Hydrofunctionalizations

When the process is catalytic, the following general scheme is likely involved.

Certain transition metal hydrides (and main group hydrides) are useful for delivering more than just "H2" to olefins and alkynes. In these cases the net transformation is the addition of a hydrogen and another funcation group.

R HLnMn

LnMn+2 R

HO.A.LnMn+2 R

Hinsertion

syn

LnMn

R H

R.E.

R H = "H–Sn", "H–B", "H–Si", "H–C=O", "H-Zr" (non-catalytic)

B(OR)2cross-coupling

oxidation (alcohol or carbonyl)

SnBu3cross-coupling

conv. to alkenyl iodideanion formation

SiR3cross-coupling

oxidation (alcohol or carbonyl)

ZrCp2

cross-couplingconv. to alkenyl iodidereaction w/ aldehydes

CO insertion

HydrostannationAddition of Sn–H across alkyne. Bu3SnH is most commonly used. Palladium catalysis is quite common.Mixtures of regioisomers can often be a problem. "Bu3Sn" usually ends up on less hindered end of alkyne, but electronic factors can win out as well.

TBS

OH

OMe TBS

OH Ar

SnBu3

Bu3SnH1 mol% PdCl2(PPh3)2

THF, rt TBS

OH ArAcOHMeOH

60 ºC

93% (2 steps)Lindlar-type reduction was problematicTetrahedron 2009, 65, 10355.

Me

TIPSO Me TIPSO Me

Bu3Sn

Bu3SnHPdCl2(PPh3)2

THF, rt

I2

CH2Cl2TIPSO Me

I

45% (2 steps)Org. Lett. 2009, 11, 3282.

Me

OMe

OHHO

Bu3SnHPdCl2(PPh3)2

THF, rt

OMe

OHHO SnBu3

Me OMe

OHHO

Me

SnBu3

+

61% yield 18% yieldJ. Org. Chem. 2009, 74, 6452.

HydrostannationWith alkynoates the tin usually ends up on the α-position ("conjugate addition of hydride").

J. Org. Chem. 2009, 74, 703.

OTHP

TBSO CO2MeBu3SnH

Pd(PPh3)4

THF

OTHP

TBSO

SnBu3MeO2C

OTHP

TBSO

HMeO2C

SnBu3H +

45% yield(1:1)

OTHP

THPO CO2MeBu3SnH

Pd(PPh3)4

THF

OTHP

THPO

SnBu3MeO2C

H

84% yield

HydroborationMetal catalysed hydroboration of alkenes and alkynes can be accomplished with dialkoxyboranes, most commonly catecholborane and pinacolborane. Dialkoxyboranes not as sensitive as dialkylboranes.

OBH

O

OBH

O

catecholborane(HBcat)

pinacolborane(HBpin)

HBcat +O

O

catB

OBcat

requires temps of70–100 ºC to

hydroborate olefins

0.5 mol%RhCl(PPh3)3

C6H6, 0ºC

no catalyst

C6H6, 0ºConly product

A

B

B : A83 : 17

Angew. Chem. Int. Ed. Engl. 1985, 24, 878.

Mechanism is quite similar to hydrogenation by Wilkinson's cat.

J. Am. Chem. Soc. 1992, 114, 9350.J. Am. Chem. Soc. 1992, 114, 6679.

HydroborationMetal catalysed hydroboration of alkenes and alkynes can be accomplished with dialkoxyboranes, most commonly catecholborane and pinacolborane. Wilkinson'c catalyst is commonly employed, but other can be used as well.

Stereoselectivity and regioselectivity can be higher than "traditional" hyrdoborations. Dialkoxyboranes not as sensitive as dialkylboranes. Chemoselectivity toward olefins/alkynes over ketones/aldehydes much higher.

O

O

O

O

BPSO BPSO

catecholboraneRh(PPh3)3Cl

J. Am. Chem. Soc. 2001, 123, 10942.

cuprate

BO

O

NaBO3

85%alcohol

OBH

O

OBH

O

catecholborane pinacolborane

HydroborationWilkinson's catalyst is commonly employed, but other can be used as well. The regioselectivity of the process can be quite dependent on both substrate and catalyst identity.

Ar1. HBcat, catalyst

2. H2O2, NaOHAr

OH

ArOH+

RhCl(PPh3)3 (argon)RhCl(PPh3)3 (in air)[Rh(COD)2]BF4/dppbCp2TiMe2

> 992499

0

< 176

1100

J. Am. Chem. Soc. 1992, 114, 9350.J. Am. Chem. Soc. 1996, 118, 1696.

Bu1. HBcat, catalyst

2. H2O2, NaOHBu

OH

BuOH+

RhCl(PPh3)3 Cp*2Sm(THF)

1< 1

99> 99

1. HBX2, Wilk. cat.

2. H2O2, NaOH(E)-C3H7CH=CHC3H7 1-octanol + 2-octanol + 3-octanol + 4-octanol

HBcatHBpin

0100

THFCH2Cl2

00

00

1000

HydroborationPalladium catalyzed hydroboration of dienes provides access to allyl boronates.

R+ HBcat

Pd(PPh3)4

C6H6, rt H

R

PdBcatL

Me

R

Bcat

R

HMe

yield (%)

81 (syn > 99%)89 (syn > 99%)Tetrahedron Lett. 1989, 30, 3789.

Alkynes can also be substrates. Not only is regioselectivity a problem, but stereoselectivity can also be a factor (net syn hydroboration not guaranteed).

HBX2

catalyst

Cp2Ti(CO)2Rh(CO)(PPh3)2Cl

RhCl(PPh3)3[Rh(cod)Cl2]/4Pi-Pr3

1009948

1

000

99

01

520

HR

R

H BX2

H

R BX2

R

X2B H+ +

HBcatHBpinHBpinHBcat

p-TolC4H9p-TolPh

Asymmetric Hydroboration

Enantioselective hydroborations are possible, but are quite limited at this time.

Me+ HBcat

1 mol%[Rh(COD)((S)-QUINAP)]OTf

then H2O2, NaOH

MeOH

91% ee

+ HBcat

1 mol%[Rh(COD)((S)-QUINAP)]OTf

then H2O2, NaOH91% ee

OH

N

PPh2

(S)-QUINAP

J. Chem. Soc., Chem. Commun. 1993, 1673.

HydrosilylationUnlike borohydrides, silicon hydrides generally do not add to olefins or alkynes without a catalyst. Hydrosilylation is an important industrial reaction for generating silicon-containing materials. While there are a number of intermolecular examples that use simple silanes, the real synthetic utility is with intramolecular hydrosilylations.

O Si

R

Me MeH

R

HO

HN(SiMe2H)2neat, Δ

or ClSiMe2Hbase

ROSi

H

Me Me

nn

catalyst

OSi

Me Me

H

R

nn

or

Alkynes are very common, but olefins can also be used.

common catalysts: H2PtCl6, Pt(DVDS), Cp*Ru(CH3CN)3PF6, RhCl(PPh3)3, Rh(acac)(CO)2

SiMe2O

Me2Si

PtPt(DVDS)

H2O2, KHCO3KF, MeOH, THF

O

R

OH

nn R

OHO

Tamaooxidation

the hydrosilylation products arerelatively robust and can serve

as a protecting group until removalis needed

Hydrosilylation

i-Pr OPMB

MeO O

OH OPMB

TMS1. (Me2SiH)2NH

2. cat. Pt(DVDS) THF

i-Pr OPMB

MeO O

H

SiMe2

O

OPMBTMS

H2O2, KHCO3KF, MeOH, THF

i-Pr OPMB

MeO O O OH OPMB

TMS

J. Am. Chem. Soc. 2004, 126, 2495.

Hydrosilylation

J. Am. Chem. Soc. 2005, 127, 17644.

1 mol% Cp*Ru(CH3CN)3PF6

HSiMe2Cl, CH2Cl2, 15 min

EtSiCl

Me MeCO2Et

EtEtO2C

Me

HOthen, Et3N

Et

EtO2C

Me2SiO

Me

C6H6

180 ºC(sealed tube)

SiMe2

O

Me

EtCO2Et

87% yield

TBAF

DMF60 ºC

MeCO2Et

Et

HO

69% yield(protodesilylation)

H2O2, DMFTBAF, 60 ºC

MeCO2Et

Et

HO

65% yield

OH

HydrozirconationNot catalytic, but still highly useful.

ZrCl

ClZr

Cl

HLiAlH4

THF

zirconocenedichloride

Schwartz'sreagent

Reaction with olefins results in formation of the terminal alkylzirconium species. This can be through direct reaction of a terminal olefin, or by initial reaction with an internal olefin followed by a series of eliminations/isomerizations to the terminal species.

Cp2ZrCl2 = = Cp2Zr(H)Cl

Cp2Zr(H)ClCp2Zr

Cl

Cp2Zr(H)ClCp2Zr

Cl Cp2Zr(H)ClCp2Zr

Cl

> > > > >&

order of reactivity (tetrasubstituted and trisubstituted cyclic do not react)

HydrozirconationThe alkylzirconium products can be readily converted into many different functional groups.

RCp2ZrCl

RBr

RI

RCl

I2

Br2

or NBS

PhICl2or NCS

OCp2Zr

Cl

R

O2

H2OHO R

H2O2, NaOH, H2Oor TBHP or mCPBA

CO

Cp2ZrCl

OR

H3O+

RH

O Br2

MeOH RMeO

O

H2O2

RHO

O NBS

RBr

O

HydrozirconationSchwartz's reagent also reacts readily with alkynes to give alkenylzirconium intermediates. Syn addition is observed. React with aldehydes in the presence of a Lewis acid and are useful in transmetallation reactions and cross couplings.

RL

RS Cp2Zr(H)Cl

RL

ZrClCp2H

RS

RL

IH

RSI2(retention of configuration)

CO

RL

H

RS

OZrClCp2 H+

RL

H

RS

OH

AgClO4

RHO RL

H

RS

HOR

Zirconation on less substituted side predominates. By using a slight excess of Cp2Zr(H)Cl the mixture can be equilibrated to enrich this preference.

Zirconium-Catalyzed CarboaluminationAlkylzirconocenes to do "carbozirconate" alyknes. But zirconocene dichloride (Cp2ZrCl2) can catalyze "carboaluminations" of alkynes with high syn selectivity. AlMe3 is most commonly used.

Mechanism still not entirely clear. The one most consistent with data:

Me3Al + Cp2ZrCl2Cl

ZrCp2MeCl

Me2Al

RC CHAlMe Clδ+

RC CH

ZrCp2Meδ–

Me

R H

AlMe2

+ Cp2ZrCl2

Me Cl

Me3AlCl + Cp2ZrClMe

Me

R H

Al

Me ZrCp2Cl

Cl

Me

R H

cat. Cp2ZrCl22-3 equiv AlMe3

CH2Cl2, DCE or toluenert

Me

R H

AlMe2

furtherreactions

syn-selective

Mechanism discussion:J. Am. Chem. Soc. 1983, 103, 4985.J. Am. Chem. Soc. 1996, 118, 9577.

J. Am. Chem. Soc. 1978, 100, 2252.J. Am. Chem. Soc. 1985, 107, 6639.H2O promoted: Angew. Chem. Int. Ed. 1993, 32, 1068.

Zirconium-Catalyzed CarboaluminationThe resulting σ-alkenylaluminum intermediate can undergo several transformations. Retention of congiuration is generally observed.

R H

cat. Cp2ZrCl2AlMe3

Me

R H

AlMe2

Z-selective

Pure. Appl. Chem. 1981, 53, 2333.

D2O

Me

R H

D Me

R H

X

I2, NCS,NBS ClCO2Et Me

R H

CO2Et

9-BBN–OMe

Me

R H

BR2

BuLi

Me

R H

AlMe2Bu

aluminate intermediate

RCHO

Me

R H

RHO

CO2Me

R H

CO2H

ClCH2OMe

Me

R H

CH2OMe

Zirconium-Catalyzed CarboaluminationMore examples:

R H

AlMe3, Cp2ZrCl2DCE R

Me AlMe2

H a. switch to hexaneb. BuLi

c.

R

Me

H

R

OHO

RSynthesis 1980, 1034.

O

Bu H+

a. cat. Cp2ZrCl2 AlMe3, DCEb. switch to Et2O

c. CuCNd. 1-hexynyllithium

O

HBu

Me

95% yieldJ. Org. Chem. 1990, 55, 1425.

Cu

HBu

Me

NC

Bu via

H

OH

AlMe3cat. Cp2ZrCl2

DCE, rtOH H

Me

AlMe2

> 98% E

80 ºC

72 hrs OH AlMe2

Me

H

> 98% ZOH I

Me

H

60% yield

I2

J. Org. Chem. 1997, 62, 784.

thermal isomerization of homopropargylic alcohols

Olefin IsomerizationsInitially considered a bit of a nuisance in olefin reductions, but has become a useful strategy if controlled properly. Typical catalysts are those used in hydrogenation reactions (Pd, Rh, Ru, Ir). Typically give the more substituted olefin. No one general catalyst.

Main utility lies in being able to isomerize terminal olefins into the more thermodynamically favorable internal olefins.

MeMe

OMe

HAr

MeMe

Me

HAr

Ph3P=CH2Me

Me

MeMe

HAr

RhCl3•3H2O

EtOH, Δ

Org. Lett. 2002, 4, 4483.

100% 100%

NO

H

HO

Cbz

1. NaH, CS2 MeI, THF, 97%

2. allyltributyltin hν, C6H6, 87% N

OH

CbzN

OH

Cbz

Me

PdCl2(CH3CN)2

CH2Cl2, rt94%

Tetrahedron Lett. 2005, 46, 1459.

allyl is easily installed propenyl is difficultto install

Olefin IsomerizationsIsomerization of allylic alcohols, ethers, and amines also quite useful. Gives aldehydes, enol ethers, and enamines, respectively.

NMe

OH 1 mol%Crabtree's cat.

(H2 added and removedbefore substrate)

THF, rt NMe

O

Tetrahedron Lett. 2009, 50, 4141.

NEt2

< 1 mol%{Rh[(S)-BINAP][cod]}ClO4(H2 added and removed

before substrate)

THF, rt

Me

NEt296–99% ee

Me

O(R)-citronellal (natural is 80% ee)

H3O+

2 steps

Me

OH

> 1000 tons/year ofL-menthol producedby this route. 1/3 of

world demand.

J. Am. Chem. Soc. 1984, 106, 5208.

Olefin IsomerizationsSeveral different mechanisms are possible depending on catalyst and conditions.

M H X+ XHM

XH + M H

Isomerization by metal hydrides

Isomerization by low-valent metals

M(n) X+X

XH + M(n)M(n+2)H

M OH+ O OH +

Isomerization by low-valent metals

X MH

M X

HydroformylationAs the name implies, hydroformylation is the process of adding the components of H2 and CO to an olefin. While other metals are possible, the use of Rh complexes is most common (usually Wilkinson's catalyst). Typically terminal olefins are used. Very important industrially.

RhClL3 + RH2, CO

R

H O

RhL

CO

LR

H O

H

The reaction is reversable, so high pressures of CO must often be used. However, this can be a useful means of removing an aldehyde. Aldehydes on sp2 and sp3 carbons both work. Retention of stereochemistry is observed.

R

O

H

RhCl(PPh3)3RhH

ClLLL

O

Rlow temp

RH

stoichiometric becauseRhCl(CO)L2 is less reactive

high temp(> 100 ºC)

H

R

β-elimination alsooccurs at high temp

Hydroformylation

NO

HCbz

O3CH2Cl2

–78 ºC86% N

OH

Cbz

O

RhCl(PPh3)3

toluene, 45 ºC69% N

OH

Cbz

Me

Tetrahedron Lett. 2005, 46, 1459.

TrO

Me

O(o-DPPB)

Me

0.7 mol% [Rh(CO)2acac/4 P(OPh)3toluene, 90 ºC, 20 bar (H2/CO, 1:1)

90%, dr 96:4

TrO

Me

O(o-DPPB)

Me O

O

OH

PPh2o-DPPBTetrahedron Lett. 1998, 39, 1901

NR1

R2

0.1 mol% [Rh(CO)2acac]/ chiral ligandtoluene, 60 ºC, 10 bar (H2/CO, 1:1)

> 97% conv., b/l 66:34 – 84:16N

R1

R2

CHON

R1

R2

CHO+

92–96% eeAngew. Chem. Int. Ed. 2010, 49, 4047

HydroacylationIn some cases, the acylmetal intermediate can be intercepted by alkenes and alkynes before the decarbonylation occurs. Cyclic products result.

Bu

MeH

O Rh(cod)2BF4BINAP

CH2Cl284%

O

Me

H

Bu

CHO

PhPh

O

H

Rh(dppe)ClO4

DCE, ethylene65%

RH

O

XR

X

OMe5 mol%

Rh(R,R)-Me-DuPHOS)BF4

CH2Cl2, rt80–97% yield, 93–98% ee

J. Am. Chem. Soc. 2009, 131, 6932.X = O, S, S(O)