Amination and amidation of aryl iodides catalyzed by copper(I)- phenanthroline complexes

Article abstract of DOI:10.1016/j.tetlet.2005.08.146

Four kinds of copper(I)-phenanthroline complexes ([Cu^I(phen) ₂]Cl, [Cu^I(phen)Cl]₂, [Cu^I(phen) ₂]BF₄, and Cu^I(phen)PPh₃Cl) were prepared and used as catalysts for amination and amidation of aryl iodide to investigate the influence on the yields of products due to differences of the structures. These complexes were found to work as catalysts on these reactions and showed that the differences of structures of copper(I) complexes significantly influenced the yield of aryl-nitrogen bond forming processes.

Full text of DOI:10.1016/j.tetlet.2005.08.146

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7559–7562
Amination and amidation of aryl iodides catalyzed by
copper(I)–phenanthroline complexes
Kazuyuki Moriwaki,* Kazuyoshi Satoh, Masahiro Takada,
Yoshio Ishino and Toshinobu Ohno*
Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 11 July 2005; revised 22 August 2005; accepted 26 August 2005
Available online 16 September 2005
Abstract—Four kinds of copper(I)–phenanthroline complexes ([CuI(phen)2]Cl, [CuI(phen)Cl]2, [CuI(phen)2]BF4, and CuI-
(phen)PPh3Cl) were prepared and used as catalysts for amination and amidation of aryl iodide to investigate the influence on
the yields of products due to differences of the structures. These complexes were found to work as catalysts on these reactions
and showed that the differences of structures of copper(I) complexes significantly influenced the yield of aryl-nitrogen bond forming
processes.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Arylamines and arylamides are prevalent and important
compounds in biological, pharmaceutical, and electronic
materials.1–6 Their extensive importance has developed
many synthetic methods for the formation of aryl-nitro-
gen bonds. Both classical Ullmann coupling processes7,8
and the related Goldberg coupling reaction9,10 have
been commonly used in laboratory and industrial scale
in spite of necessity to use high temperature, highly
polar solvents, and large amounts of copper reagents
(Scheme 1).
more commonly used and excellent methods in labora-
tory scale.11,12 However, copper mediated coupling is
still the reaction of choice for large and industrial-scale
production owing to an economic attractiveness and
various types of copper-catalyzed systems have been
developed and reported.13–16
When we followed these copper-catalyzed systems, we
often felt the difficulty of reproducibility because there
were many factors, which influenced the properties
and yields of coupling reactions: hygroscopic degree,
grain size, valency, stability, and solubility of copper re-
agents; selection of solvents and ligands; ligands/copper
reagents ratio; basicity, hygroscopic degree, grain size of
bases; how to combine their factors. Furthermore, in
general, ligands and copper reagents are added sepa-
rately into the reaction systems without making a cop-
per complex except a few examples.17,18 However,
investigating what structures of copper complexes have
higher activity for the coupling reaction is considered
to lead to understand the mechanism of the reaction
and proper molecular design for more active catalysts.
During the last decade, significant advances have oc-
curred in the cross-coupling methodology for aryl-nitro-
gen bond forming process, Pd catalyzed reaction of aryl
halides such as Hartwig–Buchwald coupling became the
Since Goodbrand and Hu reported 1,10-phenanthroline
(phen) produced significant rate accelerations for
Ullmann condensation,13 we have been interested in
the function of 1,10-phenanthroline. It is considered
that 1,10-phenanthroline makes some complexes with
copper salts and the complexes work as catalysts though
the real active species are unknown (Scheme 2).
Scheme 1.
Keywords: Amination; Amidation; N-Arylation; Phenanthroline;
Copper; Complex; Catalysis.
*
Corresponding authors. Tel.: +81 6 6963 8053; fax: +81 6 6963
8049; e-mail: ohno@omtri.city.osaka.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.146

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K. Moriwaki et al. / Tetrahedron Letters 46 (2005) 7559–7562
amine was performed in toluene at 110ꢁC and is shown
in Table 1.22 These four complexes were found to work
as good catalysts for this reaction and [CuI(phen)2]Cl 1
was the most effective complex among them (Table 1,
entries 1–4). It is very interesting that two similar struc-
tures of copper complexes [CuI(phen)2]Cl 1 and [CuI-
(phen)2]BF4 3 had different activity for the N-arylation
as catalysts. As a reason, it is considered that the coor-
dination ability of Clꢀ is higher than that of BFꢀ4 so that
[CuI(phen)2]Cl 1 has five coordinated Cu-center though
[CuI(phen)2]BF4 3 has four coordinated Cu-center with
BFꢀ4 ion as a counter anion. In case that 10 mol %
of CuICl23 and 50 mol % of 1,10-phenanthroline with
respect to the amine were added separately into the
systems (Table 1, entry 8), the yield was 42% and lower
than those of [CuI(phen)2]Cl 1 or [CuI(phen)Cl]2
though there was a possibility of generation of them
in situ.
2
Scheme 2.
Kitagawa and Munakata reported the synthesis and
properties of binuclear [CuI(phen)X]2 complexes and
mononuclear [CuI(phen)2]X complexes and that there
are some differences in their properties and reactivity,
for example, binuclear [CuI(phen)X]2 complexes revers-
ibly react with CO whereas mononuclear [CuI(phen)2]X
complexes do not react with CO.19 We intended to use
some well-defined copper complexes having 1,10-phen-
anthroline as catalysts for aryl-nitrogen bond forming
processes and investigate the influence on the yields of
coupling products due to differences of the structures.
The influence of bases on the yields of 4,40-dimethyltri-
phenylamine in the presence of [CuI(phen)2]Cl 1 as an
optimum catalyst was investigated to find that NaOtBu
was the most effective and using milder bases such as
K3PO4, K2CO3, and Cs2CO3 significantly resulted in
low yields (Table 1, entries 5–7). The similar tendency
was observed in case of using the other complexes as
catalysts.
Amidation of iodobenzene with benzamide was also per-
formed by using these copper(I) complexes in a similar
manner of amination and is shown in Table 2.24
In this study, four kinds of copper(I)–phenanthroline
complexes [CuI(phen)2]Cl 1,19 [CuI(phen)Cl]2 2,19 [CuI-
(phen)2]BF4 3,20 and CuI(phen)PPh3Cl 421 are prepared
according to previous papers and used as catalysts for
the synthesis of arylamines and arylamides.
As a result, all copper(I) complexes were found to cata-
lyze the amidation (Table 2, entries 1–3) by using
25
K3PO4 as a base. To our knowledge, this is the first
example of amidation of aryl halides catalyzed by cop-
per(I) complexes. Using strong base such as NaOtBu
resulted in no reaction in contrast to the results of
N-Arylation of p,p0-ditolylamine with iodobenzene cata-
lyzed by 8 mol % of four complexes with respect to the
Table 1. Amination of iodobenzene with various copper(I) complexes and bases
Entry
Catalyst (mol %)
Basea
Reaction time (h)
LC yield (%)
1
2
3
4
5
6
7
8
[CuI(phen)2]BF4 3 (8)
CuI(phen)PPh3Cl 4 (8)
[CuI(phen)Cl]2 2 (4b)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
CuICl/phen (10/50)
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K3PO4
K2CO3
Cs2CO3
NaOtBu
5
5
5
59
36
62
80 (75c)
9
8
6
42d
5
20
20
20
5
a All bases except NaOtBu were ground with an agate mortar and dried on heating up to 100ꢁC in vacuo before using.
b Total amount of copper(I) ion is 8 mol % with respect to an amine.
c Isolated yield obtained by column chromatography on silica gel using n-hexane–toluene (7/3) as eluent.
d As 2,20-bipyridine is one of typical bidentate ligands, the effect was compared with that of phenanthroline in the similar condition (CuICl/
bipiridine = 10/50, base: NaOtBu, reaction time 5 h; LC yield 26%).

K. Moriwaki et al. / Tetrahedron Letters 46 (2005) 7559–7562
Table 2. Amidation of iodobenzene with various copper(I) complexes and bases
7561
Entry
Catalyst (mol %)
Basea
Reaction time (h)
LC yield (%)
1
2
3
4
5
6
7
[CuI(phen)2]BF4 3 (8)
[CuI(phen)Cl]2 2 (4)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
[CuI(phen)2]Cl 1 (8)
CuICl/phen (10/50)
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
NaOtBu
K3PO4
20
20
20
20
20
20
20
87
92
94 (90b)
72
11
0
70
a All bases were treated in the same way of amination (see Table 1).
b Isolated yield obtained by column chromatography on silica gel using n-hexane–EtOAc (1/1) as eluent.
3. Borsenberger, P. M.; Weiss, D. S. Organic Photoreceptors
for Imaging Systems; Marcel Dekker: New York, 1993.
4. Law, K.-Y. Chem. Rev. 1993, 93, 449.
5. Lindley, J. Tetrahedron 1984, 40, 1433.
6. Ohno, T.; Moriwaki, K.; Miyata, T. J. Org. Chem. 2001,
66, 3397.
7. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
8. Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.
9. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
10. Dharmasena, P. M.; Oliveira-Campos, A. M.-F.; Raposo,
M. M. M.; Shannon, P. V. R. J. Chem. Res. (S) 1994,
296.
11. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
12. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
13. Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64,
670.
14. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459.
15. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 581.
amination (Table 2, entry 6). Since the proton of amide
is more acidic than that of amine, it is considered that
using strong base lead to the formation of an excess of
the deprotonated amide to give a non-reactive cuprate
complex, which impedes desired catalytic cycle of ami-
dation as Buchwald and co-workers explained in their
reports of amidation on their systems.26
In conclusion, copper(I)–1,10-phenanthroline complexes
[CuI(phen)2]Cl 1, [CuI(phen)Cl]2 2, [CuI(phen)2]BF4 3,
and CuI(phen)PPh3Cl 4 were prepared and used as the
catalysts for amination and amidation of iodobenzene
with p,p0-ditolylamine and benzamide, respectively.
These complexes were found to work as the catalysts
on these reactions and showed that the differences of
structures among these complexes significantly influ-
enced the yield of carbon–nitrogen bond forming
processes. To our knowledge, amidation of aryl iodi-
des catalyzed by copper(I) complexes was the first exam-
ple. In case that CuICl and 1,10-phenanthroline were
added separately into the systems, the yield of amination
was lower than those of [CuI(phen)2]Cl 1 or [CuI-
(phen)Cl]2 2 though there was a possibility of generation
of them in situ.
16. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727.
17. Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahe-
dron Lett. 2001, 42, 4791.
18. Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315.
19. Kitagawa, S.; Munakata, M. Inorg. Chem. 1981, 20,
2261.
20. Schilt, A. A.; Taylor, R. C. J. Inorg. Nucl. Chem. 1959, 9,
211.
21. Jardine, F. H.; Rule, L.; Vohra, A. G. J. Chem. Soc. (A)
1970, 238.
Though the mechanism and correlation between activity
and structures of catalysts could still not be completely
elucidated from these results, investigating what struc-
tures of copper complexes have higher activity for the
coupling reaction is important for proper molecular de-
sign of more active catalysts. We are still in the process
of studying the mechanism and developing the systems
for large and industrial-scale production of arylamines
and arylamides and will be reporting on them in the near
future.
22. Typical procedure of amination is as follows: Under
nitrogen atmosphere, 1 mmol of p,p0-ditolylamine, 1 mmol
of iodobenzene, 2 mmol of base, and 8 mol % of a catalyst
with respect to an amine were added in 10 mL of dry
toluene, followed by heating to the reflux temperature of
110 ꢁC, stirring at the same temperature for definite time
(5 or 20 h), and cooling down to room temperature to stop
the reaction. The reaction mixture was filtrated with
disposable ODS cartridge column and diluted to a definite
volume with acetonitrile, followed by determination of
chemical yields with HPLC analysis. HPLC: Nacalai
Cosmosil 5C18 MSII, 4.6 · 150 mm column. Mobile
phase: A, acetonitrile; B, water; A/B 85:15.
23. CuICl was prepared by reduction of CuIICl2 with sodium
sulfite, see: Keller, R. L.; Wycoff, H. D. Inorg. Synth. 1945,
2, 1.
References and notes
1. Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart,
1999.
2. Negwer, M. Organic-Chemical Drugs and their Synonyms:
An International Survey, 7th ed.; Academie Verlag GmbH:
Berlin, 1994.

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K. Moriwaki et al. / Tetrahedron Letters 46 (2005) 7559–7562
24. Amidation were performed in the same way of amination
by using 1 mmol of benzamide, 1 mmol of iodobenzene,
2 mmol of base, and 0.08 mmol of a catalyst (8 mol % with
respect to an amide) (see Ref. 22). Dilution of the reaction
mixture after reaction was carried out with methanol
instead of acetonitrile, followed by HPLC analysis.
HPLC: Nacalai Cosmosil 5C18 MSII 4.6 · 150 mm col-
umn. Mobile phase: A, 5 mM of aqueous KH2PO4
solution adjusted by 5 mM of H3PO4; B, methanol; A/B
55:45.
26. Buchwald and co-workers have reported a proposed
reaction mechanism in case of using strong base as a
scheme below, see: Klapars, A.; Huang, X.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 7421.
25. K3PO4 was found to be the most effective base on
this reaction, but thorough drying of this reagent is
necessary before using to give good results. Insufficient
drying of K3PO4 was found to give rise to significant
depression of chemical yields and reproducibility on this
reaction.