Allylation of C=O Bonds

Reviews: Schinzer, D. Synthesis 1988, 263–273; Fleming, I.; Dunogues, J.; Smithers, R. Org. React. 1989, 37, 57–575; Hoffman, R. W. Pure Appl. Chem. 1988, 60, 123–130; Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293–1316 (chiral allyl & allenyl silanes); Yus, M.; González-Gómez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774–7854 (enantioselective catalysis)

H

OR1

Carreira: Chapter 5.1 – 5.9

OHR1

MXn

M = Li, Mg, Sn, Si, B, Cr, Ti, Zn, Zr

epoxidation

dihydroxylation

cycloaddition hydroformylation

ozonolysis

hydroboration

olefin methathesis hydrogenation

Of all of the alkyl groups that can be introduced into a molecule, the allyl group is arguably the most versatile. The double bond can participate in a number of synthetically useful transformations.

While simple allyl Grignard or allyllithium reagents can be used as the nucleophile, they are often far too reactive to be used in stereoselective reactions. Can be quite basic, and reaction rate is too fast to be overly selective. With substituted allyl groups (e.g., crotyl), there is also the question of olefin

geometry and which end reacts.

H

OR1

OHR1

MXnR2

R2OH

R1

R2

OHR1

R2depending on M, any could be formed

syn & antidiastereomers

Preparation and Reactivity

MgX

The reactivity of the reagents derived from the alkali and alkaline earth metals can be tamed by swaping the metal with a main group and transition metal element. Of particular importance are

reagents derived from silicon, boron, tin, and chromium.

Li

K

R2B–OMeB

R

R

allylborane

R3Si

allylsilane

X–SiR3

B(OMe)3

then HORexchange

BOR

OR

allylboronate

R3Sn

allylstannane

X–SnR3

X

X = Br, I

CrCl2 CrCl2

prepared in situ

The above allyl reagents display a wide range of reactivities toward aldehydes and ketones:

allylsilanes: typically no reaction in the absense of a strong Lewis acid activation

allylstannanes: will react with heating or in the presence of modest Lewis acid activation

allylboronates: can react with aldehydes in the absence of activators at room temp (slow)

allylboranes: can react with aldehydes in the absence of activators even at –100 ºC

Crotyl Metal ReagentsBoth (Z)- and (E)-crotyl metal reagents can be prepared from 2-butene and an alkali metal reagent.

The degree of selectivity depends on the metal used and how easily it isomerizes.

HMe

H

HM

MMe

a crotyl metalreagent

MeH

H

HM

endo exo

M endo:exoMgBr 1:3

Li 3:1Na 10:1K 125:1 (slow)

Ca 500:1

Me Met-BuOK

BuLi KMe

(Z)-2-butene

K

Me(E)-crotyl potassium(kinetic)

(E)-crotyl potassium

(thermodynamic)

t-BuOKBuLi

(E)-2-buteneMe

Me

slow(time, rt)

FB(OMe)2 FB(OMe)2

Me

BOMe

OMeB

OMe

OMeMe

(Z)-boronate (E)-boronate

Reactivity of (E)- & (Z)-allyl reagents(E)-substituted reagents tend to react faster than the (Z) stereoisomers. For other substitution patterns

a kinetic resolution can be used to enrich the allylmetal reagent.

Me

MeH

O

MeO BO

OMeMeMe

Me

+

0.9 equiv 90:10 E : Z

Me

Me

OH

OMe

> 98 : 2 anti : syn

Allylchromium reagents are stereoselective irrespective of the starting configuration of the allyl halide precursor. Both halide isomers react, but the allylchromium reagent undergoes rapid equilibration to

form the thermodynamically favored (E)-isomer.

Me

X

XMe

CrCl2

CrCl2

Me

CrCl2

CrCl2Me

fast

R H

O

R

OH

Me

Reactivity TrendsThe transition state that is thought to be active and the observed stereoselectivity is dependent on the

type of allylation reagent used. The different reactivity tpes arise from how Lewis acidic the metal is and how configurationally stable the reagent is.

R

MXn

MXnR

(Z)

(E)

+R H

O

+R H

O

R

OH

Ranti

R

OH

Rsyn

Type 2

Type 3

Type 1Type 3

Type 1Type 2

Type 1E → anti & Z → synclosed, cyclic T.S.MXn = BR2, BX2, B(OR)2 SnX3, SiX3

Type 2E & Z → synopen T.S.MXn = SnBu3, SiMe3

Type 3E & Z → anticlosed, cyclic T.S.MXn = CrCl2, Cp2TiX Cp2ZrXSeems like a lot of information, but the mechansism

of each tells the stroy

Transition StatesSeveral different mechanisms/transition states are possible. All based on the nature of the metal.

Type 1 & 3 reagents are Lewis acidic enough to activate the aldehyde without additional promoters. This results in a closed, six-membered transition state (Zimmerman-Traxler).

Type 2 reagents do not activate the aldehyde by themselves and require an additional Lewis acid promoter. This results in a open transition state. Two have been proposed. Either can be used

depending on the sterics of the specific system.

OM

H

RH

R

Lig

Lig

from (E)-reagent

RR

OH

anti

OM

H

RR

H

Lig

Lig

from (Z)-reagent

RR

OH

syn

H RO

HR

MR3 R

HO

HR

R3M

antiperiplanar synclinal(favorable orbital

interactions)

LA

LA

or

MR3R

(E)

R

MR3

(Z)

RR

OH

syn

Allylation with Boron ReagentsAll are type 1 reagents and react through a Zimmerman-Traxler-type transition state. (E)-substituted

reagents lead to anti products, while (Z)-substituted reagents lead to syn products.

OB

H

RH

R

Lig

Lig

from (E)-reagent

RR

OH

anti

OB

H

RR

H

Lig

Lig

from (Z)-reagent

RR

OH

syn

The greatest utility of the boron reagents are the different reagents available for carrying out enantioselective reactions. These use stoichiometric amounts of the source of chirality, but all are

reasonably inexpensive.

MeB

2

allyl diisopinocampheylboranes(Ipc2BAllyl)

BrownB

tartrate-derived allylboronatesRoush

O

O

CO2i-Pr

CO2i-Pr

B

Corey

N

N

Ph

Ph

Ts

TsB

PhH

9-BBN-derived reagentsSoderquist

Brown AllylationPrepared easily from either (+)- or (–)-α-pinene. The allyl reagent is stable under inert atmosphere as a stock solution. The crotyl reagents isomerize upon storage and must be generated and used in situ.

MeB

2

dIpc2BAllylMeMe

Me

(+)-α-pinene

a. BH3•SMe2

b. MeOH

MeBOMe

2

Preparation of allyl: J. Am. Chem. Soc. 1983, 105, 2092. (Org. Synth. 2011, 88, 87.)Preparation of crotyl: J. Am. Chem. Soc. 1986, 108, 5919

MeB

2

dIpc2BCrotyl

RZ

RE

MgBr

K

Me

KMeor

R

O

H

dIpc2BAllylor

lIpc2BCrotyl

R

OH

RZ RE

(–)-Ipc2BOMe

(note changein rotation)

Et2O, –78 ºCthen NaOH, H2O2

dIpc2 from (+)-α-pinenelIpc2 from (–)-α-pinene

Brown AllylationStereoselectivity model

BO

RZ

RE

Me

Me

MeMe

MeMe

HH

O

BH

RZ

RE

Me

Me

MeMe

MeMe

HH

R

Favored transition state(Si face addition)

H

R

Disfavored transition state(Re face addition)

R

O

H

dIpc2BAllylor

lIpc2BCrotyl

R

OH

RZ REEt2O, –78 ºC

then NaOH, H2O2

rapid reaction at –78 ºC

R % eeCH3 >99Bu 96Ph 96t-Bu 99

w/ dIpc2BAllylR % ee

CH3 90Ph 88

CH2=CH 90

w/ dIpc2B-E-Crotyl

dr 95:5

Brown Allylation of α-Chiral AldehydesThe selectivity of the Brown reagents typically overrides any facial preference of the aldehyde.

J. Org. Chem. 1987, 52, 319.J. Org. Chem. 1989, 54, 1570.

OMe

H

Me

OHMe

Me

OHMe

Me

+

dIpc2BAllyllIpc2BAllyl

96 : 45 : 95

OMe

OBzH

OHMe

OBz

OHMe

OBz

+

dIpc2BAllyllIpc2BAllyl

94 : 64 : 96

OMe

OBzH

OHMe

OBz

OHMe

OBz

+

dIpc2B-(Z)-AllyllIpc2B-(Z)-Allyl

73 : 271 : 99

Me Me

Roush AllylationPrepared from either (+)- or (–)-DIPT and the allyl boronic ester. The boronate reagent is sensitive to

moisture, but can be distilled and stored under inert atmosphere at –10 ºC.

Preparation of allyl: J. Am. Chem. Soc. 1985, 107, 8186Preparation of crotyl: J. Am. Chem. Soc. 1990, 112, 6339 (Org. Synth. 2011, 88, 181.)

MgBr

K

Me

KMeor

R

O

H R

OH

RZ RE

BO

O

i-PrO2C

i-PrO2C

4 Å sieves, toluene, –78 ºC

RZ

RE

B(Oi-Pr)3

B(Oi-Pr)3

Bi-PrO

i-PrO

Bi-PrO

i-PrORZ

RE

L-(+)-DIPT

L-(+)-DIPT

BO

O

i-PrO2C

i-PrO2C

BO

O

i-PrO2C

i-PrO2C

RZ

RE

Roush AllylationStereoselectivity model

R % een-C9H19 79c-C6H11 87

t-Bu 82Ph 71

w/ Allylw/ E-Crotyl

dr >97:3

R

O

H R

OH

RZ RE

BO

O

i-PrO2C

i-PrO2C

4 Å sieves, toluene, –78 ºC

RZ

RE

% ee88917366

w/ Z-Crotyldr >97:3% ee

86837055

O

B

O

O

H

RRZ

RE

i-PrO2C

Model calculations: J. Am. Chem. Soc. 2002, 124, 10692

O

B

O

O

H

RRZ

RE

CO2i-Pr

OOi-Pr

attractiveinteractions

O

i-PrO

Favored T.S.(Si face addition)

Disfavored T.S.(Re face addition)

n/n repulsion

Soderquist Allylation of KetonesAsymmetric allylation of ketones has been a difficult problem. To address this Soderquist has developed

an allyl borane based on 9-BBN. The TMS-substituted version works well for allylation of aldehydes (94-99% ee), >98:2 dr), but their reactivity with ketones is very slow (2 days, 25 ºC) and less selective

(62% ee). The phenyl substituted reagent was designed to be more reactive toward ketones.

J. Am. Chem. Soc. 2005, 127, 11572

RL

O

RS RLEt2O, –78 ºC

(R)(R)B

PhH

BMeO

PhCHN2 B

PhHMeO

B

PhMe2N O

Me PhPh

OHMe2N

Me

(0.5 equiv)

resolution

MgBrB

SiMe3HThe TMS derivativeis also a useful reagentfor aldehyde allylations

(J. Am. Chem. Soc. 2005, 127, 8044)

HO RS(R)-reagent

Soderquist Allylation of Ketones

J. Am. Chem. Soc. 2005, 127, 11572

RL

O

RS RLEt2O, –78 ºC

B

PhH

HO RS(R)-reagent

Stereoselectivity model

RL RSPh MePh Et

4-BrC6H4 MeEt Me

% ee9694 (w/ S-reagent)98 (w/ S-reagent)87 (w/ S-reagent)

CH2=CH Me 81 (w/ S-reagent)i-Pr Me 92 (w/ S-reagent)Ph H 90

O B

H Ph

RS

RL

O

RS

RL

Favored T.S.(Re face addition)

Disfavored T.S.(Si face addition)

(R)(R)B

PhHO

RS

RL B

PhMe2N O

Me PhPh

OHMe2N

Me

(recyclabe)

(S)

Soderquist Double Allylation Reactions

J. Am. Chem. Soc. 2009, 131, 1269

HB

Ph

H(S)(S)

B

Me3Si HC

+THF25 ºC15 min

B

Ph

H

(S)(S)B

Me3Si H

trans-1

B

Ph

H

(S)(S)B

Me3Si H

trans-2

rapidequilibrium

does not reactwith ketones

reacts with ketones

R1 Me

Ofirst add

B

PhH(S)(S)

B

Me3Si HR1

MeO

(S) (S)

(S)

B PhH

B

SiMe3

HR1Me

O

(S)

(S)

1,3-borotropicshift

R2

O

H

then add

H2O2NaOH, Δ(workup)

R1

Me OH

R2

OH

(~60:40)

single diastereomer>98% ee

Diastereoselective Boron Allylation ReactionsReactions of allyl- and crotylboron reagents with chiral aldehydes are subject to the Cram and Felkin-Ahn models described previously. But we must also

take into account the added sterics of the crotyl group.S

M

L

O

HFelkin

M

S

L

O

Hanti-Felkin

OB

H

Me

O

O

Me

Me

Me

MeH

Me

RHBO

HH

RMeMe

O

O

Me

Me

Me

Me

H

syn-pentane minor

(anti-Felkin)major

(Felkin)

R

Me

OH

Me

Felkinproduct

OB

Me

H

O

O

Me

Me

Me

MeH

Me

RHBO

MeH

RMe

H

O

O

Me

Me

Me

Me

H

syn-pentane

minor(Felkin)

major(anti-Felkin)

R

Me

OH

Me

anti-Felkinproduct

(E)-crotyl

(Z)-crotyl

Diastereoselective Boron Allylation ReactionsWith chiral boron reagents, the facial selectivity of the chiral aldehyde is often

overruled by the chiral reagent.S

M

L

O

HFelkin

M

S

L

O

Hanti-Felkin

OO

MeMe

O

H

J. Org. Chem. 1990, 55, 4117

BO

OCO2i-Pr

CO2i-Pr

MeO

O

MeMe

OH

Me OO

MeMe

OH

Me+

(R,R)

matched case: (R,R)-reagent (shown)dr = 91:9

mismatched case: (S,S)-reagentdr = 2:98

Felkin product anti-Felkin product

O

H

J. Org. Chem. 1989, 54, 1570

OH

Me

OH

Me+

matched case: dIpc2BCrotyl (shown)dr = 98:2

mismatched case: lIpc2BCrotyldr = 5:95

Felkin product anti-Felkin productMe

BzOMe Me

BzO BzO

MeB

2dIpc2BCrotyl

Me

similar results with Z-crotyl

Allylation with Silicon and Tin ReagentsAllylsilanes and allyl stannanes are not Lewis acidic. Because of this they cannot activate the

aldehyde themselves and so require an external Lewis acid promotor. They react through an open transition state. Both antiperiplanar and synclinal transition state have been proposed and either can

be employed depending on the sterics of the system. With crotyl reagents, the sense of diastereoselectivity is often independent of the olefin geometry (though the ratio may differ).

H RO

HR

MR3 R

HO

HR

R3M

antiperiplanar synclinal

LA

LA

or

MR3R

(E)

R

MR3

(Z)

RR

OH

syn

J. Am. Chem. Soc. 1980, 102, 7107; J. Org. Chem. 1994, 59, 7889; Tetrahedron Lett. 1983, 24, 2865

The synclinal transition state is thought to take advantage of secondary orbital interactions

C O

H2CCH

CH2

M = Sn, Si

M

aldehydeLUMO

olefinHOMO

In general the allylsilanes are popular due to their

stability over allylboranes.

Allylation Reactions With Chiral AldehydesBecause Si and Sn are not directly involved in the transition state, we must consider both Cram

chelation and Felkin-Ahn models in allylation reactions with chiral aldehydes.

H

O

OTBS SnBu3

Lewis acidOH

OTBS

OH

OTBS

+

BF3•OEt2: dr = 5:95MgBr2: dr = 21:79

Felkin product

H

O

OBn SnBu3

Lewis acidOH

OBn

OH

OBn

+

BF3•OEt2: dr = 39:61MgBr2: dr = >250:1

Felkin product

OR

HH O

LA

HH

H

Bu3Sn

Felkin-Ahn

H

HO

HSnBu3

RO Mg

BrBr

Cram chelation

sterically mostdemanding

sterically leastdemanding

Chiral Allylsilanes and AllylstannanesThere are also several methods available for preparing chiral allyl silanes and stannanes. These

undergo diastereoselective reactions with aldehydes. The chirality is transferred from the allylsilane/stannane to the product.

J. Am. Chem. Soc. 1982, 104, 4962 & 4963

Me SiMe3

Ph(R,E)-silane

HR

O+

achiralaldehyde

TiCl4 PhOH

RMe

major enantiomer

PhOH

RMe

+

SiMe3

Ph(R,Z)-silane

HR

O+

achiralaldehyde

TiCl4 PhOH

RMe

major enantiomer

PhOH

RMe

+Me

MeH

H

SiR3

HPh

MeH

H SiR3H

Ph

A1,3-strain

OR

H

H

MeH

RO

H

H

PhSiR3

PhOH

RMe

Formation of Tetrahydrofuran ringsSlightly different reactivity can be achieved if dimethylphenylsilanes (Me2SiPh, DMPS) are used. Here

a 1,2-silyl shift competes with elimination.

J. Am. Chem. Soc. 1991, 113, 9868

Me

PhMe2Si

HR

O+

MeOMe

O

BF3•OEt2

–78 to –30 ºC OCO2MeR

MeH H

SiMe2PhMe

dr 30:1

H

ROH

MeH

HSiR3

Me

CO2MeF3B CO2MeH

MeSi

MeH

O R

R3

Allylation of acetalsAllylsilanes can also react with acetals. Here the electrophile is an oxocarbenium ion. Using TMSOTf

as the Lewis acid gives higher yields. Similar selectivities observed with other Lewis acids.

J. Am. Chem. Soc. 1991, 113, 6594; J. Org. Chem. 1991, 56, 5755.

Me

PhMe2SiOMe

OMe+CO2Me

OMeTMSOTf

–78 ºCdr 20–30:1

BnO CO2Me

OMe

Me

OMeBnO

H

OH

MeH

HSiR3

OMe

CO2MeMe

OBn

OBnO Me

Me

PhMe2SiCO2Me

OMe

TMSOMe +

Enantioselective Allylation with AllylsilanesJim Leighton (Columbia) has developed several chiral silicon-based reagents for enantioselective allylations of aldehydes, ketones, and imines. They likely react through a closed transition state.

J. Am. Chem. Soc. 2002, 124, 7920; Angew. Chem. Int. Ed. 2003, 42, 946Angew. Chem. Int. Ed. 2006, 45, 3811; J. Am. Chem. Soc. 2011, 133, 6517

Cl3Si RE

RZ

NH

Me Ph

OHMeNH HN CH2ArArCH2

Et3N, CH2Cl2 DBU, CH2Cl2

NSi

NCH2Ar

CH2Ar

RE

RZ

ClMe

Ph

NSi

O

Me

RE

RZ

Cl

2:1 dr @ Si 1 stereoisomer

(1S,2S)-pseudoephedrine

Both can be prepared in high yield and purity and on large scale. The

strain associated with silacycle makesthe silicon atom more Lewis acidic.

XSi

X R

Cl XSi

X R

ClO

O

RH RH

pentavalentsilicate

• less strained

Cat A Cat B

Enantioselective Allylation with AllylsilanesSome examples...

J. Am. Chem. Soc. 2002, 124, 7920; Angew. Chem. Int. Ed. 2003, 42, 946Angew. Chem. Int. Ed. 2006, 45, 3811; J. Am. Chem. Soc. 2011, 133, 6517

H

OBnO

(R,R)-allyl-Cat B

CH2Cl2–10 ºC

OHBnO

67% yield, 97% ee

OHBnO

85% yield, 88% ee

allyl-Cat A

Toluene–10 ºC

H

O(S,S)-

allyl-Cat B

CH2Cl2–10 ºC

OH

86% yield, 98:2 dr

OH

86% yield, 95:5 drR

OBn(R,R)-

allyl-Cat B

CH2Cl2–10 ºC

R

OBn

R

OBn

H

O

(S,S)-E-crotyl-Cat Bcat. Sc(OTf)3

CH2Cl2, 0 ºC

OH

78% yield, 99:1 dr

OH

82% yield, 97:3 dr

OTBS

(S,S)-Z-crotyl-Cat Bcat. Sc(OTf)3

CH2Cl2, 0 ºC

OTBSOTBS

MeMe MeMe Me

Selectivity Model with Diamine ReagentsA similar model could be envisioned for the pseudoephedrine reagents, but is more complicated due

to the stereogenic silicon and pseudorotation processes. The diamine ligand can be recovered in >90% yield after the reaction.

J. Am. Chem. Soc. 2002, 124, 7920; Angew. Chem. Int. Ed. 2003, 42, 946Angew. Chem. Int. Ed. 2006, 45, 3811; J. Am. Chem. Soc. 2011, 133, 6517

N Si

O

N

R

H

Ar

ArCl

N Si

O

N

Ar

Ar

Cl

H

H

H

HH

RERZR

RERZ

R

OH

RE RZR

OH

RE RZ

favored