Mild method for ullmann coupling reaction of amines and aryl halides

Article abstract of DOI:10.1021/ol0346584

(Matrix presented) Ullmann-type aryl amination of aryl iodides and aryl bromides in DMSO at 40-90°C gave the corresponding N-arylamines or N,N-diarylamines in good to excellent yields by using either N-methylglycine or L-proline as the ligand.

Full text of DOI:10.1021/ol0346584

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2453-2455
Mild Method for Ullmann Coupling
Reaction of Amines and Aryl Halides
,†
Dawei Ma,* Qian Cai,† and Hui Zhang‡
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China,
and Department of Chemistry, Fudan UniVersity, Shanghai 200433, China
madw@pub.sioc.ac.cn
Received April 18, 2003
ABSTRACT
Ullmann-type aryl amination of aryl iodides and aryl bromides in DMSO at 40−90 °C gave the corresponding N-arylamines or N,N-diarylamines
in good to excellent yields by using either N-methylglycine or L-proline as the ligand.
Since it was discovered 100 years ago,1 Ullmann-type aryl
amination has witnessed a number of industrial-scale ap-
plications because its products are important in the pharma-
ceutical and materials world.2 The synthetic scope of this
reaction, however, is greatly limited by its high reaction
temperature.2 This shortcoming stimulated considerable
efforts to develop Pd-catalyzed aryl amination methodology.3
Some exciting achievements have already appeared in this
field. For instance, the aryl amination of either aryl iodides
or aryl bromides can be carried out at room temperature if
certain phosphines are used as the ligands.4 However,
industrial employment of this methodology is limited in many
cases due to the air and moisture sensitivity, as well as the
higher costs of Pd and the relative ligands.
We have found that the structures of R- and â-amino acids
could induce acceleration of Ullmann-type aryl amination,
which led to the coupling reaction of aryl halides with R- or
â-amino acids at relatively low temperatures.5 Soon after
these reports, Buchwald reported that using ethylene glycol
as the ligand afforded the CuI-catalyzed coupling of alkyl-
amines and aryl iodides at 80 °C.6a Prior to that, other milder
Ullmann-type methodologies for N-arylation of several
nitrogen-containing substrates based on employing several
specific ligands were disclosed by the same group.7 Very
recently, they also reported that Ullmann-type aryl amination
of aryl bromide was carried out at 90 °C using diethylsali-
cylamide as the ligand.6a Stimulated by these results, we
realized that the amino acids might be suitable ligands for
promoting the typical Ullmann-type aryl amination. Thus, a
competitive experiment in which 1 equiv of benzylamine
† Shanghai Institute of Organic Chemistry.
‡ Fudan University.
(1) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-2384.
(2) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433-1456.
(3) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046-2067. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805-818. (c) Yang, B. H.; Buchwald, S.
L. J. Organomet. Chem. 1999, 576, 125-146.
(4) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369-7370. (b) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722-9723. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
1997, 62, 6066-6068.
(5) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583-2586.
(6) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581-584. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-
796.
(7) (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657-2640. (b) Klapars, A.; Antilla, J.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727-7729. (c) Wolter, M.; Klapars,
A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-3805.
10.1021/ol0346584 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003

and 1 equiv of L-valine were reacted with 1 equiv of
iodobenzene (Scheme 1) was undertaken and it was found
Table 2. Coupling Reaction of Aryl Halides with Benzylamine
under the Catalysis of CuI and Amino Acidsa
Scheme 1
that, in this case, not only N-phenyl valine (67% yield) but
also N-benzyl aniline (33% yield) were isolated. This result
clearly indicated that the R-amino acid had an accelerating
effect on the coupling of iodobenzene and benzylamine.
Encouraged by this result, we examined several amino
acids as the ligands using the coupling reaction of iodoben-
zene and benzylamine as a model. It is obvious that some
amino acids could couple with iodobenzene during the
reaction, thereby reducing the activity of the catalytic system.
We decided to solve this problem by choosing some less
reactive N-substituted or N,N-disubstituted amino acids as
our ligands. To compare the efficacy of each ligand, the
reaction was carried out at 40 °C and quenched after 12 h.
Table 1. Coupling Reaction of Iodobenzene with Benzylamine
under the Catalysis of CuI and Amino Acidsa
a Reaction conditions: CuI (0.5 mmol), amino acid (1 mmol), aryl iodide
(5 mmol), benzylamine (7.5 mmol), DMSO (3 mL). b A: N-methylglycine.
B: L-proline. c Isolated yield. d N-(4-Methylphenyl)-N-methylglycine was
isolated in about 5% yield.
The conversion for each reaction was examined through its
isolated yield of the corresponding arylamine. As shown in
Table 1, it was found that all amino acids we chose could
prompt the coupling reaction at this condition. The R-amino
acids gave better conversion in comparison with the â-amino
acids (compare entries 1 and 5, as well as entries 2 and 6),
while the N-substituted amino acids were superior to the
N,N-disubstituted amino acids (compare entries 1 and 2, as
well as entries 5 and 6). Using N-methylglycine as the ligand,
we found that the best ratio between CuI and the ligand was
1:2 (compare entries 1 and 11, as well as entries 9 and 10).
In the case of using 10 mmol % CuI and 20 mol %
N-methylglycine, the reaction was near completion and gave
N-benzyl aniline in excellent yield (entry 11). Although
a Reaction conditions: CuI (0.5 mmol), amino acid (0.5 mmol),
iodobenzene (5 mmol), benzylamine (5 mmol), DMSO (3 mL), 40 °C, 12
h. b Isolated yield. c CuI (0.25 mmol), amino acid (0.25 mmol). d CuI (0.25
mmol), amino acid (0.5 mmol). e CuI (0.5 mmol), amino acid (1 mmol).
f Less than 3% N-phenyl-N-methylglycine was observed. g Less than 5%
N-phenyl-N-methylglycine was observed.
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Org. Lett., Vol. 5, No. 14, 2003

many cases described later because it was found to be less
reactive toward coupling with aryl halides than N-methyl-
glycine.
Table 3. Coupling Reaction of Aryl Halides with Amines
under the Catalysis of CuI and L-Prolinea
For aryl iodides bearing an electron-withdrawing group,
N-methylglycine was also a good ligand that led to complete
the reaction even at 40 °C (Table 2, entries 1-3). However,
for aryl iodides carrying an electron-donating group, the
conversion was not satisfactory even at 60 °C using N-
methylglycine (entries 4-6). We reasoned that this problem
might result from the coupling of N-methylglycine with aryl
iodides that consumed the ligand (entry 4). Indeed, when
proline (less reactive) was used as the ligand, good yields
were observed for both electron-rich and electron-deficient
aryl iodides at 60 °C (entries 7-11). Similarly, aryl bromide
gave only moderate yields under the action of CuI and
N-methylglycine at 40 °C (entry 12), while good yields were
obtained by switching the ligand to proline and carrying out
the reaction at higher temperature (entries 13-15).
Using L-proline as the ligand, we tested the coupling
reaction using a number of aryl iodides and amines. The
results are summarized in Table 3. It was found that all
primary amines worked well, affording the corresponding
coupling product in good yields (entries 1-4, 9, 10, and 12),
while secondary amines gave slightly lower yields (entries
5 and 6). Furthermore, the present catalytic system also
worked well for the coupling of arylamines with aryl iodides
even at 90 °C, leading to diarylamines (entries 7, 8, and 11).
In conclusion, we have discovered a new catalytic system
to make Ullmann-type aryl amination work at the lowest
temperature reported to date. The key was using a suitable
amino acid as the ligand. Although in some cases the
complete conversion was restricted by coupling of the ligands
with aryl halides, the lower reaction temperature used here
and the convenient availability of the ligands are still
attractive for arylamine preparation in many cases.8
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grant 20132030), and the Qiu Shi Science &
Technologies Foundation for their financial support.
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0346584
a Reaction conditions: CuI (0.5 mmol), L-proline(1 mmol), aryl iodide
(5 mmol), amine (7.5 mmol), DMSO (3 mL). Amine: 1a for entries 1-8,
1b for entries 9-11, and 1c for entry 12. b Isolated yield.
(8) For other recent efforts on the development of more efficient catalytic
systems for Ullmann-type aryl amination, see: (a) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315-4317. (b) Gujadhur, R.
K.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791-
4793. (c) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674.
(d) Kang, S.-K.; Kim, D.-H.; Park, J.-N. Synlett 2002, 427-430. (e) Kelkar,
A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron Lett. 2002, 43, 7143-
7146.
L-proline appeared to be less effective than N-methylglycine
(compare entries 1 and 8), we selected it as the ligand in
Org. Lett., Vol. 5, No. 14, 2003
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