22 c o bond forming reactions

Myers
Williamson Ether Synthesis

Relative Reactivities:

Background

• Relative reactivities of electrophiles, with respect to the alkyl substituent:

• The synthesis of ethyl ether from sodium ethoxide and ethyl iodide was first reported by
Alexander W. Williamson in 1851:

H3C

OH

O Na+

Me, allylic, benzylic > 1º alkyl > 2º alkyl > branched 2º alkyl >> neopentyl, 3º alkyl
• Relative reactivities of electrophiles, with respect to the leaving group:

EtI

Na
H3C

Chem 115

C–O Bond-Forming Reactions: SN2 Reactions

(yield not provided)

H3C

O

CH3

OTf > OTs > OMs

I > Br > Cl

• Trimethyloxonium tetrafluoroborate (Meerwein's salt) is a powerful alkylating agent:
Williamson, W. Liebigs Ann. Chem. 1851, 77, 37!49.
Williamson, W. J. Chem. Soc. 1852, 106, 229–239.

H3C

• Since its original discovery, the Williamson ether synthesis method has become widely used in
both academic and industrial settings.

CH3
O
CH3

BF4

Intramolecular Williamson Ether Synthesis:

Overview

• Relative rates of ring formation:
R OH

base

R O

R'

X

R OR'
Ring size:

3~5>6>4>7>8

Fast
• R = 1º, 2º, and 3º alkyl
allyl, benzyl, aryl, heteroaryl

• X = I, Br, Cl, OSO2R

Slow

• R' = 1º, and 2º alkyl, allyl, benzyl

• Base = alkali metals/NH3(l), metal hydrides

• Proximity effect: in the following intramolecular etherification reaction, successive addition of
methyl groups on the substrate places the electrophile and nucleophile in closer proximity.

LHMDS, LDA, NaOH, KOH, K2CO3, Cs2CO3.

• Solvents: alcohol (alkoxide), DMF, DMSO and HMPA.
O
Mechanism

OMs

CH3
H3C

O

OMs

OMs
H3C CH3

• The reaction proceeds through an SN2 pathway.

Limitations

O

relative
rate of
ether
formation

1

3.5

3 x 103

CH3
H3C

O

OMs

H3C CH3
8.6 x 105

• For hindered substrates, base-catalyzed elimination of the alkylating agent can be problematic.
• For phenoxides, C–alkylation can compete with O–alkylation.

Kirby, A. J. Adv. Phys. Org. Chem. 1980, 17, 183–179.
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books:
Sausalito, CA, 2006; pg 497.
Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu

1


Myers

Chem 115

C–O Bond-Forming Reactions: SN2 Reactions

Examples

OCH3
OH

OCH3
O

K2CO3

Br
+

acetone
60 ºC, 98%

NO2

EtO
H3C CH3

NO2

1. t-BuOK, THF
0 ! 5 ºC

CH3

O

2. MsO
N

OH
S

(180 g)

N

CF3

5 ! 18 ºC

Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C. C.; Correia,
C. R. D. J. Org. Chem. 2005, 70, 1050–1053.

(232 g)

CH3

O
• For hindered substrates, KH often performs better than NaH.

EtO
H3C CH3

• KH is highly flammable and is supplied commercially as a 30% w/w slurry in mineral oil. In the
examples below, the authors used a 50% by weight homogenate of KH in paraffin, which is
observed to be air stable and operationally more convenient:

O
N

75%

S
(246.5 g)

H3C CH3
OH

CF3

H3C CH3

KH, BnBr

OBn

THF, 23 ºC, 99%

H3C CH3

N

Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R. K.; Shen, L.; Youells, S.; Zhang, Y. Org. Process

Res. Dev. 2007, 11, 1010–1014.
• In the following example, etherification proceeds via an epoxide intermediate. Addition of ZnBr2 was
found to promote epoxide opening:

H3C CH3
KH, BnBr

O

O

CH3

THF, 23 ºC, 91%

O

O

OH

CH3
OBn
OH

3.

HO

HO

TsO

H

• Alkyl chlorides can be converted in situ to the more reactive alkyl iodide:

F
N

H3CO

OH

CO2H

K2CO3, BnCl, KI
acetone, 60 ºC, 79%

H3CO

THF, 65 ºC

H
N

O
F

O

CO2H

O

OBn

F

Huang, H.; Nelson, C. G.; Taber, D. F. Tetrahedron Lett. 2010, 51, 3545–3546.

OBn

1. NaH, THF, 5 ºC
2. ZnBr2

F

OBn
Wu, G. G. Org. Process Res. Dev. 2000, 4, 298–300.

Bourke, D. G.; Collins, D. J. Tetrahedron 1997, 53, 3863–3878.

Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu

2


Myers
OH

OCH3
OCH3
CH3

NC

• Synthesis of a 5-HT2C receptor agonist :

OCH3
NaH, CH3I

CH3
O

Chem 115

C–O Bond-Forming Reactions: SN2 Reactions

steps

CH3
O

DMF, 0 ºC, 87%

OCH3

CH3

NC

HO

CH3

OCH3

(20 g)

O O
S
OEt
1. K2CO3, EtO
butanone, 110 ºC

CH3
EtO

NO2 2. H2, Pd/C
MeOH, 23 ºC
94% (2 steps)

steps

CH3

NH2•HCl

EtO

NH2

N

(18.6 g)

OCH3
OCH3
Peters, R.; Waldmeier, P.; Joncour, A. Org. Proc. Res. Dev. 2005, 9, 508!512

CH3
H3C

CH3O OH
O

H
N

CH3

• Synthesis of maxacalcitol (Oxarol"), an antihyperparathyroidism and antipsoriatic vitamin D3
analogue:

OH

H
OCH3

O

H3C

O

H3C

Pederin

H3C
TBSO
CH3

Wan, S.; Wu, F.; Rech, J. C.; Green, M. E.; Balachandran, R.; Horne, W. S.; Day, B. W.; Floreancig,
P. E. J. Am. Chem. Soc. 2011, 133, 16668!16679.

OH

H3C

1. NaH, THF, 23 ºC
2.

TBSO

• Synthesis of didemniserinolipid B:

H
Br

(17.2 kg)
OH

H
OH

O
H3C

N
CH3

Boc

+ MsO

O

15

O

NaH, DMSO
86%

H

O

O

H3C

Ph

CH3

CH3

H3C
TBSO
CH3

TBSO

3. L-selectride

O

15

THF, 70 ºC, 99%

H

O

N

CH3
CH3

H O CH3

THF, 70 ºC

OH
H

O

O

Boc
Ph

H3C
H3C

O

OH
steps

steps

OH

O O
S
NaO

O

O
NH2

O

H3C
TBSO
CH3

O

OH
H3C CH3

TBSO
(19.6 kg)

O

15

H3C

H3C CH3

H

HO

OH

Maxacalcitol

EtO2C
didemniserinolipid B
Marvin, C. C.; Voight, E. A.; Burke, S. D. Org. Lett. 2007, 9, 5357!5359.

Shimizu, H.; Shimizu, K.; Kubodera, N.; Mikami, T.; Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.;
Shimizu, M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.; Kobayashi, M.; Kigawa, M.; Kato, M.;
Kozono, T.; Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M. Org. Proc. Res. Dev. 2005, 9, 278!287.
Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu

3


Myers

Chem 115

C–O Bond-Forming Reactions: Diazoalkane Reagents
• Other acidic functional groups, such as phenols, can also be methylated.

Introduction
• Diazo compounds are uniquely reactive 1,3-dipoles

O
H

OH

H
N N

H

HO

O

O
CH3

N N
H

OH

HO

O
CH3

CH2N2, CH2Cl2
20 ºC, 60%

OH O
• Diazo compounds are toxic and potentially explosive. They covalently modify nucleobases and
thus are mutagens. Consequently, care must be taken when handling these compounds.

OH

H3CO

O

OH

Blade, R. J.; Hodge, P. J. Chem. Soc. Chem. Commun. 1979, 85–86.
• Alcohols are not sufficiently acidic to protonate diazomethane and require a catalyst to react.
Common catalysts include BF3•OEt2, HBF4, SnCl2 and silica gel:

Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479–1492.

Esterification and Etherification Using Diazomethane

O

BzO
BzO

OBz
OH

CH2N2, BF3•OEt2

O

BzO

CH2Cl2, 0 ºC, 74%

BzO

OBz
OCH3

Sammakia, T. Diazomethane in Encyclopedia of Reagents for Organic Synthesis.
Chavis, C.; Dumont, F.; Wightman, R. H.; Ziegler, J. C.; Imbach, J. L. J. Org. Chem. 1982, 47, 202!206.
• Diazomethane is one of the most effective reagents for the preparation of methyl esters from
carboxylic acids. The carboxylic acid protonates the diazomethane reagent to generate a
diazonium-carboxylate ion pair, which collapses to form the methyl ester.

Preparation of Diazomethane
• Diazomethane is prepared by the decomposition of a variety of N-methyl-N-nitrosoamines and is
obtained most often as a solution in ethyl ether.

• Products can typically be isolated by simple evaporation of the volatile ethereal solvent (ethereal
solutions of diazomethane are obtained by distillation using special fire-polished glassware, to
prevent explosion). Diazomethane itself is highly volatile (bp = –23 ºC).

O

OBn OBn
OBn

HO
OBn OBn

O

CH2N2, Et2O
23 ºC, 70%

• The example below utilizes N–methyl-N-nitroso-p-toluenesulfonamide (Diazald").

OBn OBn
OBn

H3CO
OBn OBn

H3C

O O
N
S
N
O
CH3

KOH
EtO

O

H2C N N
OH

Et2O, H2O, 65 ºC

Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163–7169.

Hudlicky, M. J. Org. Chem. 1980, 45, 5377–5378.
de Boer, T. J.; Backer, H. J.; Org. Synth. 1963, 4, 250–253.

Fan Liu

4


Myers

Chem 115

C–O Bond-Forming Reactions: Diazoalkane Reagents

• Reaction set-up:

• The reaction proceeds through in situ generation of the active methylating agent, diazomethane.

O

Dropping funnel
containing
(Diazald")

distillation apparatus

R

OH

+

O

TMS
N N

R

TMS

+

O

N N

Receiving flask
containing a solution
of CH2N2 in Et2O,
cooled to –15 ºC

special joints, NOT
ground-glass
O

OH
EtO
KOH, H2O, Et2O
heated to 65 ºC

CH3OH
O
O
R

R
OCH3

+

OH

N2

H2C N N

+

TMSOCH3

• Kits can be purchased which include non-ground glassware to decrease the likelihood of
diazomethane explosion.
• Leftover diazomethane should be quenched with dilute acetic or oxalic acid.

Kühnel, E.; Laffan, D. D. P.; Lloyd-Jones, G. C.; Martinez del Campo, T.; Shepperson, I. R.; Slaughter,

J. L. Angew. Chem. Int. Ed. 2007, 46, 7075–7078.

• If a pipette is to be used to transfer diazomethane, it must be fire polished first.
• Diazomethane is one of the most dangerous diazo compounds because of its volatility and
propensity to detonate. All operations should be conducted behind a blast shield and care must be
taken when handling this compound.

• Enols can also be methylated:

Hudlicky, M. J. Org. Chem. 1980, 45, 5377–5378.
de Boer, T. J.; Backer, H. J.; Org. Synth. 1963, 4, 250–253.

O
H3CO

Trimethylsilyldiazomethane

H3C

O

O
O

Shioiri, T.; Aoyama, T. Trimethylsilyldiazomethane in Encyclopedia of Reagents for Organic Synthesis.

H
N

OH

O
N
H

CH3

TMSCHN2
toluene, MeOH
25 ºC, 90%

O

H3C

• Because of the high volatility and toxicity of diazomethane, the safer, less volatile reagent,
trimethylsilyldiazomethane is often used, solutions of which are commercially available.
O
CH3 O
TBSO

CH3 O

TMSCHN2
OH

C6H6, MeOH
0 # 25 ºC, >69%

TBSO

H3CO
OCH3

H3C

O

O
O

H
N

OCH3

O
N
H

CH3
O

H3C
Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371–3373.

Coleman, R. S.; Tierney, M. T.; Cortright, S. B.; Carper, D. J. J. Org. Chem. 2007, 72, 7726!7735.
Fan Liu

5

Myers

Chem 115

C–O Bond-Forming Reactions: Diazoalkane Reagents

Esterification and Etherification Using Phenyldiazomethane
Sammakia, T. Phenyldiazomethane in Encyclopedia of Reagents for Organic Synthesis.

OH

OBn

H3C
N
O
HO
H3C

OH
H
O
O

O

PhCHN2, Et2O

OCH3
CH3

H

N
O
HO
H3C

20 ºC, >85%

OBn
H
O
O

O

O

Goulet, M. T.; Boger, J. Tetrahedron Lett. 1990, 31, 4845–4848.

PhCHN2, HBF4 (cat)

H

PhCHN2, HBF4 (cat)

SO2Ph

SO2Ph

Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Ploypradith, P.; Xie, S.; Shapiro, T. A.;
Posner, G. H. J. Med. Chem. 2003, 46, 2516–2533.

• Neat phenyldiazomethane is commonly prepared by vacuum pyrolysis of the sodium salt of
benzaldehyde tosylhydrazone:

OBn

CH2Cl2, –40 ºC, 81%

N

O
O
H3C

CH2Cl2, –30 ºC, 86%

Preparation of Phenyldiazomethane

• HBF4 can be used as an acid catalyst for the benzylation of alcohols and amines using
phenyldiazomethane. Amines react more slowly under these conditions:

OH

H3C

OCH3
CH3

H

O

PhCHN2, TfOH (30 mol%)

O
O
H3C

N
Ph

N

Bn

Ts
N

1. NaOCH3
H

H

N

CH3OH, 23 ºC

Ph

Ts
N

Na

H

2. evaporate and dry

90 ! 220 ºC
vacuum
76–80 ºC

N2
Ph

H

Creary, X. Org. Synth. 1990, 7, 438–443.

CH2Cl2, 0 ! 23 ºC, 60%
• Alternatively, phenyldiazomethane can be prepared by dehydrogenation of benzaldehyde
hydrazone using Swern-like conditions:

NH2+BF4–
OH

1. PhCHN2, HBF4 (cat)
CH2Cl2, –40 ºC
2. basic work-up, 68%

Liotta, L. J.; Ganem, B. Tetrahedron Lett. 1989, 30, 4759–4762.

NH2+BF4–
OBn

N
Ph

NH2
H

1. (COCl)2, DMSO
Et3N, THF, –78 ºC
2. filtration of Et3N•HCl

N2
H
Ph
(solution in THF)

Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789–1792.
Wommack, A. J.; Moebius, D.; Travis, A.; Kingsbury, J. S. Org. Lett. 2009, 11, 3202–3205.
Fan Liu

6

Myers

Chem 115

C–O Bond-Forming Reactions: Diazoalkane Reagents

• More complex esterification reagents can be generated by in situ oxidation of their corresponding
N-tert-butyldimethylsilylhydrazones with (difluoroiodo)benzene:

• Diazoalkanes can also be generated in situ from the corresponding tosyl hydrazone at high
temperature:

NO2

H
O

H
N N
H
TBS

TBS

O
H

O

OBz

H
O

I

Ph

N

HO
F ,

OBz

O

H
O
O

O

110 ºC,

O

CH3

CH3

Ts
N

H

CH3

OBz

HO

Ph

CH3

µwave, 155 ºC

H3C

Ph

O

K2CO3, PhF
+

72%

H3CO

HO

N

OBz

N2

NO2
H3CO

N2
H

O

84%

K2CO3, dioxane

H

H3CO

2-chloropyridine
CH2Cl2, –78 " 23 ºC

NO2

Ts
N

CH3

H
O

NO2

O

F

H
O

Sc(OTf)3 (0.01 mol%)
0 " 23 ºC, >95%

TBS
N
N
H

H3C

74%

Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Angew. Chem. Int. Ed. 2010, 122, 5113–5116.

Rhodium-Mediated Etherification Reactions
TBS
N
N
H
H3CO
H3CO

H
NO2

Reviews:

F
Ph

I

+

HO
H3C

OH
O

CO2H

Valdes, C.; Barluenga, J. Angew. Chem. Int. Ed. 2011, 50, 7486–7500
Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479–1492.

F

O

2-chloropyridine
CH2Cl2, –78 " 23 ºC

• Diazo compounds bearing an electron-withdrawing group are considered much safer than
diazomethane because of resonance stabilization by the electron-withdrawing group. In addition,
stabilized diazo compounds tend to much less volatile.

82%

• Treatment of simple !-diazoketones in aqueous acids provides the corresponding alcohols.

O
HO
H3C

OH
OO

O
OCH3

O2N

Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222–12223.
Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436–5445.

OCH3

O
N2

MeS
F

aq. HCl, acetone
40 ºC, 62%

O
MeS

OH
F

Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683–5689.

Fan Liu

7


Myers

• Ethyl diazoacetate can be deprotonated with LDA at low temperature. The resulting anion can be
trapped with electrophiles.
O
H

Chem 115

C–O Bond-Forming Reactions: Diazoalkane Reagents

O

LDA, THF, –90 ºC

Li

OEt
N2

H3C

O

H3C

OEt
–75 ºC, THF

N2

Reviews:

Heydt, H. Sci. Synth. 2004, 27, 843–937.

OH

O

O

Synthesis of Diazo Compounds

N2

51%

• In addition to the methods described above for the generation of reactive diazo reagents, diazo
compounds can be prepared by the following methods:

CO2Et
• Regitz Diazo Transfer Reaction

• Rhodium catalysts readily transform "-diazoesters into stabilized carbenoids, which readily
etherify alcohols:

• Reaction of an enolate with sulfonyl azide affords diazo compounds:

OH
O

H3C
N2

Rh2OAc4 (1 mol%)
C6H6, 80 ºC, 80%

CO2Et

O
H3C

O
CO2Et

O

H3CO

O

O O
S
N3

+
CH3

K2CO3, MeCN

O

23 ºC, 96%

H3CO

OH

N2

O

Rh2OAc4 (1 mol%)

CO2Et

C6H6, 80 ºC, 77%

O
O

C6H13

CO2Et

Koskinen, A. M. P.; Munoz, L. J. Chem. Soc. Chem. Commun. 1990, 652–653.

• Formation of medium-sized rings is entropically unfavorable and competitive C–H insertion by the
rhodium carbenoid is observed:

OEt
O

Rh2OAc4 (5 mol%)
C6H6, 80 ºC, 77%

O

O

O

OH

N2

OH

+
H3C

CH3

(120 equiv)

Rh2OAc4 (1 mol%)
CH2Cl2, 23 ºC, 92%

O

O
O

1. NaHMDS, –78 ºC

N

Ph
N2

2. PNBSA, 85–87%

Bn

69%

O

Bn

• The above reaction is highly sensitive to the enolate counterion, the quenching reagent, and the
sulfonyl azide structure: using triisopropylsulfonyl azide (trisyl azide) instead led to selective azide
transfer.

• Intermolecular trapping is also possible:

CO2Et

N

Ph

CO2Et

Moody, C. J.; Taylor, R. J. J. Chem. Soc. Perkin Trans. 1 1989, 721–731.

O

O

CO2Et

+

12%

Ph

• p-nitrobenzenesulfonyl azide (PNBSA) was found to be an effective diazo transfer agent for
carboximide enolates:

O

N2

OH

CH3
N2

H3C
C6H13

O

Ph

CO2Et
O

CH3
CH3

Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron 1994, 50, 3195!
3212.

O

O
Ph

N
Bn

O

O
O

1. KHMDS, –78 ºC
2. Trisyl-N3
3. AcOH, 25 ºC

N

Ph
N3
91%

O

Bn

Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030.
Fan Liu

8


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C–O Bond-Forming Reactions: Diazoalkane Reagents

Chem 115

• When only one electron-withdrawing group is present on the substrate, a second electronwithdrawing group is usually introduced to activate the parent compound towards diazo transfer.
The second electron-withdrawing group is removed at the end of the reaction:

O

O
F3C

CH3

O
OCH2CF3

1.

O

F3C

O
MsN3, Et3N

CF3

LiHMDS, THF, –78 ºC

S

O

N2

H2O, CH3CN
25 ºC, 92%

S

O

S

O
OCH2CF3

LiHMDS, THF, –78 ºC

2. MsN3, Et3N

N2

H2O, CH3CN
25 ºC, 81%

Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964.

• Reaction of acyl chlorides or anhydrides with diazomethane yields diazo compounds:

H3C

H
HO2C

H3C

CH3

H

CH3
CH3

CH3
H

1. (COCl)2, C6H6
2. CH2N2, 23 ºC
>78%

N2
O

H

CH3
CH3

Smith, A. B.; Dorsey, B. D.; Visnick, M.; Maeda, T.; Malamas, M. S. J. Am. Chem. Soc. 1980, 108,
3110–3112.

• Diazotization of primary amines also affords diazo compounds:

OEt

H2N
•HCl

O

NaNO2, NaOAc
H2SO4 (cat), H2O

OEt

N2
O

0 ºC, >70%

Wuzr, R. P.; Charett, A. B. Org. Lett. 2002, 4, 4531–4533.

Fan Liu

9


Myers

Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling

Chem 115

Reviews:

Initial Reports:

Hartwig, J. F. Organotransition Metal Chemistry, 1st Edition; University Science Books: USA,

• Buchwald and co-workers reported an intramolecular C-O coupling procedure following a

mechanism similar to that of Pd-catalyzed amination. Bidentate phosphine ligands afford high
conversions to product.

2009.

Condition A:

Frlan, R.; Kikelj, D. Synthesis, 2006, 14, 2271!2285.
Schlummer, B.; Scholz, U. Adv. Synth. Cat. 2004, 346, 1599!1626.
Reaction Highlights

X
• The main challenge in the Pd-catalyzed C-O bond forming reactions is to prevent "-H elimination
of the alcohol substrate. Many factors, including Pd source, ligand, base, solvent, and
temperature can influence the efficiency of the reaction.

CH3
CH3
OH

Pd(OAc)2 (5 mol%)
Tol-BINAP (6 mol%)
K2CO3 (1.2 equiv)
toluene, 100 °C

X: Br or I

CH3
CH3

O

60%
89%

I:
Br:

Condition B:

• Much of the improvement in this field has come from the development of ligands, which permits
couplings of substrates with varying steric and electronic parameters.

OH
CH3
CH3

• The development of ligands has also improved the reactivity of unactivated aryl halides.

Pd(OAc)2 (3 mol%)
dppf (3.6 mol%)
NaOt-Bu (1.2 equiv)
O

toluene, 80 °C

Br

CH3
CH3

69%

General Mechanism
Condition C:

O
Ar

Pd(OAc)2 (5 mol%)
dppf (10 mol%)
NaOt-Bu (2.0 equiv)

OH

R1
R2

LnPd

Ar!X

toluene, 90 °C

Br

R2

R1
Ln Pd H

Ar

elimination

Ln Pd Ar
X

R2
O
H
Pd
Ar
Ln
R1
HO

LnPd
O
+
+
R1
R2
ArH

Base•HX
Base

Ln Pd Ar
X

R2

Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333!10334.

• Electron-deficient aryl bromides were found to be more reactive than electron-neutral and
electron-rich aryl bromides.

R1
HO

H

Condition A (24!36 h) gives product cleanly while Condition B gives product with a faster
reaction rate (1!6 h). Condition C works well for secondary alcohols.

R1

"-H

O

66%

reductive
elimination
O

H

R2

O
+
Br

Pd(dba)2 (10 mol%)
dppf (12 mol%)

O

NaOt-Bu
(1.2 equiv)

100 °C, toluene

Ot-Bu
69%

Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109!13110.

Alpay Dermenci

10


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Chem 115

Metal-Catalyzed C"O Bond-Forming Reactions: Buchwald"Hartwig Coupling

• The methodology was extended to intermolecular cross-coupling with primary and secondary
alcohols.

Pd2(dba)3 (1.5 mol%)
Tol-BINAP (3.6 mol%)

X
+
R1

R2OH

• Ligands and Their Applications
• A series of ligands developed by Buchwald and co-workers improved reactivities of a combination of
substrates, including unactivated aryl halides and triflates.

OR2

P(t-Bu)2

P(t-Bu)2

toluene, !

R1

(1.2 equiv)

Ligand A
Aryl halide

Alcohol

Br

Product
O

OH
H3C

NC

CH3

CH3
CH3

NC

Temp (°C)

Yield (%)a

50

80 (76)

Ligand B

X

Pd(OAc)2 (2.0 mol%)
Ligand (3 mol%)
K3PO4 (2.0 mol%)

HO
+
(1.2 equiv)

CH3
CH3

i-Pr

NC

70

O

i-Pr
OH

77 (73)

Aryl halide

Phenol
Br

NC

HO

H3C
Br

100

Ligand

OH

Product

CH3

O
A

OTf

CH3
96 (95)a

H3C

HO

i-Pr

O

B

i-Pr
84

t-Bu

O
70

65 (<5)

Br

H3C

H3C

HO

O
83

C
CH3
aValues

Yield (%)

O

t-Bu
Br

R

53 (<10)

t-Bu

t-Bu

O

toluene, 100 °C
14"24 h

O

Ot-Bu
NaOt-Bu

Ligand C

Biaryl Ether Synthesis

R

Br

P(t-Bu)2
Ph

(H3C)2N

CH3

in parentheses are yields with no catalyst (DMF as solvent).
aReaction

Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395"3396.

run with 0.1 mol% Pd(OAc)2, 0.15 mol% ligand.

Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 4369"4378.
Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202"12206.
Alpay Dermenci

11


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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling

• It was discovered that binaphthyl ligands such as D and E can improve reactivity and yield and
allow for the intermolecular coupling of primary alcohols and aryl halides with minimal arene
reduction.

Intramolecular Synthesis of Cyclic Aryl Ethers

Substrate
P(t-Bu)2
N(CH3)2

Product

Temp. (oC)

OH

P(t-Bu)2
H

50

Aryl halide
Cl
H3C

CH3

Ligand E

Alcohol
(2 equiv)
n-BuOH
PhCH2OH
i-BuOH
EtOH

Product
OR
H3C

CH3

H3CO
Ligand

Yield (%)

E
E
E
E

90
95
88
93

71

O

Cl

Ligand D

Yield (%)

H3CO

OH

50

71

Br

O

OH
70

74
O

Cl

Conditions: Pd(OAc)2 (2–3 mol%), ligand E (2.5–3.5 mol%), Cs2CO3, toluene.

Cl

n-BuO
n-BuOH

E

88

Application to the Synthesis of MKC-242

HO
n-BuOH
Cl

N

E
n-BuO

Br

N

O

O
O

Br

Pd(OAc)2 (3 mol%)
Ligand A (3.5 mol%)
K3PO4 (1.5 mol%)
toluene, 70 oC
90 h

OR
n-BuOH
PhCH2OH

D
D

OCH3

80
80

OCH3

O
O

Br

CH3
N

O

79

O

N
Boc

n-BuOH

n-BuO

N
Boc

D

72

Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10770!
10771.

H
N
MKC-242
(antidepressant)

O
O

O

O

O

CH3
N

O

O
94%

O
O

Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907!12908.
Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202!12206.
Alpay Dermenci

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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling

• The substrate scope was expanded to include secondary, allylic and propargylic alcohols with
ligands F and G.

CH3
H3C

CH3
H3C

CH3
P(t-Bu)2
CH2t-Bu

H3C

• (CH3)4-t-BuXPhos and RockPhos allow for improved coupling of aryl halides with phenols and
secondary/primary alcohols, respectively.

CH3
P(t-Bu)2
i-Pr

H3C

Ligand F

CH3
OCH3

H3C

CH3

H3C
i-Pr

Pt-Bu2
i-Pr

Ligand G
i-Pr

i-Pr
Cl

HO
+

n-Bu

(CH3)4-t-BuXPhos

Pd(OAc)2 (2 mol%)
Ligand F (2.4 mol%)

CH3

Cs2CO3 (1.5 equiv)
Bu3N, 100 °C, 70%

CH3
(2 equiv)

O

CH3

n-Bu

Cl

N

Pd(OAc)2 (2 mol%)
Ligand G (2.4 mol%)

HO

Br
+
CH3

H3C

Cs2CO3 (1.5 equiv)
toluene, 70 °C, 90%

Pd(OAc)2 (2 mol%)
(CH3)4-t-BuXPhos (3 mol%)

HO
+

K3PO4, toluene, 100 °C, 91%

O

Cl
+

• This methodology can be used in conjunction with Cu-mediated Ullman-type couplings (discussed in
that chapter).

[allylPdCl)2] (0.5 mol%)
RockPhos (1.5 mol%)

HO
O

N

(2 equiv)

I

CuI (10 mol%)
1,10-phenanthroline (20 mol%)

Br

+

Cs2CO3, i-PrOH, 110 °C
81%

H3C

O

Oi-Pr

H3C
CH3

H3C

Oi-Pr

O

CH3

(2 equiv)

Br

OPh

N
H3C

(1.2 equiv)

O

CH3

CH3

RockPhos

CH3

H3C
H3C

Pt-Bu2
i-Pr

H3C
i-Pr

4Å MS, Cs2CO3
Bu3N, 90 °C, 72%

O
O

N

OH

H3C
CH3 (2 equiv)

Boc

Br
+

Pd (OAc)2 (3 mol%)
Ligand F (3.6 mol%)
Cs2CO3, Bu3N, 50 °C

84%

Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146!8149.

N

HO

[allylPdCl)2] (0.5 mol%)
RockPhos (1.5 mol%)

Boc

N

O

Cs2CO3, toluene, 90 °C

(3 equiv)
98.5% ee

86%, 98.5% ee

Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 4321!
4326.
Wu, X.; Fors, B. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9943!9947.
Alpay Dermenci

13


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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling

• The superiority of these ligands stems from their effectiveness in promoting reductive elimination.

• Ph5FcP(t-Bu)2 was later found to be a superior ligand, while substituting the ferrocene ring with
electron-donating substituents was found to increase both the reaction rate and yields.

locked
P(t-Bu)2

t-Bu Ar
t-Bu
P Pd OAr
H3C
i-Pr
i-Pr
H3C

rotatable
t-Bu Ar
t-Bu
P Pd OAr
i-Pr
i-Pr

Fixes PdII over the
triiisopropyl ring

H3C

CH3 i-Pr

CH3
X = Cl or Br

OCH3

toluene, 80 °C

(1.2 equiv)

Ar

Ar = p-MeOC6H4: (p-MeOPh)5FcP(t-Bu)2
Ar = p-CF3C6H4: (p-CF3Ph)5FcP(t-Bu)2

Br

Pd(dba)2 (5 mol%)
Ph5FcP(t-Bu)2 (5 mol%)

NaO
+

CH3

OCH3
(1.2 equiv)

O
CH3

toluene, 23 °C, 70 h
99%

OCH3

Pd(dba)2 (5 mol%)
Ph5FcP(t-Bu)2 (5 mol%)

OH
CH3
CH3

• Hartwig and co-workers discovered that the sterically hindered FcP(t-Bu)2 promotes reductive
elimination and formation of diaryl ethers from unactivated aryl halides.

Pd(dba)2 (2-5 mol%)
FcP(t-Bu)2 (2-5 mol%)

Ar

Ar

conformationally rigid

• Hartwig Ligands

NaO

Ar

Ph
Ph5FcP(t-Bu)2

CH3 i-Pr

+

Fe

Ph

i-Pr

X

P(t-Bu)2
Ar

Ph

Ph

t-Bu Ar
t-Bu
P Pd OR
H3CO
i-Pr

i-Pr

Fe

Ph

Br

toluene, 23 °C, 10 min
93%

O

Pd(dba)2 (5 mol%)
(p-MeOPh)5FcP(t-Bu)2
(7.5 mol%)

O

CH3
CH3

O
CH3

Br

OCH3

X = Cl, 82%
X = Br, 85%

NaO
+

H3C

OCH3
(1.2 equiv)

toluene, 80 °C, 3 h
91%

H3C

OCH3

FcP(t-Bu)2 = ferrocenyldi-tert-butylphosphine
P(t-Bu)2

Br

Fe

Pd(dba)2 (5 mol%)
(p-CF3Ph)5FcP(t-Bu)2
(7.5 mol%)

NaO
+

H3C

OCH3
(1.2 equiv)

Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224!3225.

toluene, 80 °C, 18 h
29%

O
H3C

OCH3

Shelby, Q.; Kataoaka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718!10719.
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553!5566.
Alpay Dermenci

14


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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling

• Other Ligands

• Primary alcohols are selectively coupled in the presence of secondary alcohols:

• In addition to ligands developed by Buchwald and Hartwig, Singer and co-workers have developed
a structurally different ligand, bippyphos (prepared on multi-kilogram scale), which allows coupling
of aryl halides and alcohols.

OH
Br
OH

H3C
+
N
N

N

N

Pd2(dba)3 (0.5 mol%)
bippyphos (2 mol%)

N

CH3

HO

(3 equiv)
N

MeOH, 65 ºC, 100%

Cl

P(t-Bu)2

Pd(OAc)2 (1 mol%)
Ligand (2 mol%)

O

CH3

H3C

Cs2CO3, toluene
80 °C, 69%
regioselectivity >99%

OCH3
Gowrisankar, S.; Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.; Neumann, H.; Beller, M. J. Am.
Chem. Soc. 2010, 132, 11592!11598.

bippyphos
• Application to synthesis of butoxycaine, a local anesthetic:
Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis, 2003, 1727–1731.
Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Proc. Res. Dev. 2008, 12, 480!489.
• Beller and co-workers have developed a modified bippyphos ligand that is effective for the coupling
of aryl halides with primary and secondary alcohols.

O

OCH3

OCH3

O

OH

LiOH, CH3OH
H2O, 60 °C

n-BuOH (3 equiv)
toluene, 80 °C

Br

Ph

O

Pd(OAc)2 (1 mol%)
Ligand (2 mol%)
Cs2CO3

n-BuO

74% (2 steps)

n-BuO

N N
Ph

Ph
N

Br
+
OCH3

n-BuOH
(3 equiv)

N

P(1-adamantyl)2

Pd(OAc)2 (1 mol%)
Ligand (2 mol%)
Cs2CO3, toluene
80 °C, 76%

CH3

O
n-BuO

O
OCH3

H3C

N

CH3

HOCH2CH2N(CH2CH3)2
DCC, DMAP
CH2Cl2, 23 ºC, 72%

O
Butoxycaine

Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.;
Beller, M. Tetrahedron Lett. 2005, 46, 3237!3240.
Alpay Dermenci

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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Ullman Coupling

Reviews

Generalized Cross-Coupling:

Rao, K. S.; Wu, T. S. Tetrahedron 2012, 68, 7735!7754.
Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054!3131.
Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400!5449.
Sawyer, J. S. Tetrahedron 2000, 56, 5045!5065.

R OR'

General Reaction Features:

Original Report (Ullman, 1904):

• Good functional group compatibility.

• A base is often required.

• Mild reaction conditions.

• Typically an excess of one of the coupling partners is
necessary.

"Cu"

HO

CuI

HOR'

X = I, Br, B(OH)2, BF3–K+

Kunz, K.; Scholz, U.; Ganzer, D. Synlett, 2003, 15, 2428!2439.

X

+

RX

O

+

Ullman Coupling with Aryl Halides
• A general procedure was reported for the coupling of aryl bromides and iodides with phenols:
X

Ullman, F. Ber. 1904, 37, 853!854.

HO

Ullman, F.; Sponagel, P. Ber. 1905, 38, 2211!2212.

R2
R1

Mechanism: The mechanism for the Ullman arylation of alcohols is not well understood. It is
likely that the reaction involves a CuI species.

X
oxidative
addition

O
reductive
elimination

X

Aryl halide

Phenol
I

HO

CO2H
Br

CuIII L
O

CH3

H3C

O

HO

CH3

CH3
90%

CH3

CO2H
O

CH3
84%

CH3

CH3

2.0 equiv
OCH3
Br

Yield (%)

CH3

1.4 equiv

CuIII L

OH

R2
R1

Product

CH3

CH3

X

X

O

Cs2CO3, toluene, 110 °C

H3C

X-CuI

(CuOTf)2•PhH (2.5 mol%)
EtOAc (5 mol%)

OCH3
O

HO
CH3

79%a
CH3

2.0 equiv
a1-naphthoic

acid and 5Å molecular sieves were added.

Litvak, V. V.; Shein, S. M. Zh. Org. Khim. 1975 11, 92!96.
Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2004, 43, 5400!5449.

Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539!10540.
Angela Puchlopek-Dermenci, Alpay Dermenci

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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Ullman Coupling

Synthesis of Alkoxy Aryl Ethers

Ullman Coupling with Boronic Acids:
CuI (10 mol%)
1,10-phenanthroline
(20 mol%)

NH2

I

n-BuOH, Cs2CO3
110 °C, 71%

I

CuI (10 mol%)
1,10-phenanthroline
(20 mol%)

• Chan, Lam, and Evans have reported milder conditions for the synthesis of diaryl ethers using
boronic acids and stoichiometric amounts of copper acetate at room temperature.

NH2
CH3

OH

O

(HO)2B

I

OCH3

CH3

+

HO

I

Ph

(2 equiv)
99% ee

Cu(OAc)2 (1 equiv)

O

Cl

F

Et3N, CH2Cl2
23 ºC, 78%

I

F

2 equiv

78%

O

n-BuOH, Cs2CO3
110 ºC, 87%

N

Cl

+

CH3

N

CuI (10 mol%)
1,10-phenanthroline
(20 mol%)

Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933!2936.

OCH3

(HO)2B
CH3

toluene, Cs2CO3
110 °C, 89%

N

NH

Cu(OAc)2 (1.5 equiv)

+

CF3

Ph
O
98% ee

2 equiv

N

N

C6H5N, CH2Cl2
air, 23 ºC, 71%

CF3

Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973!976.
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1988, 39, 2941–2944.
Synthesis of Aryl Vinyl Ethers
ligand:

• Evans and co-workers employed a method involving coupling of boronic acids en route to
thyroxine.

O

N

OCH3

CH3
+

Br

Ph

(1.5 equiv)

9:1 E/Z

OH

(1.5 equiv)

I

EtO
AcHN

CH3

OTBS

+
OH

(HO)2B

I

Ph

O

110 ºC, 81%

OH

F

CuI (25 mol%)
Ligand (25 mol%)
Cs2CO3, toluene

O
Cu(OAc)2 (1 equiv)
pyridine, Et3N
CH2Cl2, 25 ºC, 84%

3 equiv

9:1 E/Z

I
Ph

110 ºC, 71%

I

O

CuI (25 mol%)
Ligand (25 mol%)
Cs2CO3, toluene

HO

O

NH2
F

O

I

OH

O

I

I
Ph

Wan, Z.; Jones, C. D.; Koenig, T. M.; Pu, Y. J.; Mitchell, D. Tetrahedron Lett. 2003, 44, 8257!
8259.

I

EtO
AcHN

OTBS

O
I

thyroxine
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937!2940.
Angela Puchlopek-Dermenci, Alpay Dermenci

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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Ullman Coupling

Carboxylic Acids

Ullman Coupling with potassium organotrifluoroborate salts ––– Batey Modification

• Coupling of phenyl boronic acid with a wide range of carboxylic acids occurs in the presence of

• Aryltrifluoroborates are more robust, more easily purified, and less prone to protodeboronation than

urea as an additive:

aryl boronic acids.
• This procedure is effective for coupling both aliphatic alcohols and phenols at room temperature

under pH-neutral conditions.
O
Ar

OH

Cu(OTf)2 (40 mol%)
urea (1.0 equiv)

PhB(OH)2

+

O
Ar

EtOAc, 60 °C, air

(3 equiv)

Cu(OAc)2•H2O (10 mol%)
DMAP (20 mol%)

OPh
ArBF3–K+

+

HOR

Ar OR
CH2Cl2, 4Å MS; O2, 23 ºC

(2 equiv)
O

O
OPh

CH3

O
OPh

H3C

94%

OPh

H3CO
88%

64%

I
78%

O

96%

HO

Ph

Ph

HO

Br

89

Br

O

93

OAc

51%

88%

O
OPh

98%

HO

H3CO

O

N
Ot-Bu
CH3

OPh

95%

O

O
BF3K

O

O

Yield

OPh

OH

OPh

BF3K

O
OPh

O
OPh

89%

O

78%

Product
O

63%

OPh

86%

Phenol/Alcohol

BF3K

60%

Br

Cl

Borate salt

O2N

O
OPh

OPh

OPh

OPh
NC

O

O

O

O

HO

N
Ot-Bu
CH3

93

H3CO
O
O

BF3K

O

99

Zhang, L.; Zhang, G.; Zhang, M.; Cheng, J. J. Org. Chem. 2010, 75, 7472!7474.
HO
H3C

BF3K

O

H3C

O

O

55

Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381!1384.
Angela Puchlopek-Dermenci, Alpay Dermenci

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Chem 115

Metal-Catalyzed C!O Bond-Forming Reactions: Ullman Coupling

Examples in Natural Product Synthesis

Cl

N

N

N

OH Br
TBSO

O

EtO
O

Br
CuBr•SMe2 (2 equiv)
K2CO3 (2 equiv)
pyridine (2 equiv)

H
N

N
H

X'

directing group

O

N3

O

EtO
O

MeCN, 80 ºC
67%

N
H

OCH3
OCH3

H3CO

N
TBSO
O
O
HN

N
H H

O

Cl

X
O

O

BnO

N
H
O

X'

steps
OCH3
OCH3

N

"atropisomers"
OTBS
O

H
N
O

Boc
NCH3

N
H

HN

HO
H3C
HO
HO
H2N
CH3
O
O

O

HN

O

N
H H

O

O

N
H

CH3
CH3

OCH3
OCH3

N
H
O

OH
O

H
N
O

N
H

NHMe
CH3
CH3

NH2
OH
OH

N
H
O

Boc

NCH3

Cl

O

H
N

O
OH
HO

O

H
N

O

Cl

HO

OTBS
O

OH

O

O

H
N

NHDdm
H3CO

O
steps

N
H H

O

BnO

OCH3
OCH3
1:3
(X' = H, X = Cl) : (X' = Cl, X = H)

O
O

Cl
Br HO

Cl

TBSO

MeCN, 74%

CH3

N
N

O

CuBr•Me2S (5 equiv)
K2CO3, pyridine

CH3

NHDdm
H3CO

NHBoc

1:1
(X' = H, X = Cl) : (X' = Cl, X = H)

O

H
N

H
N

N3

H3CO
N
N

Br

O

BnO

BnO

O
X

TBSO

NHBoc

N

N
N

vancomycin

Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughes, R. Chem. Eur. J. 1999, 108, 3054!3131.

Angela Puchlopek-Dermenci, Alpay Dermenci

19


Myers

Chem 115

Metal-Catalyzed C"O Bond-Forming Reactions: Ullman Coupling
Selective C–N over C–O Intramolecular Ullman Coupling
OCH3

OCH3

HO

(HO)2B
O
H3CO2C

O
Cu(OAc)2
(2 equiv)

H

N

N
H3C

NHBoc
O

Cl

Cl

O
H3CO2C

Et3N, CH3OH
4Å MS
> 50%

OCH3

H
N

steps

O
N
O H3C

O

Cl
OH

O

H
N

Cl
OH

H3CO

Cl
OCH3

N
H

O

Cl

Cl
OH

Duocarmycin A

N
H

O

N
H

OCH3
OCH3

O
Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630"
6631.

Cl

Cl
OH

OCH3

Enantioselective Ullman Coupling

CuI (20 mol%)
N-methylproline (40 mol%)
K3PO4, dioxane

O
Br

O
H3CO

90 ºC, 39%

HO

O
H3CO

OCH3

er = 72 : 28
er = 92 : 8 (recrystallization)

!
O

CuCl, NaH
76%

H3CO

OCH3

N

O

H3CO

OH
Br

steps

HN

Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2003, 125, 9032"9034.

H3CO

O

O

H
N

N
Bn

BnO

O

H3C

H
N

O

HO2C

NHBoc
O

Cl

DMSO, 23 °C
67%

Br

BnO

OH

Br

CuI, CsOAc

NHBn

H
N

N
H3C

OCH3

!

OH

Br

BBr3
CH2Cl2, "40 °C

O
HO

H3CO
Corsifuran A

Adams, H.; Gilmore, N. J.; Jones, S.; Muldowney, M. P.; von Reuss, S. H.; Vemula, R. Org.
Lett. 2008, 10, 1457"1460.

O

O

+
HO

O
HO

H3CO

(+)-pterocarine
45% (92:8 er)

(+)-galeon
43% (92:8 er)
Salih, M. Q.; Beaudry, C. M. Org. Lett. 2013, doi:10.1021/ol402096k

Angela Puchlopek-Dermenci, Alpay Dermenci

20