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Y R4
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)
Y Ar L2Cu
Ar
(II)
X Cu(I)XL2 +2L
transmetallation
YAr
reductive elimination
Ar
Cu(I)X
Ar
Y Ar
Ar
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465
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
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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X R1
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.
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(I) + Ar Ar Cu(III)XAr
Ar + Ar
Ar
Step #4:
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467
OMe
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
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.