Ullmann Condensation

NEXT REACTIONPREVIOUS REACTIONTABLE OF CONTENTS SEARCH TEXT464

ULLMANN BIARYL ETHER AND BIARYL AMINE SYNTHESIS / CONDENSATION(References are on page 697)

Importance:

[Seminal Publications1-4

; Reviews5-11

; Modifications & Improvements12-46

]

In 1904, F. Ullmann observed that the reaction of aryl halides with phenols to give biaryl ethers was significantly improved in the presence of copper powder.

2 The copper mediated synthesis of biaryl ethers is known as the

Ullmann condensation (Ullmann biaryl ether synthesis). In 1906, I. Goldberg disclosed the copper-mediated formation of an arylamine by reacting an aryl halide with an amide in the presence of K2CO3/CuI (Goldberg reaction/Goldbergmodified Ullmann condensation). The general features of the Ullmann condensation are: 1) aryl iodides, bromides, and chlorides are all good substrates with the following reactivity trend: I > Br > Cl >> F (the opposite trend is observed in uncatalyzed SNAr reactions); 2) aryl fluorides usually do not react under the reaction conditions; 3) the introduction of several aryloxy groups is possible in a stepwise manner; 4) the aromatic halide can contain many different substituents and even reactive functional groups (e.g., OH, NH2, CHO) need not be protected unlike in the Ullmann biaryl coupling; 5) electron-withdrawing substituents (e.g., NO2, CO2R, COO

-) in the ortho and para positions

have a marked activating effect and the yields for these substrates are excellent; 6) electron-donating substituents anywhere on the aromatic ring do not significantly decrease the reactivity of the aryl halide compared to the

unsubstituted aryl halide; 7) the required temperature ranges from 100 to 300 °C in the presence of copper metal or a copper-derived catalyst and with or without the use of solvents; 8) the catalytic activity of the copper depends on the method of preparation; 9) a wide variety of solvents work well and most of them contain a heteroatom with a lone pair of electrons; 10) the solvent helps to solubilize the catalytically active copper species by way of complexation; 11) the phenol component can be introduced in the form of free phenols or phenolate salts; 12) when free phenols are used, a base (K2CO3) is added to the reaction mixture, but other salts proved to be ineffective; 13) if Cu2O or CuO is used instead of copper, no base is required, since these substances serve as bases; and 14) since phenols and phenolates are sensitive to oxidation, the use of an inert atmosphere is often required. There are few typical side reactions of the aryl halide component: 1) reductive dehalogenation especially when the phenol is relatively unreactive; 2) Ullmann biaryl homocoupling; and 3) exchange of halogens with the Cu(I)-salt. Several modifications have been introduced to improve the somewhat harsh original reaction conditions (high temperatures, often low yields and the use of stoichiometric amounts of copper), which primarily utilize coupling partners other than aryl halides: 1) arylboronic acids in the presence of Et3N, molecular sieves and Cu(OAc)2 (Chan-Evans-Lam modification);

23-25 2) potassium aryltrifluoroborates (Batey modification);

42,43 3) aryl iodonium salts (Beringer-Kang

modification);12,29

4) aryl lead compounds (Barton plumbane modification);17

and 5) aryl bismuth compounds (Barton modification).

15,16,18

Mechanism:47,16,48,24,49,10

The exact nature (oxidation state) of the Cu-intermediate is not known, but radical mechanisms have been ruled out based on radical scavenger experiments. Two possible (speculated) pathways are shown.

X

R1

Y

R2

Biaryl ether or amine

R1R2

Cu(0) metal or Cu(I)-salts

(≤1 equiv)

base, solvent100-300 °C

+

Y

aryl halide phenol or arylamine

Biaryl ether and amine synthesis (Ullmann 1903 & Goldberg 1906):

Modified Ullmann biaryl ether / thioether and biaryl amine synthesis:

Z

R3

Y

R4

+

Biaryl ether/amine/sulfide

R3R4

Y

R1-4 = H, CN, NO2, CO2R, I, Br, Cl, I; X = I, Br, Cl, SCN; Y = OH, NH2, NHR, NHCOR; solvent: DMF, pyridine, quinoline, DMSO,

nitrobenzene, glycol, diglyme, dioxane; base: K2CO3, Et3N, pyridine; Cu(I)- and Cu(II)-salts: CuI, Cu2O, Cu(OAc)2; ligand: diamines

When Y = NH2, OH, SH and Z = B(OH)2 (Chan-Evans-Lam modification), Z = BF3K (Batey mod.), Z = Si(OMe)3 or Sn(alkyl)3 (Lam

mod.), Z = (I-aryl)+BF4- (Beringer-Kang mod.), Z = Pb(OAc)3 (Barton plumbane mod.), Z = BiPh2X2 (Barton mod.)

Cu(I)- or Cu(II)-salts

(≤1 equiv)

base, solvent, ligandroom temperature

Ar X

L2Cu(III)

X

Ar

L2Cu(III)

YAr

Ar

Ar Z

L2Cu(II)

X

Ar

L2Cu(II)

YAr

Ar+ e-

- e-

Ar Y Ar

oxidative addition

Y Ar

Cu(I)XL2

X

Cu(II)X2

transmetallation

Y ArX

Cu(I)X

+ 2 L + 2 L

X2Cu(II)L2

reductiveelimination

reductiveelimination

Cu(0) ox.


ULLMANN BIARYL ETHER AND BIARYL AMINE SYNTHESIS / CONDENSATION

Synthetic Applications:

The intramolecular Ullmann condensation was used by D.L. Boger and co-workers to form the 15-membered macrocyclic ring of the cytotoxic natural product, combretastatin D-2.

50 This compound possesses unusual meta- and

paracyclophane subunits, which are also found in a range of antitumor antibiotics. The first approach where the final step was a macrolactonization was unsuccessful, so the researchers chose to form the biaryl ether moiety as the key macrocyclization step. Methylcopper was found to mediate the cyclization and gave moderate yield of the corresponding biaryl ether. Finally boron triiodide mediated demethylation afforded the natural product.

The highly oxygenated antifungal/anticancer natural product (±)-diepoxin σ was prepared in the laboratory of P. Wipf.

51 The coupling of the two substituted naphthalene rings was achieved via the Ullmann condensation of a

phenolic compound with 1-iodo-8-methoxynaphthalene. The aryl iodide coupling partner was used in excess and the condensation was conducted in refluxing pyridine in the presence of a full equivalent of copper(I)-oxide.

In the laboratory of K.C. Nicolaou, a novel mild method for the preparation of biaryl ethers was developed.22

The di-ortho-halogenated aromatic triazenes underwent efficient coupling with phenols in the presence of CuBr. This mild modified Ullmann condensation was utilized in the synthesis of the DOE and COD model ring systems of vancomycin.

The Ullmann biaryl amine condensation was used in the synthesis of SB-214857, a GPIIb/IIIa receptor antagonist.52

D. Ma and co-workers coupled aryl halides with β-amino acids and esters under relatively mild conditions using CuI as a true catalyst.

O

O

IOMe

OHCu(I)Me (1.5 equiv)

pyridine, 25 °C, 45 min

then dilute with pyridineto 0.004M

reflux, 24.5h; 37%

OMe

O

O

O

BI3(1 equiv)PhN(Me)2

(1.2 equiv)

benzene25 °C, 1h

OH

O

O

O

Combretastatin D-2

OH

OH

CH3O

OH

ICH3O

+

CH3O

OH

OH

CH3O

O

Cu2O (1 equiv)pyridine

(1.7 equivalents)

reflux, 20h70%

OO

O

O

OH

O O

steps

(±)-Diepoxin σ

NH

HN

O

O

Ph

R

OH

Br Br

NN N

NH

HN

O

O

Ph

R

Br

NN N

O

CuBr-Me2S(2.5 equiv)

pyridine(3 equiv)

R = CO2Me

K2CO3

(2.5 equiv)MeCN, 75 °C

15h; 77%

steps

NH

HN

O

O

Ph

R

O

OH

H

Model COD ring system ofvancomycin

I

NMe

O

H2NCO2H

CuI (10 mol%)DMF (250 mol%)

H2O (cat.)

90 °C, 48h67%

HN

N

O

HO2C

Me

R

R = CO2t-Bu

R

steps

HN

N

O

HO2C

MeO

N

HN ·HCl

SB-214857


ULLMANN REACTION / COUPLING / BIARYL SYNTHESIS(References are on page 699)

Importance:

[Seminal Publications1,2

; Reviews3-9

; Modifications & Improvements10-21

]

In 1901, F. Ullmann reported the reaction of two equivalents of an aryl halide with one equivalent of finely divided

copper at high temperature (>200 °C) to afford a symmetrical biaryl and copper halide.1 This condensation of two aryl

halides in the presence of copper to give symmetrical or unsymmetrical biaryls is now referred to as the Ullmann reaction (Ullmann biaryl synthesis or Ullmann coupling). Since its discovery, the Ullmann reaction has become a general method for the synthesis of numerous symmetrical and unsymmetrical biaryls. The general features of this reaction are: 1) halogenated benzene rings as well as halogenated heteroaromatic compounds are substrates for the coupling; 2) the order of reactivity is I > Br >> Cl, but aromatic fluorides are totally inert; 3) the reaction can take place both inter- and intramolecularly and has been used to form macrocycles (4- to 24-membered rings);

6 4) electron-

withdrawing groups (e.g., NO2, CO2Me, CHO) ortho to the halogen substituent increase the reactivity of the aryl halide; 5) generally substituents in the ortho position, which have a lone pair increase the reactivity regardless whether they are EWG or EDG, but these substituents have no noticeable activating effect in the meta or parapositions;

22 6) substrates that are very electron rich (e.g., multiple alkyl or alkoxy groups) tend to give lower yield of

the biaryl; 7) certain unprotected functional groups (e.g., OH, NH2, CO2H, SO2NH2) open alternative reaction pathways therefore inhibit the coupling;

23 8) bulky groups located ortho to the halogen tend to retard or inhibit the

coupling reaction due to steric hindrance; 9) when unsymmetrical biaryls are prepared, the highest yield is obtained when one of the aryl halides is activated (more electron rich), while the other is less reactive; 10) in order to achieve good results, activated copper (preferably prepared prior to use) must be used;

17 11) highly active copper metal can

be prepared by reducing CuI with lithium naphthalenide or by reducing CuSO4 with Zn powder; 12) usually

temperatures over 100 °C are necessary to initiate the coupling but the use of highly active Cu-powder allows lower temperatures; 13) the most common solvent is DMF, but for higher temperatures PhNO2 or p-NO2C6H4CH3 are used;

10,11 14) sonication often improves the efficiency of the coupling;

18,19 15) Cu(I)-salts (e.g., Cu2O, Cu2S) also

mediate the coupling although they are less active than the activated copper metal;12

and 16) Cu(I) thiophene 2-carboxylate (CuTC) was found to be an efficient mediator under mild conditions (usually room temperature) in NMP.

21

There are a few modifications: 1) the reaction conditions of the Ullmann coupling become significantly milder when Ni

(0) complexes are used in place of copper metal;

13,9 and 2) for the preparation of highly substituted biaryls the use of

preformed aryl copper species has been successful (Ziegler modification).16,20

Mechanism:24-26,14,27-32,9

The exact mechanistic pathway of the Ullmann coupling is not known. There are two main pathways possible: 1) formation of aryl radicals or 2) the formation of aryl copper [ArCu

(I), ArCu

(II) and ArCu

(III)] intermediates. Currently the

most widely accepted mechanism assumes the formation of aryl copper intermediates, since many of these species can be isolated and they can react with aryl halides to give biaryls.

+

X + XCu-powder

> 200 °C

Symmetrical biaryl

+ 2 Cu(I)X

Synthesis of symmetrical biaryls (Ullmann, 1901):

R1, R2 = H, CN, NO2, CO2R, I, Br, Cl; X = I, Br, Cl, SCN; solvent: DMF, pyridine, quinoline, nitrobenzene, p-nitro toluene

R1R1

R1R1

X

R1

X

R2

Synthesis of unsymmetrical biaryls:

Unsymmetrical biaryl

R1R2

Cu(0) or Cu(I)-salts

(1-5 equiv)

solventheat or sonication

+ + Cu(I)XCu(I)X

Ar X + Cu(0)Ar X + Cu(I)

Ar X + Cu(I) Ar + Cu(I)X

Ar + Ar Ar Ar

Pathway involving aryl radicals: Pathway involving arylcopper intermediates:

Ar X + Cu(0)Ar Cu(II)X

Ar Cu(II)X + Cu(0)Ar Cu(I) + Cu(I)X

Ar Cu(I) Ar X+ Ar Cu(III)XAr

Ar Cu(III)XAr Ar Ar + Cu(I)X

Step #1:

Step #2:

Step #3:

Step #4:

Step #1:

Step #2:

Step #3:


ULLMANN REACTION / COUPLING / BIARYL SYNTHESIS

Synthetic Applications:

The Ziegler-modified Ullmann reaction was used for the total synthesis of pyrrolophenanthridinium alkaloid tortuosine by L.A. Flippin and co-workers.

33 First, N-Boc-5-methoxyindoline was lithiated at C7 with s-BuLi in the presence of

TMEDA, and then it was transmetallated to the corresponding organocopper species that smoothly underwent the Ullmann reaction with a 3-iodoaryl imine. The resulting biaryl product was treated with anhydrous HCl in chloroform, which promoted the cyclization followed by dehydration to give the natural product.

In the laboratory of A.I. Meyers, the oxazoline-mediated asymmetric Ullmann coupling was utilized to establish the chirality about the biaryl axis of mastigophorenes A and B.

34 The key coupling step was conducted in DMF in two

stages: first the reaction mixture (0.66M) containing freshly prepared activated Cu-powder was heated at 95 °C for 8h, and then it was diluted with DMF (0.11M) and refluxed for 3 days. Interestingly, during these studies it was revealed that smaller chiral auxiliaries lead to higher atroposelection, a fact which was not previously recognized.

The first total synthesis of taspine was accomplished by T.R. Kelly and co-workers.35

The central biaryl link was established by a classical Ullmann coupling using activated copper bronze. It is noteworthy that no other cross-coupling strategy was successful to make the C-C bond between the aromatic rings due to the severe steric hindrance.

L.S. Liebeskind et al. demonstrated that CuTC could be efficiently used to mediate the Ullmann reaction at room temperature under very mild conditions tolerating a wide variety of functional groups.

21 One of the examples features

an intramolecular process while the other demonstrates the coupling of halogenated heteroaromatics.

N

Boc

OMe s-BuLi-TMEDA

Et2O-45 °C, 2h

thenCuI-P(OEt)3 N

Boc

OMe

Cu

P(OEt)3

RR

I

N

Cy

then adddilute HCl

CHO

R

R

+

R = OMe

60%

OMe

N

Boc

HCl

CHCl3

N

R

R

O

Cl

81%

Tortuosine

Me

MeO OMe

Br

O

N

Cu-powder(activated)

DMF, 95 °C, 8h

then dilutereflux, 3d 85% (3:1)

MeO OMe

O N

OMeMeO

ON

steps

OMe

H3C OMe

OMe

OMe

H3C

(−)-Mastigophorene A

I

CONHPrMOMO

MeOCu-bronze> 200 °C

66%

O

MeO

O

OMe

O

O

NMe2

CONHPrMOMO

MeO

PrHNOC OMOM

OMe

steps

Taspine

I

N

IMe

CuTC, NMP

r.t., 15h; 88%

N

Me

SI

CuTC (2.5-3 equiv) NMP

r.t., 48h; 77%S

S

[2,2']BithiophenylTricyclic product

404. Ullmann Reaction

F. Ullmann, Ann. 332, 38 (1904); F. Ullmann, P. Sponagel, Ber. 38, 2211 (1905).

Copper-mediated coupling of aryl halides. Biaryl ether synthesis is similarly accomplished with aryl halides and phenols:

P. E. Fanta, Chem. Rev. 38, 139 (1946); 64, 613 (1964); A. A. Moroz, M. S. Shvartsberg, Russ. Chem. Rev. 43, 679 (1974); P. E. Fanta, Synthesis 1974, 9; M. F. Semmelhack et al., J. Am. Chem. Soc. 103, 6460 (1981); D. W. Knight, Comp. Org. Syn.3, 499-507 (1991). Cf. Glaser Coupling.

Copyright © 2001 by Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

Documents

Ullmann Condensation