Allylation of C=O Bonds Carreira: Chapter 5.1

Allylation of C=O Bonds Carreira: Chapter 5.1 – 5.9

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. ozonolysis epoxidation MXn O OH dihydroxylation R1 R1 H hydroboration

oleﬁn methathesis M = Li, Mg, Sn, Si, B, hydrogenation Cr, Ti, Zn, Zr cycloaddition hydroformylation

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. syn & anti diastereomers R2 MX O n OH OH OH R1 R1 R2 R1 R1 H depending on M, any could be formed R2 R2

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) Preparation and Reactivity 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.

R X–SiR3 R2B–OMe MgX R3Si B R allylsilane Li allylborane OR X–SnR3 K B(OMe)3 R3Sn B then HOR OR allylstannane exchange allylboronate

CrCl2 X CrCl2

X = Br, I 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 Reagents Both (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. M endo:exo M M MgBr 1:3 H H Me M Li 3:1 H H Na 10:1 a crotyl metal H Me K 125:1 (slow) reagent Me H endo exo Ca 500:1

t-BuOK slow t-BuOK Me (time, rt) Me Me BuLi K K BuLi Me Me Me (Z)-2-butene (E)-2-butene (E)-crotyl (E)-crotyl potassium potassium (thermodynamic) (kinetic)

FB(OMe)2 FB(OMe)2

OMe OMe B Me B OMe OMe

Me (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.

O Me OH Me Me + O Me H Me MeO B Me O Me Me OMe

0.9 equiv 90:10 E : Z > 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.

CrCl X 2 CrCl2

Me Me fast O OH CrCl2 R H Me X Me CrCl2 R Me Reactivity Trends The 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.

Type 1 Type 1 Type 2 O Type 3 E → anti & Z → syn + R MXn R H closed, cyclic T.S. (E) MX = BR , BX , B(OR) OH OH n 2 2 2 SnX3, SiX3 R R Type 2 R R E & Z → syn syn anti open T.S.

O MXn = SnBu3, SiMe3 + MXn Type 3 Type 1 R H Type 3 R Type 2 E & Z → anti (Z) closed, cyclic T.S.

MXn = CrCl2, Cp2TiX Seems like a lot of information, but the mechansism Cp ZrX of each tells the stroy 2 Transition States Several 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).

Lig Lig H OH H OH M Lig M Lig R O R H O R R R H R R R from (E)-reagent anti from (Z)-reagent syn

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. LA O R MR H R R3M 3 LA OH (E) O R H or H R MR3 R H R R R MR3 syn (Z) antiperiplanar synclinal (favorable orbital interactions) Allylation with Boron Reagents All 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.

Lig Lig H OH H OH B Lig B Lig R O R H O R R R H R R R from (E)-reagent anti from (Z)-reagent 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.

Me Ph Ts B N 2 B Ph N H Ph Ts allyl diisopinocampheylboranes CO2i-Pr (Ipc BAllyl) Corey B 2 O Brown B CO2i-Pr O 9-BBN-derived reagents tartrate-derived allylboronates Soderquist Roush Brown Allylation Prepared 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.

d Ipc2BAllyl or l OH O Ipc2BCrotyl R R H Et2O, –78 ºC RZ RE then NaOH, H2O2

Me MgBr B 2 Me Me

Me Me d a. BH3•SMe2 BOMe Ipc2BAllyl 2 b. MeOH K Me B R (+)-α-pinene (–)-Ipc2BOMe Me E 2 (note change or RZ in rotation) Me K d Ipc2BCrotyl

d Preparation of allyl: J. Am. Chem. Soc. 1983, 105, 2092. (Org. Synth. 2011, 88, 87.) Ipc2 from (+)-α-pinene Preparation of crotyl: J. Am. Chem. Soc. 1986, 108, 5919 l Ipc2 from (–)-α-pinene Brown Allylation Stereoselectivity model dIpc BAllyl 2 d d or w/ Ipc2BAllyl w/ Ipc2B-E-Crotyl l OH % ee % ee O Ipc2BCrotyl R R CH >99 CH 90 R 3 3 R H Et2O, –78 ºC Bu 96 Ph 88 RZ RE then NaOH, H2O2 Ph 96 CH2=CH 90 t-Bu 99 rapid reaction at –78 ºC dr 95:5

Me Me

H H H H Me H Me Me H Me B B R O Me Me R Me R Me E E O R RZ RZ

Favored transition state Disfavored transition state (Si face addition) (Re face addition) Brown Allylation of α-Chiral Aldehydes The selectivity of the Brown reagents typically overrides any facial preference of the aldehyde. O OH OH Me Me Me H +

Me Me Me d Ipc2BAllyl 96 : 4 l Ipc2BAllyl 5 : 95

O OH OH Me Me Me H + OBz OBz OBz

d Ipc2BAllyl 94 : 6 l Ipc2BAllyl 4 : 96

O OH OH Me Me Me H + OBz OBz Me OBz Me

d Ipc2B-(Z)-Allyl 73 : 27 J. Org. Chem. 1987, 52, 319. lIpc B-(Z)-Allyl 1 : 99 J. Org. Chem. 1989, 54, 1570. 2 Roush Allylation Prepared 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.

i-PrO2C O

B RZ O i-PrO2C OH O RE R R H 4 Å sieves, toluene, –78 ºC RZ RE

i-PrO i-PrO2C B(Oi-Pr)3 L-(+)-DIPT O MgBr B B i-PrO O i-PrO2C

K i-PrO i-PrO2C B(Oi-Pr)3 L-(+)-DIPT O Me or B RE B RZ Me K i-PrO O i-PrO2C R Z RE

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

i-PrO2C w/ E-Crotyl w/ Z-Crotyl O w/ Allyl dr >97:3 dr >97:3 B R Z R % ee % ee % ee O i-PrO2C OH n-C9H19 79 88 86 O RE c-C6H11 87 91 83 R R H 4 Å sieves, toluene, –78 ºC t-Bu 82 73 70 RZ RE Ph 71 66 55

O Oi-Pr i-PrO C attractive 2 interactions i-PrO O O H CO2i-Pr H B B O O O R R E O O E R R RZ n/n repulsion RZ Favored T.S. Disfavored T.S. (Si face addition) (Re face addition)

Model calculations: J. Am. Chem. Soc. 2002, 124, 10692 Soderquist Allylation of Ketones Asymmetric 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.

O (R)-reagent HO RS

RL RS Et2O, –78 ºC RL

Me Me Ph Ph MeO H Ph Ph B Me2N PhCHN MeO Me N OH O 2 B 2 B (0.5 equiv)

resolution

H H The TMS derivative SiMe3 Ph MgBr is also a useful reagent (R) for aldehyde allylations B B (J. Am. Chem. Soc. 2005, 127, 8044)

J. Am. Chem. Soc. 2005, 127, 11572 Soderquist Allylation of Ketones

Stereoselectivity model

Me Ph Me Ph RS H Ph Ph O (R)-reagent Me2N OH HO R Me N O (R) S 2 O RL B B RL RS Et2O, –78 ºC RL

(recyclabe)

H Ph Ph H RL RS % ee Ph Me 96 O O B B Ph Et 94 (w/ S-reagent) R RL L 4-BrC6H4 Me 98 (w/ S-reagent) Et Me 87 (w/ S-reagent) CH2=CH Me 81 (w/ S-reagent) RS RS i-Pr Me 92 (w/ S-reagent) Ph H 90 Favored T.S. Disfavored T.S. (Re face addition) (Si face addition)

J. Am. Chem. Soc. 2005, 127, 11572 Soderquist Double Allylation Reactions reacts with ketones H H Me3Si Me3Si C (S) H (S) B + H B B B THF H (S) 25 ºC (S) Ph 15 min Ph trans-1 O ﬁrst add rapid (~60:40) R1 Me equilibrium Me B R1 O (S) Me Si H H 3 Me3Si H Ph (S) (S) B B B H (S) Ph trans-2 does not react with ketones 1,3-borotropic then add O shift B (S) Ph Me OH OH 2 O R H H Me R1 R2 B H O R1 2 2 H NaOH, Δ (S) (workup) SiMe3 single diastereomer J. Am. Chem. Soc. 2009, 131, 1269 >98% ee M O O S Diastereoselective Boron Allylation Reactions L L Reactions of allyl- and crotylboron reagents with chiral aldehydes are subject S H H M to the Cram and Felkin-Ahn models described previously. But we must also Felkin anti-Felkin take into account the added sterics of the crotyl group.

Me (E)-crotyl Me Me Me O Me OH H O Me H R B Me O R Me B Me Me O O O Me H R Me Me syn- H H pentane H minor Me major Felkin (anti-Felkin) (Felkin) product

Me (Z)-crotyl Me Me Me O Me OH H H O Me B Me R O R H Me B Me O O O H H R Me Me Me H Me minor Me major anti-Felkin syn- (Felkin) (anti-Felkin) product pentane M O O S Diastereoselective Boron Allylation Reactions L L With chiral boron reagents, the facial selectivity of the chiral aldehyde is often S H H M overruled by the chiral reagent. Felkin anti-Felkin (R,R) CO2i-Pr Me O Me Me Me Me B CO2i-Pr Me Me O O O Me O Me O H O + O

O OH OH Felkin product anti-Felkin product J. Org. Chem. 1990, 55, 4117 matched case: (R,R)-reagent (shown) dr = 91:9 mismatched case: (S,S)-reagent Me dr = 2:98 B Me 2 OH OH O d Ipc2BCrotyl BzO BzO BzO H + Me Me Me Me Me Felkin product anti-Felkin product d J. Org. Chem. 1989, 54, 1570 matched case: Ipc2BCrotyl (shown) dr = 98:2 similar results with Z-crotyl l mismatched case: Ipc2BCrotyl dr = 5:95 Allylation with Silicon and Tin Reagents Allylsilanes 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). LA O R MR H R R3M 3 LA OH (E) O R H or H R MR3 R H R R R MR3 syn (Z) M = Sn, Si antiperiplanar synclinal

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

aldehyde LUMO C O In general the allylsilanes are popular due to their oleﬁn H C stability over allylboranes. HOMO 2 CH2 C H M

J. Am. Chem. Soc. 1980, 102, 7107; J. Org. Chem. 1994, 59, 7889; Tetrahedron Lett. 1983, 24, 2865 Allylation Reactions With Chiral Aldehydes Because 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.

OTBS SnBu3 OTBS OTBS H + Lewis acid O OH OH

Felkin product BF3•OEt2: dr = 5:95 MgBr2: dr = 21:79

OBn SnBu3 OBn OBn H + Lewis acid O OH OH

Felkin product Br BF3•OEt2: dr = 39:61 Br MgBr2: dr = >250:1 sterically most Mg demanding RO H H H O H Bu3Sn H sterically least H SnBu3 H O demanding H LA Cram chelation Felkin-Ahn OR Chiral Allylsilanes and Allylstannanes There 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. OH OH

Me SiMe3 R H TiCl4 Ph Ph + R + R Ph O Me Me (R,E)-silane achiral major enantiomer aldehyde OH OH

SiMe3 R H TiCl4 Ph Ph + R + R Me Ph O Me Me (R,Z)-silane achiral major enantiomer aldehyde

R Ph H SiR H H OH 3 H H H Me Ph H Ph R Me Ph Me SiR SiR3 3 O R H H H H Me A1,3-strain

J. Am. Chem. Soc. 1982, 104, 4962 & 4963 Formation of Tetrahydrofuran rings

Slightly different reactivity can be achieved if dimethylphenylsilanes (Me2SiPh, DMPS) are used. Here a 1,2-silyl shift competes with elimination.

Me Me SiMe2Ph Me OMe R H BF3•OEt2 + dr 30:1 CO2Me PhMe2Si O O –78 to –30 ºC R O H H Me

H Me H H Me Me R CO Me O F B 2 Me 3 SiR3 CO2Me O R H Si H H R3

J. Am. Chem. Soc. 1991, 113, 9868 Allylation of acetals Allylsilanes 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.

OMe OMe OMe OMe TMSOTf Me + BnO CO2Me BnO CO2Me OMe –78 ºC PhMe2Si Me dr 20–30:1

OMe Me CO Me 2 H OMe PhMe Si H BnO Me 2 Me TMSOMe + O CO2Me Me SiR3 O H H OBn

J. Am. Chem. Soc. 1991, 113, 6594; J. Org. Chem. 1991, 56, 5755. Enantioselective Allylation with Allylsilanes Jim 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. Me Ph

Me NH OH (1S,2S)-pseudoephedrine ArCHNH HN CH Ar RZ 2 2

Et3N, CH2Cl2 Cl3Si RE DBU, CH2Cl2

RZ RZ CH2Ar Ph R Both can be prepared in high yield R O E and purity and on large scale. The N E Si strain associated with silacycle makes Si Cl the silicon atom more Lewis acidic. Cl Me N N Cat A Cat B Me CH2Ar 2:1 dr @ Si O 1 stereoisomer H R X R H R X R Si Si O Cl X X Cl pentavalent silicate • less strained J. Am. Chem. Soc. 2002, 124, 7920; Angew. Chem. Int. Ed. 2003, 42, 946 Angew. Chem. Int. Ed. 2006, 45, 3811; J. Am. Chem. Soc. 2011, 133, 6517 Enantioselective Allylation with Allylsilanes Some examples...

(R,R)- OH allyl-Cat A O allyl-Cat B OH BnO BnO BnO Toluene H CH2Cl2 –10 ºC 85% yield, 88% ee –10 ºC 67% yield, 97% ee

(R,R)- (S,S)- OBn OH allyl-Cat B OBn O allyl-Cat B OBn OH

R CH2Cl2 R H CH2Cl2 R 86% yield, 95:5 dr –10 ºC –10 ºC 86% yield, 98:2 dr

(S,S)-Z- (S,S)-E- crotyl-Cat B crotyl-Cat B OTBS OH OTBS O OTBS OH cat. Sc(OTf)3 cat. Sc(OTf)3

CH2Cl2, 0 ºC H CH2Cl2, 0 ºC Me Me Me Me Me 82% yield, 97:3 dr 78% yield, 99:1 dr

J. Am. Chem. Soc. 2002, 124, 7920; Angew. Chem. Int. Ed. 2003, 42, 946 Angew. Chem. Int. Ed. 2006, 45, 3811; J. Am. Chem. Soc. 2011, 133, 6517 Selectivity Model with Diamine Reagents A 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. R R RZ RE H R R Ar O Z E Ar O Cl H H N Si H N Si Cl N N

H H favored Ar Ar

OH OH

R R

RE RZ RE RZ

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