Bismuth in Organic Synthesis

Jonathan LocknerBaran Group Meeting Bismuth in Organic Synthesis

Bismuth Factoids...

• mentioned as early as the 1450s as Wismutton or Bisemutum (old German for "white substance")

• employed in metallurgical purposes during 15th and 16th centuries (for instance, bismuth bronze was apparently used by Inca smiths)

"The decorative bronze handle of a tumi excavated at the Inca city of Machu Picchu, Peru, contains 18 percent bismuth and appears to be the first known example of the use of bismuth with tin to make bronze... The use of bismuth facilitates the duplex casting process by which the tumi was made and forms an alloy of unusual color." Science 1984 585

• specifically identified as a metallic element by 1753 (French chemist Claude François Geoffroy)

• heaviest "stable" element in periodic table, with only one "stable" isotope: 209Bi

It has long been suspected (on theoretical grounds) that 209Bi is radioactive, but it was not until 2003 that experiment proved this to be true. French physicists detected α-decay of 209Bi using the scintillating bolometer technique. Indeed, the α-decay of this element is very rare (half-life = 2 x 1019 years!) Nature 2003 876

• touted as an eco-friendly heavy metal (non-toxic and non-carcinogenic) (for instance, showcased at a 2006 IUPAC conference on green chemistry)

• relatively rare: 64th in abundance, comparable to Ag and Cd

• soft, heavy, lustrous, silver-white metal with an iridescent tinge

• serves as a suitable replacement for lead in fireworks, bullets, etc.

"Dragon's eggs are pyrotechnic stars which first burn for a period giving a visual effect then explode with a loud crackling report. Manufacture of this effect has become controversial due to the heavy metals involved in the process, particularly lead tetraoxide (Pb3O4). Nowadays, bismuth trioxide is commonly used as a more environmentally-friendly substitute for lead compounds in achieving the effect, and its occurence in fireworks displays has since become much more common." Wikipedia entry

• one of only two metals that expand on solidification, making its alloys suitable to manufacture of detailed metal castings

• PeptoBismol & Kaopectate, as well as cosmetics...

Ph3Sn Br BiI3−ZnR Rreplaced by:


83rd element, the heaviest pnictogen (group 15)

ground state configuration: [Xe]4f145d106s26p3 (five valence electrons)

most common oxidation states: +3, +5

in water, forms insoluble basic salts

high nucleofugality -- like lead(IV) and iodine(III)

Ph3Bi is better leaving group than OTf, owing to facile BiV/BiIII redox

highly oxidizing, high Lewis acidity, especially for BiV centers

1934 ! Challenger (BiV)

1949 ! Rigby (NaBiO3, Bi2O3)

1960s ! industrial catalysts (Bi-Mo...)

late 1970s to 1980s ! Barton; Dodonov: oxidation & arylation with BiV

mid 1980s ! Wada; Dubac: Barbier-type allylation & aldol with BiIII

late 1980s ! bismuthonium salts and ylides...

1990s ! catalytic oxygenation, Friedel"Crafts acylation, etc.

monographs: Organobismuth Chemistry, Suzuki & Matano, Elsevier 2001

chapter: Main Group Metals in Organic Synthesis, Vol 2, Ch 14, Wiley 2001

R'RCHOH R'RC=O

CHO + CN

BiX3(moisture-sensitive,corrosive)

Bi metal ($0.28/gm)

BiR3 (air & light sensitive)BiX5

BiAr3 (stable crystalline solids)

Ar3BiX2

Ar3RBiX(bismuthonium salts)

Ar3Bi=R(bismuthonium ylides)

(stability depends on substituents)

Ph3Bi $1.90/gm

Ph3BiCl2 $12.60/gm

BiBiCl3BiBr3Bi(OTf)3Bi2O3Bi(OAc)3Bi(NO3)•5H2OBi2(SO4)3NaBiO3Zn(BiO3)2

Bu3BiPh3BiPh3BiCl2Ph3Bi(OAc)2Ph3BiCO3Ph4BiOCOCF3

7440-69-97787-60-2CAS #88189-03-11304-76-322306-37-210035-06-0CAS #12232-99-4CAS #

3692-81-7603-33-8594-30-97239-60-347252-14-283566-43-2

C, X, O, RC, X, R, M

OC, X, R, M

OX, O

C, X, O, MO

O, MO

C, XC, X, OC, X, OC, X, OC, X, OC, X, O

general reviews: Mohan, Tetrahedron 2002 8373; Suzuki, Synthesis 1997 249

C carbon-carbonX carbon-heteroatomO oxidationR reductionM miscellaneous

Ar3BiCl2

NK

O

(2 equiv)

NO

Bi

O

ArAr

ArPyr

N O

Ar

Chem. Lett. 2005 11 1496An Ullman-type coupling that doesn't involve copper, and even works with Ar = o-Tol For any sort of addition or rearrangement, consider using catalytic BiCl3 or Bi(OTf)3

$1.40

$8.00


Oxidative cleavage of 1,2-diols (Barton, Tetrahedron 1986 5627)

Oxidative cleavage of !-ketols (J. Org. Chem. 1993 2196)

Alcohol oxidation (ACIE 2002 3028)

Oxidation of acyloins to !-diketones (Rigby, J. Chem. Soc. 1951 793)

Various oxidations using zinc bismuthate (Bull. Chem. Soc. Jpn. 1992 1131)

Catalytic oxidation of hydrocarbons: propylene (Adv. Catal. 1994 233)

O

OH

NaBiO3

AcOH"H2ORT, 12 h

H

O

OH

O

72%

OH

(o-Tol)3BiCl2"DBU

PhMe, RT, 30 min

CHO

94%

Ph3Bi (0.1 equiv)NBS, K2CO3

CH3CN, RT, 3 h(1% H2O)

72%

cf. Pb(OAc)4, NaIO4, MnO2

R

OH

R

OBi2O3

~100 °C, 15"30 minAcOH"EtOCH2CH2OH

R

O

R

O

(60"95%)

R1R2CHOH

RSH

R1SR2

R1R2C=NOH

Zn(BiO3)2

PhMe, reflux

R1R2C=O (60"100%)

(RS)2 (86"99%)

R1SOR2 (65"78%)

R1R2C=O (0"85%)

cf. BaMnO4, PCC

"superior to conventional oxidizing agents"presumed active species: Bi(OAc)3

O2

Bi"Mo"metal(s)"O

NH3

CHO

CN

Oxidation of cyclohexene (Chem. Lett. 1976 29)

Modified Prevost reaction (J. Chem. Soc., Chem. Comm. 1989 407)

Oxidative cleavage of epoxides with bismuth mandelate (Tetrahedron Lett. 1993 2601)

Bi2(SO4)3 (1.4 mol%)

EtCO2H, 65 °C, O2 (1 atm)via isomerization of peroxyradical?

CHO

90%

Bi(OAc)3, I2, AcOH

90 °C"reflux(dry system)

OAc

OAc

62"80%

Bi(OAc)3, I2, AcOH"H2O

90 °C"reflux(wet system)

OAc

OAc

70"95%+OAc

OH

cf. Ag, Hg, Tl

O

R1 R2

R1CO2H + R2CO2H

O

HO

10 mol% BiCl3t-BuOOH

CH3CN70 °C, 18 h

(80%)

O

HO O

Chemoselective allylic oxidation (Tetrahedron Lett. 2005 2581)

Dehydration (Tetrahedron Lett. 1994 5035)

OH Ph3BiBr2"I2

C6H12, RT2 h (87%)

cf. CrO3Cr(CO)6PDCRuCl3

toxic!

expensive!

BiIII"mandelate (10%)

DMSO, O2

(40"90%)

Ph3Bi(quant.)

OH

OH

O

O

+

"

"(4 h)

77%

Ph3Bi(quant.)

OH

OH

O

O

+

eg. of heterogeneous catalysis...


F

Barbier/Grignard-type allylation (Wada Tetrahedron Lett. 1985 4211)• compatible with hydroxyl, carboxyl groups (Wada Tetrahedron Lett. 1986 4771)• can be conducted in aqueous media (Bull. Chem. Soc. Jpn. 1997 2265; Chem. Lett. 2002 376)• allyl alcohols can be employed (PBr3 or TMSCl!NaI; Bull. Chem. Soc. Jpn. 2000 689)

Mohan's variation: allylation of aldehydes (J. Org. Chem. 2005 2091)

Friedel!Crafts acylation (Tetrahedron Lett. 1997 8871; 2003 2037)

Mukaiyama!aldol reaction (Tetrahedron Lett. 1992 1053)

Mukaiyama!Michael addition (J. Org. Chem. 1993 1835)

Knoevenagel condensation (Chem. Lett. 1992 1945)

Diels!Alder cycloaddition (Dubac, J. Org. Chem. 1997 4880)

Erlenmeyer!Plochl synthesis of oxazolones (Synth. Comm. 2000 3167)

Rearrangement of epoxides (Tetrahedron Lett. 2001 8129)

Enone "-arylation (Tetrahedron Lett. 2001 781; J. Am. Chem. Soc. 2001 7451)

Enone #-arylation (Tetrahedron 2006 10594; J. Am. Chem. Soc. 2004 5350)

• see also Barton, J. Org. Chem. 1999 6915

Note: with BiIII, arylation at " position; with BiV, arylation at # position

HN

OO

O

(!)-paroxetinePaxil (GSK)

F

BnN

OPBu3(p-F-Ph)3BiCl2

i-Pr2NEtCH2Cl2!t-BuOH (9:1)

RT 3 h, 79%

BnN

O

R3

OH

R1 R2

BiCl3

Al, Zn or FeR3

O

X

R2

R1+

5% Bi(OTf)3•4H2O

solvent!free!

R

O+

XArH

R

O

Ar

Ph Ph

BiCl3!3NaI

CH2Cl2, )))Ph

Ph

OOTMS

+

OH O

R1

O

R2R1

BiCl3!3NaI

CH2Cl2, )))R4

OTMS

+

O

R3

HCl

MeOHR3

R2 O

R4

10% BiCl3

80 °C20!30 min

RE

O

E+E E

R

R2

R1

R3R4

O

10% BiCl3 or1% Bi(OTf)3

CH2Cl261-88%

R2

R1R3

R4

O

+

Ar

O

+

HNPh

OH

O

O

10% Bi(OAc)3

Ac2O, reflux 1 hN O

Ar O

Ph

OR1

Ar

R2

R3

0.1% Bi(OTf)3

CH2Cl2Ar

R3

O

R1R2

R1

OR2Bi(OTf)3

R1

OTMS+

R2OH or (R2OC)2O

(p-F-Ph)3BiCl2

BiCl3 Cl2p-F-PhMgBr

Ph3Bi

Rh(COD)2BF412 h 50 °C, air

THF-H2O (84%)

(65!78%)

O O

Ph

elemental Bi generated in situ

intermediacy of allyl bismuth species?

cf. AlCl3, etc.

HCl

MeOHNaI & ))) enhance catalytic power of BiCl3

BiCl3 $ soft Lewis acid catalyst for coupling and rearrangement reactions

#-amino acids

• higher reactivity/selectivity, comparable yields to Sc(OTf)3, Yb(fod)3, etc.• no polymerization (cf. strong LA's)• Bi(OTf)3 is not decomposed by H2O; can be recovered, reused• chiral Bi catalysts?? (TBD)

eg. of heterogeneous catalysis...

cf. BF3•Et2O

via aryl transfer to transient ("-phosphonio)enolate


Reductive etherification (P. Andrew Evans, Org. Lett. 2003 3883)

Reductive etherification (J. Am. Chem. Soc. 2003 14702)

Synthesis of leucascandrolide A was reported at the ACS National Meeting, Sept 2006

Direct substitution of hydroxy group with amides (Angew. Chem. Int. Ed. 2007 409)

Biginelli reaction (Synlett 2001 863)

One-pot nucleoside synthesis (Synth. Comm. 1998 603)

Glycosylation via Ferrier rearrangement (Synthesis 2002 598)

Matano: oxazole synthesis via Bi ylides (J. Organomet. Chem. 2000 611 89)

Allylation of aldonitrones (New J. Chem. 2002 193)

Alkylation of amines via N-(alkylamino)benzotriazoles (Tetrahedron Lett. 1991 4247)

O

O

TESMeO OTBS

10 mol% BiBr3Et3SiH (1.4 equiv)

CH3CN, RT;then TBAF

93%

O

MeO OH(!)-centrolobine

MeO OTBS

"

"

complex mixture

O

O

TES

compare:

RO

OPMP

HO

O

BiBr3t-BuMe2SiH

CH3CN, 0 °C;

then 2,6-lutidineTMSOTf, 0 °C

93%

9O

OPMP

HO

9

(ds " 19:1)

(!)-mucocin

Me OR1

OOR2

CHO+ +H2N NH2

O

12 mol% BiCl3CH3CN

reflux, 5 h(72!95%)

NH

NH

OMe

R2

R1O

O

OOAc

AcO OAc

AcOTMSBr

5 mol% BiBr3CH2Cl2, 10 min

O

Br

AcO OAc

AcOO

base

AcO OAc

AcOsilylated base

BiBr3CH3CN, 4 h(65!80%)

ORO

RO

RO

+ R1

XH

(X = O, S)

5 mol% BiCl3

CH3CN, RT, 1!2 h(90!96%)

ORO

RO

XR1

R3 R1

OHR2

NuH (amide)5% Bi(OTf)3

5% KPF61,4-dioxane, RT

R3 R1

OHR2

"Bi"

R3 R1

NuR2

Ar3Bi

E

N

E

O

R

200 °C

5 min(92!96%)

O

N

R

E

E+ Ar3Bi

(quant.)

Bi powderNH4Cl (0.1 equiv)

DMF!H2OµW, 5 min (80!90%)

R3BrBiCl3!Al powder

THF!H2O, RT(34!87%)

Lewis acid or Bronsted acid catalysis?

solvolysis...

R1 R2

OSiR3 Ocat. BiBr3

Nu-SiR3 OR1

R2

NuOR1

NuR2

vs.

OCHO

O

+

Me

SiMe3 SiMe3

Me

OSiiPr3

BiBr3 (1 eq)CH3CN/CH2Cl2

Et3SiH, RT73%

O O

(ds " 99:1)

Tandem two-component etherification (J. Am. Chem. Soc. 2003 11456)

Sequential two-component cross-coupling followed by reductive etherification(J. Am. Chem. Soc. 2003 11456)

BiB

r 3 +

H2O

BiO

Br

+ H

Br

no preactivation (ROH # RX) required...

tolerates variety of FG's

$-anomer

cf. strong LA's (BF3•OEt2, SnCl4) and expensive triflates (Sc, Yb)

BiBr3 activates Si!X bond, converting TMSBr to halogenation reagent; then acts as LA catalyst, activating sugar for attack

better than using Hg

NN

N

NR1R2

NR1R2R3NN

N

OH

HNR1R2

! H2O

NOPh

ArH

+ BrN

OHPh

ArH

allylbismuth is generated, then treated with aldonitrone

Ar3BiCl2+

H2NCOR

KOtBu

CH2Cl2!50°C#RT

Ar3Bi=NCORDMAD

CH2Cl2RT!60°C

mechanism?


OO

O

H OH

CH2OMe

H

(Ph3BiCl)2OCHCl3

RT 24 hno yield given

Cembranolide diterpenes (Aust. J. Chem. 1979 1273)

SS

HO

OH

OCOPh

Ph3BiCO3;

then NaBH4 HO

OH

S

S

H

OCOPh

25%

+HO

OCOPh

S

S

H

OH

50%

TMG, 85%

Maytansinoids: oxidative cleavage of vic-diol (Barton, JCSCC 1980 1089)

Carbapenems (Barton, ACIEE 1993 867)

N

MeO

S

Ph

OOTESTESO

TESOOTES

TBAF, THF, 0 °C;

then Ph3BiCO3CH3CN, reflux

N

MeO

CHO

S

Ph

O

N

MeO

CHO

Ph

O

+

mCPBACH2Cl2, 20°C;then PhMereflux, 80%

40%

20%

(D-glucosamine served as chiral auxiliary in Staudinger reaction for !-lactam synthesis)

"-arylation of phenols (Barton, Tetrahedron 1988 4483; JCSCC 1980 827)

OH

Me

Me

Me

Me

Ph5Bi

PhH, 82%

O

Me

Me

Me

Me

Ph

"-alkenylation of phenols and !-dicarbonyl compounds (Matano, J. Org. Chem. 2004 5505)

OH

Me MeO

MeMe

Ph

Ar3BiPh

BF4

NN

NH

PhMe(76%)

"-allylation of phenols and !-dicarbonyl compounds (Matano, Tetrahedron Lett. 1995 7475)

"-alkylation of phenols and !-dicarbonyl compounds (Matano, Organometallics 2000 2258)

[Ar3MeBi+][BF4#]

review of bismuthonium compounds: Bull. Chem. Soc. Jpn. 1996 2673

So far, bismuth has been under-utilized in natural product total synthesis. Prior to P. Andrew Evans' several total syntheses involving bismuth-mediated reductive etherification, only a few examples are to be found:

OO

O

CH2OMe

HO

mixture of 2° alcohols enone

"mild oxidant"

Ph3BiF2

BF3#OEt2CH2Cl2#78 °C

TMS

Ph3BiBF4

warm to RT(thermal decomp.)

Ph

source ofallyl electrophile

"...bismuth-mediated polarity inversion of allylsilanes."

nucleophile Nu

(e.g. e- rich arenes)

other Nu:PhS

Me2SPhSO2Ph3P

an exotic methylating agent?(high nucleofugality: Ph3Bi leaving ability is ~ 2X that of triflate)

Ph3BiCl2 + PhLi Ph5Bi(stable for months)

OPh4Bi

Ar3BiF2 + BF3•OEt2

R(HO)2B

NaBF4, H2O

Ar3BiPh

BF4

All of the above rely on the high nucleofugality of Ar3Bi (facile V $ III redox)

Ar3BiF2 + MeB(OH)2

BF3•OEt2

CH2Cl2

NaBF4

H2O

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Bismuth in Organic Synthesis