Chemistry Publications Chemistry

2010

Copper-Catalyzed Allylic SubstitutionLevi M. StanleyIowa State University, lstanley@iastate.edu

John F. HartwigUniversity of Illinois - Urbana-Champaign

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Copper-Catalyzed Allylic Substitution

AbstractAllylic substitution catalyzed by copper261- 269 is a transformation that is related to allylie substitutionscatalyzed by other transition metals discussed previously in this chapter, but several features of copper-catalyzed allylations make them worth differentiating. First, copper-catalyzed allylic substitutions areconducted with different types of nucleophiles than most allylic substitutions catalyzed by other metals.Second, the regioselectivity of the copper-catalyzed reactions is typically different from that of reactionscatalyzed by complexes of other metals, particularly of reactions catalyzed by complexes of palladium. Thus,this last section of the chapter describes studies on allylic substitution catalyzed by copper, with an emphasison enantioselective examples.

DisciplinesChemistry

CommentsThis a chapter from Organotransition metal chemistry : from bonding to catalysis (2010): chapter 20.7, 999.Posted with permission.

This book chapter is available at Iowa State University Digital Repository: http://lib.dr.iastate.edu/chem_pubs/929

20.7. COPPER-CATALYZED ALLYLIC SUBSTITUTION 999

20. 7. Copper-Catalyzed Allylic Substitution (Written with Levi Stanley)

20. 7.1. Fundamentals

Allylic substitution catalyzed by copper261- 269 is a transformation that is related to ally­lie substitutions catalyzed by other transition metals discussed previously in this chapter, but several features of copper-catalyzed allylations make them worth differentiating. First, copper-catalyzed allylic substitutions are conducted with different types of nucleophiles than most allylic substitutions catalyzed by other metals. Second, the regioselectivity of the copper-catalyzed reactions is typically different from that of reactions catalyzed by complexes of other metals, particularly of reactions catalyzed by complexes of palladium. Thus, this last section of the chapter describes studies on allylic substitution catalyzed by copper, with an emphasis on enantioselective examples.

Copper-catalyzed allylic substitution is typically conducted with hard, nonstabilized carbon nucleophiles (Equation 20.64), instead of the "soft" stabilized carbon nucleophiles used most often in ally lie substitutions catalyzed by other transition metal complexes. The most common nucleophiles used in copper-catalyzed allylic substitutions are diorganoz­inc reagents, Grignard reagents, organolithium reagents, and trialkylaluminum reagents. Common allylic electrophiles include allylic halides, acetates, carbononates, phosphates, and tosylates.

R2 'Y a I ,

R1~LG~ 1~ ~ R2M R -y-Substitution

+ R1~R2 a-Substitution (20.64)

Copper-catalyzed allylic substitution typically occurs to form products from the addition of the nucleophile at the position 'Y to the leaving group. However, the tendency for copper-catalyzed allylic substitutions to form products from -y-substitution versus a-substitution depends on a number of reaction parameters, including the identity of the ally lie electrophile, the reaction solvent, the reaction temperature, and the source of the organometallic nucleophile. Early examples of ally lie substitutions with stoichiometric amounts of organocopper reagents demonstrated the importance of the identity of the organocopper species. For example, the reaction of the monoalkyl cuprate MeCu(CN)Li with a substituted cyclohexenyl acetate is regioselective for addition to the -y-position and occurs with anti stereoselectivity (Equation 20.65).270 The corresponding reaction of the dialkyl cuprate Me2CuLi also occurs with anti stereochemistry, but it gives a mixture of regioisomeric products.271 Thus, copper-catalyzed allylic substitutions are often conducted under conditions that prevent the formation of symmetrical dialkyl cuprates.

Me MeCu(CN)Li Me Me

&OM or

Mei;l +&Me Me2CuLi

(20.65)

MeCu(CN)Li 96 4 Me2CuLi 50 50

1000 CHAPTER 20: ALLYLIC SUBSTITUTION

I 1r*(C=C)

Figure 20.5. Orbital interactions proposed to account for the anti diastereoselectivity. Figure adapted from reference 272.

The observed anti stereoselectivity is proposed to result from simultaneous interaction of a 3d copper orbital with the 11'* (C=C) and <r* (C-X) orbitals of the allylic electrophile (Figure 20.5).272 Although anti diastereoselectivity is most often observed, additional fac­tors, such as chelating leaving groups273-277 or steric constraints270•278•279 on the allylic electro­phile, can override the inherent stereoselectivity.

Copper-mediated and copper-catalyzed allylic substitution reactions have been exten­sively developed over the past 40 years. Since the first report in 1969,280 much of the early literature on allylic substitution with organocopper reagents describes reactions con­ducted with stoichiometric quantities of the metaP70•271•278 However, allylic substitution reactions conducted with substoichiometric amounts of copper salts have been known since a report by Schlosser 281 in 1974, and most allylic substitutions with copper are now conducted with catalytic amounts of metal. Furthermore, the use of substoichiometric quantities of copper in combination with a chiral ligand has led to the development of catalytic, enantioselective copper-catalyzed allylic substitution reactions. A majority of this section of Chapter 20 summarizes factors that control regioselectivity and enanti­oselectivity, and illustrations of the reaction scope. However, mechanistic information is presented first to provide a foundation for understanding the synthetic methodology. This mechanistic information is still emerging and is less established than the mechanistic information on palladium-catalyzed allylic substitution.

20. 7.2. Mechanism of Copper-Catalyzed Allylic Substitution

Backvall and Van Koten proposed the most commonly cited mechanism for copper­catalyzed allylic substitution (top of Equation 20.66).282 This proposed mechanism involves initial coordination of the allylic electrophile to form an 1]2,11'-complex. Subsequent oxidative addition then sets the stereochemistry of the reaction and generates a <r-allyl intermediate in which the copper is bound to the position that is 'Y to the leaving group. In this mechanistic pro­posal, the regioselectivity of the reaction is dictated by the identity of the ligand X of the copper salt. When the ligand X is electron withdrawing, rapid reductive elimination occurs from the corresponding Cu(III) intermediate to form the 'Y-substitution product. When the ligand X is more electron donating, the <r-allyl intermediate in which the copper is bound at the 'Y-position is more stable. This greater stability is proposed to allow this intermediate to isomerize to the less sterically hindered a-substituted <r-allyl Cu(III) species through an 1]3,11'-allyl Cu(III) spe­cies. Subsequent reductive elimination would then form the a-substitution product.

Although many aspects of this mechanism have been accepted, computational studies by Nakamura283•284 and experimental studies by Bertz and Ogle285 suggest that modifica­tions to this proposal are needed to fit the current data. Bertz and Ogle obtained the first spectroscopic data on the allylcopper(III) intermediates285 that are commonly proposed in copper-catalyzed allylic substitution reactions. Their data imply that the structure of the allyl dimethylcopper(III) species contains a 11'-allyl unit.

Theoretical studies by Nakumura suggest that the regioselectivity of the allylic alkylation catalyzed by complexes of cyanocuprates can be rationalized by the unsymmetrical structure of the cuprate complex that undergoes oxidative addition of the allylic electrophile (bottom of Equation 20.66). These calculations imply that addition of MeCu(CN)Li to allyl acetate is 'Y-selective because the allyl complex contains two different ligands trans to the two termini of the 1]3-allylligand. The transition state for oxidative addition to form the isomer in which the methyl group is located trans to the acetate leaving group (R2=Me, LG=OAc in Equation 20.66) is calculated to be 3.2 kcal/mollower in energy than the transition state that forms the isomer in which the cyanide ligand (X=CN in Equation 20.66) is located trans to the leaving acetate. Because the methyl group couples with the allyl terminus located cis to it, this sequence leads to coupling of the methyl group with the allyl terminus that was located 'Y to the leaving group in the starting allylic electrophile. A further understanding of the mechanism awaits experimental studies on allylcopper(III) complexes containing CN or other ligands in an unsymmetrical species that could be involved in the catalytic cycle for 'Y-selective coupling of hard nucleophiles with allylic electrophiles catalyzed by copper complexes.

20.7. COPPER-CATALYZED ALLYLIC SUBSTITUTION 1001

R2 X

R1~LG [X-Cu'-R2]e

R2 ,X 'cu' lR'~LG ~

e

Oxidative addition -LG 6

'yu'"' R1~

Reductive elimination

'Y

R1~R2 a-substitution

/ ~OAc

+ e

Reductive elimination -cux

Me,C~_.CN /•

"~~OAc (+9.7 kcal/mol)

Me-Cu-CN

' NC~y~_.Me "~~OAc ( +9.1 kcal/mol)

-cux

ll 't,;,;,;e~4t'Cf

R1~Cuiii'R2 I

R2 '9ulll'x

R1~ X

l J Me,ce_.CN

,', u Me,C _.CN - , I ______. U

~- - 0c 'Y a 'OAc .!2oAc 'Y ~ (+21.7 kcal/mol) a

1 r f NC,ce_.Me

, u NC,C ,Me - , , : ______.. u 'Y~'-oAc !2o;:; 'YV. ( +24.9 kcal/mol)

20.7.3. Enantioselective Copper-Catalyzed Allylic Substitution

The enantioselective copper-catalyzed addition of alkyl nucleophiles to allylic elec­trophiles is now a well-established reaction. Some of first examples of this process were reported by Backvall and Van Koten.286 They showed that the addition of a Grignard reagent to an allylic acetate in the presence of a chiral arenethiolatocopper(l) complex proceeds with exclusive ')'-selectivity and measurable enantioselectivity (Equation 20.67). Subsequently, Diibnar and Knochel published on the use of diorganozinc reagents as nucleophiles in enantioselective copper-catalyzed allylic substitution.287•288 They reported additions of dialkylzinc reagents to allylic halides in the presence of a Cu(I) salt and fer­rocenyl-based chiral amines (Equation 20.68). Pineschi, Feringa, and co-workers reported early examples of enantioselective copper-catalyzed additions of dialkylzinc reagents to related cyclic 1,3-diene monoepoxides.289

n-Bu

~OAc + n-BuMgl

CuSAr-trimer (14 mol%) Et20, 0 ac

Cu

~ CuSAr=

s' 'NMe2 if Me

100:0 (ya selectivity) 42%ee

L (10 mol%) CuBr·Me2S (1 mol%)

Ph~CI + [(CHa)sCCH2l2Zn THF, -90 or -30 ac Ph~ ~H2

0

68% 95:5 ("{:a) 82%ee

~H2

~·-·" 0 t-Bu

82% 98:2 ("{:a) 96%ee

(20.67)

(20.68)

~2

R1~ "(·Substitution

Me~a Favored

'Y~Me Disfavored

(20.66)

1002 CHAPTER 20: ALLYLIC SUBSTITUTION

20. 7.3. 1. Diorganozinc Reagents as Nucleophiles

Diibnar and Knochel's initial work led to a number of additional reports on the use of diorganozinc reagents as nucleophiles in enantioselective copper-catalyzed additions to allyl halides. Zhou290 and Feringa291 reported that copper(!) complexes of phosphora­midite ligands catalyze additions of dialkylzinc reagents to allyl halides (Equations 20.69 and 20.70) with good to excellent regioselectivity and moderate to good enantioselectivity. Woodward subsequently showed that [3,[3-disubstituted a-methylene propionates formed with high enantioselectivities from the additions of a dialkylzinc reagent to electron-defi­cient allylic chlorides generated by Baylis-Hillman reactions (Equation 20.71).292•293

(Cu0Tfl2·C6H6 (0.5 mol %) L* (2 mol%)

Digylme, -30 oc Ph~ 82%

91 :9 ('y:u) 67%ee

CuOTf (1 mol%) :c ~ L*(2mol%)

Ph Br + i-Pr2Zn THF, _ 60 oc Ph ~

Cl

~~ C02Me J + Et2Zn

Ar

94% 97:3 ('y:u) 88%ee

CuTC (5 mol%) L* (10 mol%)

DME, MAO, -40 oc

L*""'

.. C02Me

Ar ''''Et

L*"" I H I MeO'C\ ~OMe ~ N ~

MAO = Methylaluminoxane (10 mol%)

Ph

(20.69)

0 >-.... , ' P-N

0/ >-~ Ph

Ph

0" >­P-N

0/ >-·•UI (20.70) Ph

53-95% 76-90% ee

(20.71)

The enantioselective copper-catalyzed addition of organozinc reagents to allylic elec­trophiles has been improved by Hoveyda and co-workers. They showed that a copper complex of a peptide-based ligand catalyzes enantioselective additions of dialkylzinc reagents to allylic phosphates in high yields and selectivities (Equation 20.72).294•295 Fur­thermore, the methodology tolerates a remarkable variety of substituents on the allylic phosphate and can be used to generate both tertiary and quaternary carbon stereocenters. Related peptide-based ligands were also developed for the copper-catalyzed synthesis of a-alkyl-[3,')'-unsaturated esters and a,a' -disubstituted-[3,')'-unsaturated esters from reac­tions of diorganozinc nucleophiles with a,[3-unsaturated carbonyl compounds bearing a leaving group at the ')'-position.296•297 Additional improvements in the amount of copper and chiralligand required, as well as the selectivities for additions of dialkylzinc reagents to allylic phosphates, were realized by using a chiral, dimeric Ag(I)-N-heterocyclic carbene complex to generate a chiral copper(I)-NHC catalyst (Equation 20.73).298•299 Related dimeric Ag(I)-NHC complexes have been used to generate copper catalysts for allylic alkylations of silicon-substituted allylic phosphates with diorganozinc reagents.300 The resulting allyl­silanes bearing silicon-substituted carbon stereocenters are formed with nearly perfect regioselectivity and excellent enantioselectivity (Equation 20.74).

I

20.7. COPPER-CATALYZED ALLYLIC SUBSTITUTION 1003

COCr:u ~NAy~ylNHn-Bu

0 -OH ""-i-Pr

R2 R2 R3

R1 ~OP(O)(OEt)2 + R32Zn

(10 mol%) (Cu0Tf)2C6H6 (5 mol %)

\ . .! . R1~

R1 = Ar, R2 = H R1 = Ar, R2 =Me 61-90% 58-92% 40:60 to 90:10 ('y:cx) > 30:1 ('y:cx) 84-95% ee 83-92% ee

R1 = alkyl, alkenyl or alkynyl, R2 = Me R1 = alkyl or alkynyl, R2 = Me 68-76% 77-78% 4.6:1 to > 30:1 ('y:cx) > 30:1 ('y:cx) 78-96% ee 82-91% ee

R2 1 Ag(I)-NHC dimer (0.5-1 mol%)

R1~0P(O)(OEt)2 + R3 Zn CuCI2•2H20 (1-2 mol%)

R2 Ra \ . .! -R1~

2 THF, -15 oc

R2 = H R2 = Me 52-94% 74-94% > 49:1 (-y:cx) > 49:1 ('y:cx) 86-97% ee 94-98% ee

§~

(20.72)

(20.73)

R I Ag(I)-NHC dimer (1-2.5 mol%)

1\ ,,., ~NN~ ~rT~

O A 11 PhMe2Si~OP(O)(OEt)2 + Et zn (CuOTfl2·CsH6 (1-2.5 mol%)

2 THF, -15 oc Et~

Ff.-\iM~2Ph ... ~(1J-NHc ~ \ ,,··H dil'I'IEJt"" 1?~ . Fl<~:i16t;:~.

R=H R= Me 72% 75% > 49:1 (-y:cx) > 49:1 ('y:cx) 98%ee 91%ee

Enantioselective copper-catalyzed desymmetrization of meso cyclic allylic bisdiethyl­phosphates has also been conducted with dialkylzinc reagents. Piarulli and Gennari initially showed that the copper(!) complex of a chiral Schiff base catalyzed the enantioselective desymmetrization of 4-cyclopentene-1,3-bis(diethylphosphate) with diethyzinc (Equa­tion 20.75).301 Piarulli, Gennari, and Feringa then improved upon the enantioselectivities

N--

(20.74)

1004 CHAPTER 20: ALLYLIC SUBSTITUTION

OP(O)(OEt)2 0 + Et,Zo

~OP(O)(OEth

L*(10 mol%) (Cu0Tf)2•C6H6 (10 mol%)

Toluene!THF (95:5) -78 to -60 ac

}>P(O)(OEt)2 Q BB%ee

Et

(20.75)

Ph ~ O

Cc~ .. ~S~ _..CHPh2 N ~

OH

for desymmetrizations of cyclohexene and cycloheptene bisphosphates by using copper(!) complexes of chiral phosphoramidite ligands.302,303

20. Z3.2. Grignard Reagents as Nucleophiles

Following the initial reports of enantioselective copper-catalyzed allylic alkylation with Grignard nucleophiles by Backvall and Van Koten/86 catalysts containing many chiralligand architectures have been studied for these reactions. Backvall and co-workers showed that the reactions of an allylic acetate with n-BuMgBr occurred with improved enantioselectivity in the presence of a catalyst containing a chiral ferrocenyl thiolate ligand (Equation 20.76).304, 305 Okamoto and co-workers reported a chiral Cu(I)-NHC complex that catalyzes the allylic alkylation of a 4-siloxy-2-buten-1-ol derivative with moderate enantioselectivity (Equation 20.77).306 However, synthetically useful levels of enantioselectivity in copper-catalyzed allylic substitution with Grignard reagents (Equa­tion 20.78) were not achieved until Alexakis's use of first-, second-, and third-generation phosphoramidite ligands (Equation 20.78)307- 309 and Feringa' s use of the Taniaphos ligand (Equation 20.79)310 in these reactions.

~OAc + n-BuMgl

L* (35 mol%) Cui (13 mol%)

Et20/toluene

TBSO_;=\.__OAc + n-HexMgBr

n-Bu

~ 88%yield

98:2 ('y:a selectivity) 64%ee

)-NMe2

~( I SLi

Fe

6 (20.76)

> 90%yield 95:5 ('y:a selectivity) (20.77)

60%ee

20.7. COPPER-CATALYZED ALLYLIC SUBSTITUTION 1005

Ph~ Chiralligand Cl + RMgBr Cu(l) salt

Ph

0 P-O NMe2 0 >·"'" "P-N

R

Ph~

:(

Ph P~

'><o a K 0/ >­Ph

o,O;M• o/J­

\_)--Me

(20.78)

Ph Ph Ph Me

(1 mol%) CuCN (1 mol%)

R2 = Et 94:6 (-y:a selectivity)

73%ee

R1~CI + R2MgBr

(1 mol%) CuTe (1 mol %)

R2 = i-Pr 90:10 ('Y:a selectivity)

83%ee

L* (1.1 mol%) CuBr•SMe2 (1.1 mol %)

CH2CI2, -78 oc

R2

(1 mol%) CuTC (1 mol %)

R = Et2

99:1 ('Y:a selectivity) 96%ee

NMe2

~ ~PPh2 J--_/

Fe Ph2P

R1v ~ Taniaphos

81 :19 to 100:0 (-y:a selectivity) 80 to 97% yield

9Q-97% ee

Alexakis and Feringa have since expanded the scope of allylic electrophiles that undergo copper-catalyzed allylic alkylations with Grignard reagents with high regio- and enantioselectivity. Alexakis showed that a copper complex of a phosphoramidite ligand is an efficient catalyst for additions of Grignard reagents to 13,'Y·disubstituted allylic chlorides (Equation 20.80) and endocyclic allylic chlorides (Equation 20.81).311 Furthermore, Feringa reported that 3-bromopropenyl ester electrophiles undergo allylic alkylations in the pres­ence of chiral allylic esters in high yield and enantioselectivity in the presence of the com­bination of Cu(I) and Taniaphos as catalyst (Equation 20.82).312

(20.79)

~CI + EtMgBr

L* (3 mol%) CuTC (3 mol %)

Et

~ .L.* =,

05=t0Me o/J-Cl

~I

~CI + n-BuMgBr

CH2CI2, -78 oc CIN I

L* (3 mol%) CuTC (3 mol %)

CH2CI2, -78 oc

92:8 ('Y:a selectivity) 85% yield 96%ee

C(_ n-Bu

96:4 ('Y:a selectivity) 98%yield

'L.* ;;=

\_)--oMe

05=t0Me o/J-

\_)--oMe

(20.81)

(20.80)

1006 CHAPTER 20: ALLYLIC SUBSTITUTION

~Me2

0

PhAO~Br + n-EtMgBr

L* (5 mol%) CuBr•SMe2 (5 mol %)

CH2CI2, -75 oc

~ Fe Ph2P

~ (20.82)

Et 0~1

87% yield 98%ee

20. Z3.3. Organoaluminum Reagents as Nucleophiles

Organoaluminum reagents also serve as nucleophiles for enantioselective, copper­catalyzed allylic alkylation reactions, and reactions of these nucleophiles occur with faster rates than those of other nucleophiles in selected cases in which a sterically hindered allylic electrophile is used. Hoveyda and co-workers reported highly enantioselective, copper-catalyzed allylic alkylation of acyclic allylic electrophiles with trialkylaluminum reagents in 2007.313 Low conversion(< 10%) was observed when Me2Zn was used as the nucleophile in the allylic alkylation of a hindered allylic phosphate, but high(> 95%) con­version was observed for the identical reaction conducted with Me3Al as the nucleophile. The method was applied to a double allylic alkylation reaction of a diene with Me3Al to form the corresponding C2-symmetric product of two alkylations with high enantiose­lectivity (Equation 20.83). A related protocol has since been developed for the enantiose­lective, copper-catalyzed addition of vinylaluminum reagents to ~-disubstituted allylic phosphates generated in situ (Equation 20.84).314

(EtOh(O)PO~OP(O)(OEth

CuCI2•2H20 (4 equiv.) AgL* (7.35 mol%)

CuCI2H20 (15 mol%)

THF, -15 •c 61% yield,> 98% ee

n-hex

1 equiv. DIBAL-H ~ n-hex == hexanes, 55 •c 1

~ ~ OP(O)(OEth ~ &Y AgL•(0.5moi%),CuCt,·2H,0(1 mol%)' I -" THF, -15 •c

87%yield > 98:2 ('Y:a selectivity)

> 98o/.o ee

(20.83)

(20.84)

t

~

•

4

20.7. COPPER-CATALYZED ALLYLIC SUBSTITUTION 1007

20.7.4. Miscellaneous Copper-Catalyzed Allylic Substitution Reactions

The scope of enantioselective, copper-catalyzed allylic substitution reactions is not lim­ited to so-called hard carbon nucleophiles and achiral acyclic linear electrophiles. A recent report from Ito, Sawamura, and co-workers showed that a diboron reagent can serve as a pronucleophile for enantioselective, copper-catalyzed boronation of (Z)-allylic carbonates (Equation 20.85).315 The corresponding chiral allylboronates were isolated in good yields with high enantioselectivities.

R~ l_OC02Me

R""' alkyl

B2pin2 (2.0 equiv.) L* (5-10 mol%)

Cu(Ot-Bu) (5-10 mol%)

THF, ooc

Tpin

R~

62-70% yield 90-95%ee

Me t-Bu ' ..

CCNxl L* = :

N p 1 ·, ...

t-Bu Me

(20.85)

The asymmetric ring opening of racemic cyclic and meso bicyclic epoxides is related to allylic substitution and has also been conducted with copper catalysts. Pineschi, Feringa, and co-workers reported the kinetic resolution of racemic, cyclic 1,3-diene monoepoxides by ring opening of the epoxide unit with dialkylzinc reagents (Equation 20.86).289 Later, Alexakis developed analogous kinetic resolutions with trialkylaluminum316 and Grignard reagents (Equation 20.87).317 Protocols for the desymmetrization of meso bicyclic substrates are also now well established. For example, oxabenzonorbornadiene derivatives react with dialkylzinc318•319 and Gringard320 reagents to form enantiomerically enriched 2-alkyl-1,2-dihydronaphth-1-ol derivatives (Equation 20.88). Finally, trialkylaluminum reagents serve as nucleophiles for enantioselective, copper-catalyzed desymmetrizations of meso bicyclic hydrazines (Equation 20.89).321- 323

Ph

d L* Cu(0Tf)2

PH

Me-0 0 >·"" "P-N + 0.5 equiv. ZnMe2

Toluene, -70 oc Racemic

M ••• VOH 44% yield 82%ee

Me3AI (0.5 equiv.) L* (2 mol%)

CuTC (1 mol %)

THF, -40 oc a Racemic

38%yield 96%ee

16:1 (SN2':SN2)

n-BuMgCI (0.5 equiv.) L* (1 mol%) OH

CuBr (1 mol0%) ()

Et20, -78 C •.. 8 ,,. n- u

45%yield 90%ee

0/ >­Ph

(20.86)

94:6 (formal SN2':SN2) 99:1 (formal SN2':SN2) (20.87) ~R2

~ Ph

l..* "!" 0 > ..... "P-N

0/ >­Ph

I PPh2 Fe

~ R~~~~:',

1008 CHAPTER 20: ALLYLIC SUBSTITUTION

¢G L* =

Et2Zn L* (7 mol%) EtMgBr Me OH

Cu(OTfh (3 mol %) ¢§·'El ~ L * (6.3 mol %)

0 ...• ,,Et Zn(OTfh (1.0 equiv.) Cu(0Tf)2 (3 mol %)

Toluene # Toluene # Room temperature -20 oc

90% yield 99:1 (anti:syn)

Ph 99%ee

0" >-P-N 0/ >-.... ,

Ph

20.8. Summary

L* =

L* (6 mol%) Cu(OTfh

87%yield

Ph 99:1 (anti:syn)

0 )-.....

' P-N 0/ >-

~ Ph

0

" H~_/(NPh ~ N\\ (Yo

81% yield 94%ee

88%ee

L* =

(20.88)

(20.89)

Enantioselective allyic substitution processes have been developed over the course of 30 years. Initial observations of the reactions of nucleophiles with palladium-allyl complexes led to the observation of catalytic substitutions of allylic ethers and esters, and then catalytic enantioselective allylic substitutions. The use of catalysts based on other metals has led to reac­tions that occur with complementary regiochemistry. Moreover, the scope of the reactions has expanded to include heteroatom and unstabilized carbon nucleophiles. Suitable electrophiles for these reactions include allylic esters of various types, allylic ethers, allylic alcohols, and allylic halides. Enantioselective reactions can be conducted with monoesters or by selection for cleavage of one of two equivalent esters. The mechanism of these reactions occurs by initial oxidative addition to form a metal-allyl complex. The second step involves nucleophilic attack on the allyl ligand for reaction of "soft" nucleophiles or inner-sphere reductive elimination for reactions of "hard" nucleophiles. The external nucleophilic attack typically occurs by reaction of the nucleophile with a cationic allyl complex at the face opposite to that to which the metal is bound. Exceptions include reactions of certain molybdenum-allyl complexes. Dissociation of product then regenerates the starting catalyst. Because of the diversity of the classes of these reactions, allylic substitution-in particular asymmetric allylic substitution-has been used to prepare a wide variety of natural products.

References and Notes

1. Trost, B. M.; Crawley, M. L. Chern. Rev. 2003, 103, 2921. 2. Tsuji, J.; Takahash.H; Morikawa, M. Tetrahedron Lett. 1965, 4387. 3. Hata, G.; Takahash.K; Miyake, A. f. Chern. Soc., Chern. Commun. 1970, 1392. 4. Atkins, K. E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970, 3821. 5. Trost, B. M.; Dietsch, T. J. f. Am. Chern. Soc. 1973, 95, 8200.