Synthesis of diarylamines catalyzed by iron salts

Article abstract of DOI:10.1002/chem.200802018

A study was conducted to demonstrate the synthesis of diarylamines catalyzed by iron salts. The study evaluated the influence acetyl as an N-protecting group. The coupling of acetanilide and iodobenzene was selected as a model reaction, to optimize the reaction conditions. It was observed that a considerable amount of the N-deprotected compound was obtained along with the desired N-acetyl diarylamine. It was also observed that diphenylamine was isolated in a significant yield, by performing a basic hydrolysis with NaOMe after the iron-catalyzed arylation. A one-pot synthesis of diphenylamine was performed by adding NaOMe to the N-arylation reaction mixture, after the acetanilide was consumed completely. It was demonstrated that the strategy overcomes the synthetic limitations associated with poor reactivity of aromatic amines under iron catalysis and serves as an alternative approach for the preparation of diarylamines.

Full text of DOI:10.1002/chem.200802018

COMMUNICATION
DOI: 10.1002/chem.200802018
Synthesis of Diarylamines Catalyzed by Iron Salts
Arkaitz Correa, Mꢀnica Carril, and Carsten Bolm*[a]
Diarylamines constitute a valuable family of organic com-
pounds that are of utmost importance in biological, pharma-
ceutical, and material sciences.[1] Therefore, the search and
development of simple and improved procedures towards
the assembly of such a desirable framework represents an
elusive goal of particular interest for industrial and academ-
ic chemists. The transition-metal-catalyzed cross-coupling of
anilines and aryl halides or their equivalents is one of the
most powerful and straightforward methods for the prepara-
tion of diarylamines. Palladium,[2] copper,[3] and nickel[4] are
among the most widely used metals to perform such
carbon–nitrogen bond-forming processes, and highly effi-
cient methods are currently available. Nevertheless, aside
from the reliability of the existing protocols, the develop-
ment of a novel catalyst based on cheaper and environmen-
tally benign metals would clearly represent a major advance
of significant synthetic practical value.
Owing to its low price, sustainability, and exceptional ver-
satility, iron has attracted a great deal of attention in the
field of catalysis, and it is lately evolving into an increasingly
powerful and convenient alternative to accomplish a vast
array of organic transformations.[5] In this respect, we have
recently demonstrated that the adequate combination of
FeCl3 and certain supporting ligands results in the formation
of catalysts suitable to effect important arylation reactions,
rendering novel protocols that display complementary ad-
vantages to the previously well-established palladium- and
copper-catalyzed arylations. In particular, the use of N,N’-di-
methylethylendiamine (DMEDA) was found to be crucial
for N-[6a–c] and S-arylations[7] as well as Sonogashira couplin-
g.[8a] The success of the cross-coupling of aryl halides with
oxygen nucleophiles relied on the use of FeCl3 in combina-
tion with 2,2,6,6-tetramethyl-3,5-heptanedione (TMHD).[9]
Although several nitrogen nucleophiles (N-heterocycles,[6a]
primary amides,[6c] and sulfoximines[6b]) smoothly underwent
the target cross-couplings, all early attempts conducted with
anilines failed, and the corresponding diarylamines were
never observed. The poor nucleophilicity of the aniline
moiety has also been manifested in the selective arylation of
other nucleophiles in the presence of competing free-amino
groups.[8a] Very recently, Fu and co-workers developed an al-
ternative iron/copper co-catalyzed N-arylation process of
both aliphatic and aromatic amines featuring the use of
10 mol% of FeCl3, 10 mol% of CuO, and 20 mol% of rac-
BINOL as the catalyst system.[6f] Likewise, after the present
work was complete, Liu and co-workers disclosed a novel ar-
ylation protocol involving the use of Fe2O3 and l-proline in
DMSO at 1358C and NaOtBu as base.[10] Despite the poten-
tial of the latter method for the N-arylation of aliphatic
amines, only three examples of aniline substitutions were re-
ported with the highest yield obtained for the corresponding
diarylamine being 54%. Apparently, an effective iron-cata-
lyzed N-arylation of anilines is still to be found. In this con-
text, we hypothesized that the use of activated substrates
could lead to a solution. Thus, the iron-catalyzed arylation
of N-protected anilines, followed by NH-liberation of the re-
sulting arylated products was proposed to provide diaryla-
mines in a new and practical tandem process.
We first evaluated the influence of acetyl as an N-protect-
ing group, and thus the coupling of acetanilide (1a) and io-
dobenzene (2) was selected as a model reaction to optimize
the reaction conditions. The results of this preliminary
screening are summarized in Table 1. When applying the
previously reported conditions for the iron-catalyzed N-ary-
lation (Table 1, entries 1 and 2), diarylamine 3a was ob-
tained in low yield along with unreacted starting material
1a. The choice of the base was found to be critical for the
reaction outcome, and the use of Cs2CO3 led to the desired
arylated product in a better yield (Table 1, entry 3), albeit
full conversion was again not achieved. Other bases
(Na2CO3, Ag2CO3, BaCO3, Li2CO3, NaOAc) provided only
trace amounts of product 3a. With toluene as the solvent
better yields were achieved than with chlorobenzene
(Table 1, entries 3 and 16). Other solvents such as butanol
[a] Dr. A. Correa, Dr. M. Carril, Prof. Dr. C. Bolm
Institut fꢀr Organische Chemie, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802018.
Chem. Eur. J. 2008, 14, 10919 – 10922
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Table 1. Reagent screening for the iron-catalyzed coupling of acetanilide
responding aniline. As expected, in the absence of catalyst
the formation of the target product was not detected.
(1a) with phenyl iodide (2).[a]
Next the scope of the process was investigated by explor-
ing the cross-coupling of numerous acetanilides with differ-
ently substituted aryl iodides[13] under the optimized condi-
tions for the synthesis of 4a (Table 2). A variety of acetani-
lides bearing both electron-donating and electron-withdraw-
ing substituents smoothly underwent the arylation/deprotec-
tion sequence to deliver the corresponding diarylamines in
good to excellent yields (Table 2, entries 1–15). Likewise,
variously substituted aryl iodides could be employed but
several electronic restrictions were observed. Whereas the
coupling of 4-iodoanisole and 4-fluoroacetanilide (Table 2,
entry 9) took place to lead to diarylamine 4d in excellent
yield, other experiments performed with such an electron-
rich aryl iodide and related acetanilides were unsuccessful.
Moreover, the steric effect was highly significant, and when
using ortho-substituted aryl iodides only trace amounts of
the desired diarylamines 4 were obtained regardless of the
electronic nature of the substituent. Interestingly, ortho sub-
stituents in the acetanilide were better tolerated, and the
corresponding diarylamines 4 could be accessed, albeit in
moderate yields (Table 2, entries 16–18).
Entry
Fe source
Ligand
Base
Solvent
3a [%][b]
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeACHTUNGTRENNUNG(acac)3
FeCl3·6H2O
Fe2O3
FeACHTUNGTRENNUNG(OAc)2
FeCl3
FeCl3
L1
L1
L1
L1
L2
L2
L3
L4
L5
L6
L6
L1
L1
L1
L1
L1
L1
K3PO4
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhCl
10
21
75
K2CO3
Cs2CO3
NaOMe
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
traces[c]
65
23
0
traces
traces
traces
traces
traces
traces
traces
traces
41
9
10
11
12
13
14
15
16
17
PhMe
4a (91)[c]
[a] Reaction conditions: 1a (1.0 equiv),
2 (1.5 equiv), Fe source
(0.1 equiv), ligand (0.2 equiv), base (2.0 equiv), solvent (1 mLmmolÀ1),
1358C, under argon. [b] Yield of isolated product after flash chromatog-
raphy. [c] FeCl3 (0.15 equiv) and DMEDA (0.30 equiv) were employed.
Yield of isolated diphenylamine (4a) after arylation and subsequent de-
protection with NaOMe; acac=acetylacetonate.
In summary, we have developed a practical and conven-
ient synthesis of diarylamines based on a tandem iron-cata-
lyzed N-arylation of acetanilides followed by cleavage of the
acetyl group. This strategy overcomes the synthetic limita-
tions associated with the poor reactivity of aromatic amines
under iron catalysis and serves as a complementary alterna-
tive approach for the preparation of diarylamines.
Experimental Section
General procedure for the synthesis of diarylamines: A sealable tube
equipped with
a magnetic stir bar was charged with acetanilide 1
(1.0 equiv), aryl iodide 2 (1.5 equiv, if solid), Cs2CO3 (2.0 equiv), and
FeCl3 (0.15 equiv). The aperture of the tube was then covered with a
rubber septum, and an argon atmosphere was established. Aryl halide 2
(1.5 equiv, if liquid), N,N’-dimethylethylendiamine (0.30 equiv), and tolu-
ene (1 mLmmolÀ1 of acetanilide) were added by using a syringe. The
septum was then replaced by a teflon-coated screw cap, and the reaction
vessel was placed in an oil bath kept at 1358C. After the mixture had
been stirred at this temperature for 24 h, it was cooled to room tempera-
ture, and NaOMe (9.0 equiv) and toluene (0.5 mL) were added. After
the reaction mixture had been stirred under reflux for 1.5 h, it was
cooled to room temperature and then diluted with dichloromethane. The
resulting solution was directly filtered through a pad of silica and concen-
trated to yield the diarylamine 4, which was purified by silica gel chroma-
tography. The identity and purity of the known products was confirmed
by 1H and 13C NMR spectroscopic analysis, and the new products were
fully characterized.
and acetonitrile proved entirely inadequate, leading to de-
protection of 1a and unreacted starting material, respective-
ly. In reference to the nature of the catalyst, the most effec-
tive system resulted from combining FeCl3 with DMEDA,
while other iron sources and diamine-type ligands exhibited
lower catalytic activity (Table 1, entries 5–15).[11] Interesting-
ly, increasing the catalyst loading (to 15 mol% of FeCl3 and
30 mol% of DMEDA) had a perceptibly beneficial effect
on the reaction outcome, and full conversion was achieved.
Now, however, a considerable amount of the N-deprotected
4a was obtained along with the desired N-acetyl diarylamine
3a. By performing a basic hydrolysis with NaOMe[12] after
the the iron-catalyzed arylation, diphenylamine (4a) was
isolated in a remarkable 91% yield (Table 1, entry 17). A
one-pot synthesis of diphenylamine (4a) was performed by
adding NaOMe to the N-arylation reaction mixture once the
acetanilide (1a) was completely consumed. Notably, other
N-protecting groups (benzoyl, trifluoroacetyl, tert-butyloxy-
carbonyl (Boc), tosyl, and benzyl) were not suitable under
the optimized conditions of the N-arylation. Either no reac-
tion occurred or deprotection was observed to yield the cor-
Acknowledgements
The authors are grateful to the Fonds der Chemischen Industrie for fi-
nancial support. A.C. thanks the Basque Government for support by
“Programa de Perfeccionamiento de Doctores en el extranjero del De-
partamento de Educaciꢂn, Universidades e Investigaciꢂn” and M.C.
10920
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Chem. Eur. J. 2008, 14, 10919 – 10922

Synthesis of Diarylamines
COMMUNICATION
Table 2. Synthesis of various diarylamines 4.[a]
thanks the Spanish Ministry of Education and Science (MEC) and the
Spanish Foundation of Science and Technology (FECYT).
Entry 1
2
4[b]
Yield
[%]
Keywords: anilines · arylation · catalysis · cross-coupling ·
iron
1
2
4a
4b
91
66
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Chem. Eur. J. 2008, 14, 10919 – 10922
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C. Bolm et al.
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[13] All attempts conducted with different aryl sources (aryl bromides,
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Received: October 1, 2008
Published online: November 14, 2008
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Chem. Eur. J. 2008, 14, 10919 – 10922