The Ullmann reaction involves the copper-catalyzed formation of a carbon-carbon bond between two aryl halides. It occurs through an oxidative addition of the aryl halide to a copper(I) species, followed by reductive elimination forming the biaryl product. The Ullmann reaction can be used to synthesize symmetrical and unsymmetrical biaryls, diarylamines, diaryl ethers, and has been applied in gossypol and indole syntheses.
3. INTRODUCTION
In 1901, Ullmann reported a useful technique for the formation of a new C-C bond between two aryls
by the condensation of two molecules of aromatic halide in the presence of finely divided copper
which is known as Ullmann reaction. Diphenyl amines, diphenyl ethers and diphenyls can be
synthesised. This is the first transition metal mediated coupling reaction for the formation of aryl aryl
bond
4. INTRODUCTION
There are two different transformations referred as the Ullmann Reaction. The "classic"
Ullmann Reaction is the synthesis of symmetric biaryl via copper catalysed coupling. The
"Ullmann-type" Reactions include copper catalysed Nucleophilic Aromatic Substitution
between various nucleophiles (e.g. substituted phenoxides) with aryl halides. The most
common of these is the Ullmann Ether Synthesis.
5. INTRODUCTION
Aryl lodides are good for this reaction but aryl bromides and chlorides also react when
electronegative substituents, which activate the halogen, like nitro, ester etc. are present at ortho and
para position. Order of reactivity is
Arl >ArBr>ArCl
6. Ullmann Reaction Mechanism
Step 1
The mechanism of the Ullmann reaction involves the formation of an active copper(I) species upon the introduction of the aryl halide to an excess of
metallic copper under relatively high temperatures (>200oC).
Step 2
This copper(I) species undergoes further oxidative addition with another haloarene molecule, linking the two molecules (as illustrated below).
7. Step 3
In the final step of the Ullmann reaction mechanism, the copper compound formed by the two aryl halide molecules undergoes reductive elimination,
resulting in the formation of a new carbon-carbon bond between the two aryl compounds (as illustrated below).
Ullmann-type reactions proceed through a catalytic cycle, and in one mechanism the copper is postulated to undergo
oxidation to Cu(III). As some Cu(III) salts have been prepared, the suggestion for the mechanism is intriguing (see
also Chan-Lam Coupling):
8. Applications of the Ullmann Reaction
A. Synthesis of biaryls and polyaryls::
a. Symmetrical biaryls:
9. Applications of the Ullmann Reaction
b. Unsymmetrical diaryls:
With a mixture of two different aryl halides, three products are obtained which has poor synthetic
value for the yield of the desired product is low and difficult to isolate. In some cases, however, the
unsymmetrical product is only formed, e.g.
11. Applications of the Ullmann Reaction
B. Synthesis of diarylamines:
An arylamine and an aryl halide are refluxed in the presence of anhydrous potassium carbonate and
copper powder.
12. Applications of the Ullmann Reaction
C. Synthesis of diaryl ether:
A phenolic compound and an aryl halide are refluxed in the presence of potassium hydroxide or
K2CO3 and copper. The reaction has been employed in the synthesis of thyroxine.
13. Applications of the Ullmann Reaction
D. Gossypol synthesis:
Meyers and Willemsen developed the first asymmetric synthesis of (S)-(+)-gossypol via a traditional
Ullmann coupling. Heating a 40% solution of bromonaphthyl oxazoline derivative in freshly distilled
DMF and activated copper at reflux for 1 h gave the binaphthyl derivative by Ullmann coupling in 80%
yield as a 17:1 diastereoisomeric mixture. This is the key step for the total synthesis of (S)-(+)
gossypol.
Gossypol has antimalarial activity and it is used in china as oral male contraceptive.
15. Applications of the Ullmann Reaction
E. Indole synthesis
Banwell and co-workers developed the synthesis of indoles via Pd(0)-mediated Ullmann cross-
coupling of o-halonitrobenzene and with arrange of a-halo enones followed by reductive cyclization