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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/Goldberg modified 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 23-25 42,43 modification); 2) potassium aryltrifluoroborates (Batey modification); 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
Biaryl ether and amine synthesis (Ullmann 1903 & Goldberg 1906): X R1 aryl halide Y R2 phenol or arylamine Cu(0) metal or Cu(I)-salts (1 equiv) base, solvent 100-300 C R1 Y R2

Biaryl ether or amine

Modified Ullmann biaryl ether / thioether and biaryl amine synthesis: Z R3

1-4

Y R4

Cu(I)- or Cu(II)-salts (1 equiv) base, solvent, ligand room temperature R3

Y R4

Biaryl ether/amine/sulfide

R = 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.)

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.
Ar L2Cu
oxidative addition
(III)

Y Ar

X Ar L2Cu
(III)

X + e- eAr L2Cu(II) YAr

reductive elimination

Y Ar L2Cu

Ar
(II)

X Cu(I)XL2 +2L

X X2Cu L2 +2L Cu(0) ox. Cu(II)X2

(II)

transmetallation

YAr
reductive elimination

Ar

Cu(I)X

Ar

Y Ar

Ar

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465

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.
OMe OH O O I OMe O BI3 (1 equiv) PhN(Me)2 (1.2 equiv) O O benzene 25 C, 1h OH O

Cu(I)Me (1.5 equiv) pyridine, 25 C, 45 min then dilute with pyridine to 0.004M reflux, 24.5h; 37%

O O Combretastatin D-2

The highly oxygenated antifungal/anticancer natural product ()-diepoxin 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.
O O steps O CH3O O OH O O O OH

CH3O CH3O I + (1.7 equivalents) OH OH CH3O OH Cu2O (1 equiv) pyridine reflux, 20h 70%

OH

()-Diepoxin

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

OH Br O R N H

N N Br CuBr-Me2S (2.5 equiv) pyridine (3 equiv) K2CO3 (2.5 equiv) MeCN, 75 C 15h; 77% R N H Ph N O O H N O N N Br steps R N H O H N O OH H

H N Ph O

R = CO2Me

Ph O Model COD ring system 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 -amino acids and esters under relatively mild conditions using CuI as a true catalyst.
I R Me N O CO2H CuI (10 mol%) DMF (250 mol%) H2O (cat.) 90 C, 48h 67% R = CO2t-Bu R HO2C H N O N Me steps N O SB-214857 N Me HO2C H N O

HN

HCl

H2N

466

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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 1 copper at high temperature (>200 C) to afford a symmetrical biaryl and copper halide. 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) electronwithdrawing 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 para positions;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 2carboxylate (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 (0) 13,9 and 2) for the preparation of highly substituted biaryls the use of Ni complexes are used in place of copper metal; preformed aryl copper species has been successful (Ziegler modification).16,20
Synthesis of symmetrical biaryls (Ullmann, 1901): X R
1

X R1

Cu-powder > 200 C R1 R1 + 2 Cu(I)X

Symmetrical biaryl

Synthesis of unsymmetrical biaryls: X R1 X R2 Cu(0) or Cu(I)-salts (1-5 equiv) solvent heat or sonication R1 R2 + Cu(I)X
(I) + Cu X

Unsymmetrical biaryl

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

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.

Pathway involving aryl radicals:

Step #1: Step #2: Step #3:

Pathway involving arylcopper intermediates: Ar Ar X + Ar + Cu(I) Cu(I)X

Step #3:

Ar Ar

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

Step #1:
Step #2:

Ar Ar Ar

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

Ar Ar Ar Ar

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

(I) Ar + Cu X

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

Ar + Ar

Ar

Step #4:

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467

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.
OMe N I Cu P(OEt)3 N Boc R R + then add dilute HCl 60% R = OMe R R Boc CHO HCl N CHCl3 81% R R Tortuosine

OMe

s-BuLiTMEDA Et2O -45 C, 2h

OMe

Cy

Cl

N O Me

N Boc

then CuI-P(OEt)3

In the laboratory of A.I. Meyers, the oxazoline-mediated asymmetric Ullmann coupling was utilized to establish the 34 chirality about the biaryl axis of mastigophorenes A and B. 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.

OMe MeO OMe Br N O Cu-powder (activated) DMF, 95 C, 8h then dilute reflux, 3d 85% (3:1) MeO OMe MeO OMe steps H3 C H3C O N N O OMe OMe OMe

()-Mastigophorene A

The first total synthesis of taspine was accomplished by T.R. Kelly and co-workers. The central biaryl link was established by a classical Ullmann coupling using activated copper bronze. It is noteworthy that no other crosscoupling strategy was successful to make the C-C bond between the aromatic rings due to the severe steric hindrance.
MeO MeO MOMO I OMe CONHPr Cu-bronze > 200 C 66% MOMO PrHNOC CONHPr OMOM steps O MeO O O OMe Taspine O NMe2

35

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.
Me N N I Me I CuTC, NMP r.t., 15h; 88% S Tricyclic product I CuTC (2.5-3 equiv) NMP r.t., 48h; 77% [2,2']Bithiophenyl S S

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.