Cu-Catalyzed Cross-Coupling Reactions~from Pd to Cu~
12th/May/2012 Ozawa Jun (M1)1.

Introduction

2.

Sonogashira-type reactions

3.

Stille-type reactions

4.

Buchwald-Hartwig-type reactions

5.

Perspectives

1. Introduction
The discovery of a cross-coupling reaction is one of the most striking breakthrough inorganic chemistry and it has brought us a lot of benefit:(i) it has expanded the scope for what we can synthesize and(ii) it has changed the methodology for the retrosynthesis, enabling us to shorten thesynthetic procedures.

X+M
easily accessible to biar yl str uctur es!

Cu-catalyzed coupling reactions have longer history than Pd-catalyzed ones: for example,
Glaser coupling was reported in 1869, almost 100 years before Mizorogi-Heck reaction wasreported in 1971, 1972.
CuCl2 PhPh

Ph

baseC. Glaser Ber. Dtsch. Chem. Ges. 1869, 2, 422- 1/19 -After the discovery of Pd-catalyzed couplings in 1970s, Pd chemistry has developed
drastically:
1971, 1972 Mizorogi-Heck (alkene)
1972 Kumada-Tamao-Corriu (R-MgX')
1975 Sonogashira-Hagihara (terminal alkyne)
1977 Negishi (R-ZnX')
1977, 1978 Migita-Kosugi-Stille (R'-SnY3)
1979 Suzuki-Miyaura (R-BY2)
1988 Hiyama (R'-SiY3)
1994 Buchwald-Hartwig (R-NHR' or R-OH)

The Pd reactions above achieve(i) catalytic amount of Pd loading,(ii) low reaction temperature, and(iii) high yields.
Whereas,the pioneering Cu reactions required non-catalytic amount of Cu source and very highreaction temperature (~ 200 deg. or more).
Then, Cu chemistry gradually got neglected.

In these days, however, Cu is again attracting the attention of researchers around theworld as an alterative of Pd in coupling reactions, becouse Pd is a precious metal andthe reserve is much less than Cu, so it will cost more to use Pd.

Recently "oxidative" coupling reactions have been studied actively becouse they are
benign to earth; no need for preparing organometallics and halides, which results inreducing wastes. But it is still difficult in oxidative couplings to control reaction sites;
therefore, they are hardly applicable to the syntheses in industry or labolatories. So usual
non-oxidative coupling reactions are still in demand.

+PhSnBu3

Pd(Ph3P)4I

Ph

The coupling reaction like this is difficult to conduct in an oxidative coupling manner.

- 2/19 -2. Sonogashira-type reactions
Pioneering work of alkyne couplings using Cu
Glaser coupling
CuCl2 Ph2 Cu

PhO2

Ph + Cu2O

Phaq NH3
C. Glaser Ber. Dtsch. Chem. Ges. 1869, 2, 422
Castro-Stephens coupling
ICuIPhPhCu
aq NH3R

Ph + CuI

80 ~ 120 deg.
Py (solv.)
under N2

R75 ~ 99%

R. D. Stephens and C. E. Castro JOC, 1963, 28, 3313

Both reactions are the 2-step conversion and require stoichiometric amount of Cu(I) , that is,copper acetylides are isolated and they react with another reagent in the next step.
The reactions below achieve to conduct the coupling with a catalytic amount of Cu.

homocoupling of alkynes
CuI (5 mol%), O2
TMEDA (5 mol%)
RR

R

acetone82 ~ 97%
A. S. Hay JOC 1962, 27, 3320

CuI (2 mol%), O2
TMEDA (1.5 mol%)
DBU or DABCO (1 eq)
RRMeCNR
54 ~ 99%
U. Beifuss JOC 2009, 74, 5648

- 3/19 -heterocoupling of alkynes
IR+Y

R'CuI (5 mol%), 2Ph3P, K2CO3Y

DMF ot DMSO, 120 deg.
under N2R'R

BrR
M. Miura JOC 1993, 58, 4716

I+Y

RCu(phen)(Ph3P)Br (10 mol%)
K2CO3toluene, 110 deg.
under ArRY
70 ~ 97%

D. Venkataraman OL 2001, 26, 4315

substrate scope of Miura's case- 4/19 -I

I

I

O2N
1aCl
1bII

MeOMe

1c1d1e

I
I

Br

Br

Br

O2N
1f1g1hnPh

C5H112a19aHO2bBr

Ph1i

I19b2dIPh
19c1jt BuOTHPO
2cPhNO2AcO
2enC H5 1119dITHPO2fnC H
6 13

19e2g

I

Ii Pr

19f

Copper acetylides are polymeric by nature and are almost insoluble in many organic solvents;
they don't dissolve even in DMF completely without ligands. By adding some appropriate
ligands in advance, copper acetylides make complexes with them and become monomericspecies that are soluble in organic solvents, resultig in these "catalytic" reactions.

In the step 25 to 26, one ligand must leave from25, so excess equivalent of ligands or more
electron-donating ligands are ineffective; 2 eq ofPh3P is the best for Miura's conditions.

- 5/19 -Do Cu(III) species generate from Cu(I) like Ar-L2Pd(II)-(alkyne) in Pd-catalyzed crosscoupling?
The fact is verifted that the oxidative addition and reductive elimination of Cu(I) can occur
in the presence of ArX, so it is possible that Cu(I) undergoes the steps similar to Pd(0) incross-coupling reactions.

S. S. Stahl and X. Ribas Chem. Sci. 2010, 1, 326

N-Arylation of pyridone occurs with ArBrand catalytic amount of [Cu(MeCN)4PF6]- 6/19 -other examplesO+RO

CuCl (10 mol%)
Et3N (1 eq)
RR'benzene
45 ~ 60 deg., 1 ~ 10 hr

ClR'63 ~ 92%

R, R' = alkyl

A. S. Zanina Mendeleev Communications 1994, 4, 207

RX+CO2(1 atm)

CuI (8mol%)
Et3P or bipy (8mol%)
Cs2CO3 (3 eq)

+ R'O
RO

DMA, r.t., 24 hr

R = alkyl, allyl, benzyl
R' = Ar, alkyl
X = I, Br

R'~ 91%

K. Inamoto and Y. Kondo Org. Biomol. Chem. 2012, 10, 1514

I+RAr

OH

[Cu(phen)(PPh3)2]NO3 (10 mol%)
Cs2CO3 (2 eq)toluene
110 deg., 24 or 48 hr

R = alkyl, Ar, halogens

ArRO
62 ~ 96%

D. Venkataraman OL. 2002, 4, 4727

- 7/19 -5. Perspectives
Cross-coupling reactions catalyzed by Cu have been growing steadily, but there're still somedisadvantages:(i) large catalyst loading
The Cu-catalyzed couplings usually require 1 ~ 10 mol% of Cu source; on the other hand, thePd-catalyzed couplings need 0.01 ~ 5 mol% of Pd source. Even though Cu itself is cheaper
than Pd (Pd(OAc)2: 47500 yen/10 g, Cu(OAc)2: 27700 yen/100 g at Sigma Ald.), large catalystloading offsets the merit of lower price of Cu.

Pd catalyst is outstanding...

BrB(OH)250 ppb ~ 2.5 ppm Pd+R

H2O, w, Na2CO3

R'R

R'~ 99% yield

N. E. Leadbeater JOC, 2003, 68, 5660
N. E. Leadbeater JOC, 2005, 70, 161
The Pd loading is 0.0000008 mol% and turnover number is 1250000!
(ii) lack of understanding of the ligand effect
The catalytic systems are usually developed by random tryals because it is still in a black box
what we should take care about when tuning the system.
the ligands shown in this paper

Ph3P

NNNOH

O

Et3P

NHON

N

N

N

N

O

NEt2

NHMe

NHMe

NHMe

NHMe

CO2H
PhN

Ph- 8/19 -4. Buchwald-Hartwig-type reactions
Pioneering work using Cu
Ullmann condensation
NH2

Br

H
N

Cu (0.1 eq)++ KBr~ 200 deg.

CO2K

CO2H

F. Ullmann Ber. Dtsch. Chem. Ges. 1903, 36, 2382 (amination)
F. Ullmann Chem. Ber. 1905, 38, 2211 (etherification)
I. Goldberg Chem. Ber. 1906, 39, 1691 (amination, amidation)
This Ullmann-Goldberg condensation has been used until most recently, 1994, among
other Cu-promoted couplings, to obtain diaryl- or triamines because there was no otherpractical method. But the reactions also require harsh prolonged heating at 200 deg. or
higher, so its application is limited.
Many bidentate ligands have been recently reported as efficient ligands for the amination
reactions and those systems are overcoming such limitations.
Arylation of alkyl amines
Primary and cyclic secondary amines can be arylated, but secondary non-cyclic aminesshows low reactivity, most likly due to steric reasons.

Br + R'R

NH2CuI (5 mol%)
L (5-20 mol%)
K3PO4 (2 eq)

OH90 deg, 18 ~ 22 hr
DMF or neat

RNHR'O

L=NEt271 ~ 95%
L. S. Buchwald OL 2003, 5, 793

substrate scope

N-arylation occurs in the presence of OH(entry 2).

- 9/19 -N- vs O-arylation (S. L. Buchwald JACS 2007, 129, 3490)
OO

N

N

L2

L1

Other non-linear aminoalcohols withmore than 4 atoms between N and O
can be also arylated selectively (C-N:up to > 50 :1; C-O: up to 20: 1).

L2 is used for various O-arylation of alkyl alcohols. (S. L. Buchwald JOC 2008, 73, 284)

XR+ R'OH

CuI (5 mol%), L2 (10 mol%)
Cs2CO3 (1.5 eq)
tolueneO
RR'This system is not efficient forsecondary non-cyclic alcohols.

- 10/19 -What brings these N/O selectivities?
Computational study was conducted by Buchwald (S. L. Buchwald JACS 2010, 132, 6205).
There were several possible pahtways to produce Ar-Nuc compounds.

LnCuI

H-Nuc

The free energy of each pathway was calculated.
the coordination step

The coordination of an alcohol is much more favorable than that of an amine in each case.
This step is not selectivity-determining.
the steps, (a), (b), (d), (e)

(a)

(e)

(d)

(b)

The energies of TSOA and TSSig are much higher than IAT or SET, so IAT of SET is morefavorable than the other 2 pathways.
In the case of (ket)Cu complexes, SET is preferred both when Z is O and Z is NH; (phen)Cu
complexes also favor SET when Z is NH, but don't when Z is O and then IAT is preferable.
*IAT: Iodine Atom Transfer- 11/19 -The energis of the steps
after IAT or SET.

In all the pathways, thegeneration of C(III) species
is not desirable and instead
Cu(I)/Cu(II) mediatedpathways are preferred.

- 12/19 -Summarized free-energy profiles

Elctron-rich ligands promote SET machanism, where e- is transferred from the Cu(I)-Nuccomplex. N-bound Cu(I) complexes are rather e- rich and undergo SET pathway even if theligand is phen or similar ones; O-bound complexes undergo IAT pathway when the ligand isnot-so-electron-donating, because alkoxides are worse electron donor than amides.
The pathways via Cu(III) species are unfavorable surely because Cu(III) is unstable, soCu(II) intermediate returns to rather stable Cu(I) instead.
Toluene, the solvent used for O-arylation (IAT, non-anionic/cationic pathway), may slow
down N-arylation (SET, anionic/cationic pathway) relatively.

- 13/19 -other N-arylation
Arylation of arylamines
diarylamines

NH2CuI (10 mol%)
L (20 mol%)
K3PO4 (2 eq)

X+RHN

DMSO, 70 ~ 100 deg., 24 hrRR'L=(2 eq)

NHR'CO2H

S. L. Buchwald JOC, 2008, 73, 5167
triarylamines
NNH2CuI (4 mol%)
L (4 mol%)
KOt Bu (3 eq)

XR

R'2+toluene, 115 deg., 3.5 hr
RR'(2.1 eq)

H
N

L=PhN

Ph

R

R'

triaryl/diaryl ratios are up to 95/2
R. V. Chaudhari T L 2002, 43, 7143
R. V. Chaudhari J. Mol. Catal. A: Chem. 2004, 223, 45
The authors don't mention in the papers about what results in the selectivity, di- or triaryltion.
Arylation of amides
CuI (0.2 ~ 10 mol%)
L (5 ~ 20 mol%)
K3PO4 (2 eq)

OAr

X+RHN

R'dioxane, 110 deg., 24 hr
NHMe

OAr

R'N
R
~ 100%NHMe

or

L=NHMeNHMe( )
S. L. Buchwald JACS 2002, 124, 7421

- 14/19 -The rates of N-arylation deffer as the type of amines differ: normal amines, aniline
derivatives, and amides

O

H2NI

HN+CuI (5 mol%)
L (10 mol%)
K3PO4 (2 eq)

H2NON

toluene
100 deg., 18 hr

95%

NHMe

L=NHMeS. L. Buchwald JACS 2002, 124, 7421

CuI (5 mol%)
L (20 mol%)
K3PO4 (2 eq)

NH2+H2N

NH2DMF, 90 deg.
18 ~ 20 hrBrOHN
H80%O
NEt2

L=S. L. Buchwald OL 2003, 5, 793

after all, aniline derivatives < normal amines < amidesThis is probably due to the difference of pKas and nucleophilicities of RR'NH.
Amides are the worst nucleophiles but show the lowest pKa; in contrast, normal amines
are the best nucleophile but show the highest pKa, which may result in the order of the Narylation rates.
ORpKa
nucleophilicityrateN HHPhHN H

H2N H

172735lowmiddlehighfastslow

middle- 15/19 -3. Stille-type reactions

Pioneering work to obtain biaryl comopunds using Cu
Ullmann coupling
O2NBr2+ 2Cu
NO2+ 2CuBr
200 deg.
or moreNO2

F. Ullmann Chem. Ber. 1901, 34, 2174
Biaryl compounds can be synthesized using Cu, but the reaction requires stoichiometricamount of Cu and very high reaction temperature, and is not applicable to heterocoupling,say, Aryl1-Aryl2, or Aryl-vinyl coupling.

In Stille coupling, additional Cu(I) is known to accelerate the reaction:
V. Farina and L. S. Liebeskind reported in 1994 that Cu(I) scavenges ligands of Pd andaccelerates the rate-determining transmetalation.
V. Farina and L. S. Liebeskind
JOC 1994, 59, 5905

One of the ligand must be dissociated so thatthe transmetalation can occur, and CuI helps
the step.

They also reported in the paper, this is more
important for the development of Cu-catalyzed
couplings, that Sn/Cu transmetalation does
occur only in highly polar solvents like NMP,
and it is an equilibrium reaction.
(In 2003 organotin reagents are revealed to be
independent of the rate enhancement:P. Espinet Organometallics 2003, 22, 1305.)- 16/19 -To enhance the transmetalation in Cu-catalyzed coupling, there're 2 choices:(i) using an excess of CuX to drive the transmetalation or(ii) adding some reagent(s) that scavenge Bu3SnX.
Both cases were tryed by L. S. Liebeskind.
CuTC (1.5 eq)(i)

RSnBu3 + R'I

R-R'NMP, 0 deg. ~ r.t.

SnBu3

CuBr (0.2 eq), CsF (1.2 eq)+(ii)
ClIPhClNMP, 60 deg. 8 hr

Ph91%
L. S. Liebeskind JACS 1996, 118, 2748substrate scope of (i)The reactions finish within minutes under low temperatures with high yields.
Carbonyl groups and ArX, even Aryl iodides (except o-iodonitrobenzene, entry 14), aretolerated in this reaction, which results in the chemoselectivity that is not achieved undertypical Stille reaction conditions.
The reactions are excellently stereoretentive, precluding a radical chain mechanism (entries
1, 15 and 12, 13).
- 17/19 -The CuTC-catalyzed coupling was employed in some total syntheses.
Conventional Stille conditions brought
lower than 30% yield at prolongedreaction time and 60 deg..
CuTC+

NMP, -10 deg.
1 hr, 80%

U. Koert ACIE 2001, 40, 2063

CuTC+

NMP, 0 deg. to r.t.
45 min, 60%

It took 18 hours for the conventional
Stille coupling to finish though theyield was almost the same.

R. E. Maleczka, Jr. OL 2002, 4, 2841

- 18/19 -The cross-coupling reactions using other organometallics are also developed.
Kumada-Tamao-Corriu-type

Li2CuCl4AcO

OTs+AcO

Me(CH2)8MgBr(CH2)9Me

THF

K. Mori Eur. J. Org. Chem. 2001, 3797

Suzuki-Miyaura-typeOAlkylX+Ar

BOAlkyl

X+Ar

Alkyl Ar~ 87%

CuI (10 mol%)
LiOt Bu (2 eq)

9-BBN

DMF, 12 hr
60 or 80 deg.

Alkyl Alkyl~ 71%

X = I, Br, Cl, OTs(, OMs)
L. Liu ACIE 2011, 50, 3904
This reactions don't proceed when CuI is replaced with Pd(OAc)2!

Hiyama-type
KF (1.2 eq)
CuI (1.5 eq)
R

X+R CF3

CF3SiEt3

R = Ar or Bn
X = I or Br

DMF/NMP (1/1)
80 deg., 24 hr~ 94%
T. Fuchikami T L, 1991, 32, 91- 19/19 -