthesis 178 OMe OMe O hν [2+2] OMe CO (CO) Cr C OMe (CO)5Cr C 4 R L(CO)4Cr CH3 (CO)nCr CH 2 CH insertion 3 CH3 N 3 N R N N R 2 R R R R 2 R R 2 3 1 3 3 R1 3 R1 R1

O OMe reductive CH3 N R2 elimination -for example R 3 R1

OMe h H S ν Me S one isomer (CO)5Cr C + MeO N CH Cl CH H 2 2 N penam derivative 3 CO Me 2 O H (related to thienamycin) MeO2C R Hegedus, L.S. Topics Organomet Chem 2004,13, 157

Schrock Carbenes (alkylidenes) -somewhat newer - earliest version is.... > -40o Cp TiCl low T Me Cp Ti CH ** 2 2 +2 AlMe3 Cp Ti 2 2 2 Al Cl Me Tebbe reagent or Δ Cp Ti CH Cp Ti 2 2 179 2 -however one makes it....it is good at converting carbonyls into alkenes O R' "Cp Ti=CH " 2 2 + CH2 R R' R O R CH2 R OR' R'O not feasible with O phosphorus ylide (Wittig) R chemistry CH R N 2 N

-also works with carbonyls that are highly enolizable, whereas the Wittig reagent would simply deprotonate R Hartley, R.C.; McKiernan, G.J. J. Chem. Soc., Perkin Trans. 1 2002, 2763 -alternative set of conditions, see: R Grubbs, R.H.; Pine, S.H. "Comprehensive Organic Synthesis" 1991, vol 5, Ch 9.3 (p1115)

Problems - replacing =CH with =CHR' gives a selectivity problem 2 Nico Petasis (USC) =C=CR2, =CHPh, =CHTMS do work, however

CH2 -acid chlorides do give enolates O "Cp2Ti=CH2" R O-TiCp Cl R Cl 2

R Pine, S.H. Org. React. 1993, 43, 1. R Petasis, N.A. Pure. Appl. Chem. 1996, 67, 667. 180 Mechanism - a metathesis type mechanism X = H, CR' , X H 3 2+2 2 CH Cp2Ti=CH2 + O OR', NR'2 Cp Ti 2 Cp2Ti C 2 + R X O retro 2+2 O R X R

if X = Cl, it's a better leaving group, so...

H + X- Cl 2 Cp Ti Cp Ti C Cp Ti 2 CH2 2 2 CH2 O X O O R R R

Metathesis of Alkenes -these 2+2 / retrograde 2+2 cycloadditions become the dominant reaction pathway with several transition metal carbenes/alkylidenes N N N N Mes Mes PCy Ph PCy Mes Mes 3 3 Ph Ph Cl Cl Cl Ru N Ru Ph Ru Cl Ru Cl Cl O Mo Cl Cl Ph PCy PCy3 O 3 PCy3 F C O 3 1 1st generation nd CF3 CF 2 3 4 2 generation 5 CF 3 3 Grubbs-Hoveyda Schrock (pre)catalyst Grubbs' (pre)catalysts -higher reactivity -more easily handled -less stable, less easily -much more functional group tolerant handled -less reactive (4 is close) -not that functional group tolerant 181 -use in organic synthesis - Ring Closing Metathesis (RCM) true (living) catalyst R R R R R R 2+2 H2CM 2+2 retro M M M M + 2+2

-has enormous synthetic utility -can close rings of many sizes: normal to large - the 8-12 sizes are the toughest MeO MeO O 6 mol% O 94% -this poor control over 2 O O alkene stereochemistry PCy Ph MeO is common MeO 3 Cl Ru Ph Cl PCy3

10 mol% 3 82% HO OSiPh Bu-t PCy HO OSiPh Bu-t 2 3 Ph 2 Cl Ru O Cl O PCy3 O O Grubbs 1 O O 5-10 mol% 1 Schrock cat. 95% F C N 3 F3C N O N OTBDMS O O Mo Ph OTBDMS F C O 3 CF 182 3 CF3 CF3 -one alkyne can be used in these ring closing metathesis reactions; get a diene as product

H2C M R' R' 2+2 R' 2+2 retro M M M M R' 2+2 R'

R Maifeld, S.V.; Lee, D. Chem. Eur. J. 2005, 11, 6118 R Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919. R Mori, M. Adv. Synth. Catal. 2007, 349, 121. (in fact entire issue is on metathesis) R Villar, H.; Frings, M.; Bolm, C. Chemical Society Reviews 2007, 36, 55.

3 CH3 O PCy O 73% N st 3 Ph H C H 1 gen Cl N 3 Ru H Grubbs cat Cl PCy3 R Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919. R Mori, M. Adv. Synth. Catal. 2007, 349, 121 (entire issue is on metathesis) R Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55. R Maifeld, S. V.; Lee, D. Chem.-Eur. J. 2005, 11, 6118. Cross Metathesis - Intermolecular -metathesis of two alkenes can be intermolecular, but there is normally a problem with selectivity -in some cases, an alkene can be chosen such that metathesis with itself is slowed down to almost zero -in these cases, it is possible to do cross-metathesis with a second, unhindered alkene

-the 'slow' alkene is normally either H2C=CH-EWG or H2C=CH-BIG

OEt SiR R P 3 CN OEt O O O O R 183 OBz CH Cl , 3 mol% OBz + 2 2 CO2Me CO2Me Mes N N Mes Ph 4 Cl Ru 91%, 4.5:1 E/Z Cl PCy3 2nd gen Grubbs

R Connon, S.J.; Blechert, S. Angew. Chem. int. Ed. Engl. 2003, 42, 1900. Note: There is much work and progress in the RCM of diynes, using alkylidyne (carbyne) intermediates

R Furstner, A.; Davies, P.W. or Mo(CO) + Cl OH Chem. Commun. 2005, 2307. (t-BuO)3W 6(cat) Ring Closing Metathesis reviews - many, many, many - selected ones include.. R Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243. R Conrad, J. C.; Fogg, D. E. Current Organic Chemistry 2006, 10, 185. R Grubbs, R. H.; Trnka, T. M. 'Ruthenium in Organic Synthesis' 2004,153 R Mulzer, J.; Oehler, E. Top. Organomet. Chem. 2004, 13, 269 R Grubbs, R. H Tetrahedron 2004, 60, 7117 R Hoveyda, A.H.; Schrock, R.R, Angew. Chem. Int. Ed. Engl. 2003, 42, 4592 (Mo) R Hoveyda, A.H.; Schrock, R.R Chem.-Eur. J. 2001, 7, 945 (asymmetric) R Furstner, A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3012. R Jafarour, L.; Nolan, S.P. J. Organomet. Chem. 2001, 617-618, 17. R Tanka, T.M.; Grubbs, R.H. Acc. Chem. Res. 2001, 34, 18. R Schrock, R.R., Tetrahedron 1999, 55, 8141. (Mo) 184