Amino acid promoted CuI-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles

Article abstract of DOI:10.1021/jo0504464

CuI-catalyzed coupling reaction of electron-deficient aryl iodides with aliphatic primary amines occurs at 40 °C under the promotion of N-methylglycine. Using L-proline as the promoter, coupling reaction of aryl iodides or aryl bromides with aliphatic primary amines, aliphatic cyclic secondary amines, or electron-rich primary arylamines proceeds at 60-90 °C; an intramolecular coupling reaction between aryl chloride and primary amine moieties gives indoline at 70 °C; coupling reaction of aryl iodides with indole, pyrrole, carbazole, imidazole, or pyrazole can be carried out at 75-90 °C; and coupling reaction of electron-deficient aryl bromides with imidazole or pyrazole occurs at 60-90 °C to provide the corresponding N-aryl products in good to excellent yields. In addition, N,N-dimethylglycine promotes the coupling reaction of electron-rich aryl bromides with imidazole or pyrazole to afford the corresponding N-aryl imidazoles or pyrazoles at 110 °C. The possible action of amino acids in these coupling reactions is discussed.

Full text of DOI:10.1021/jo0504464

Amino Acid Promoted CuI-Catalyzed C-N Bond Formation
between Aryl Halides and Amines or N-Containing Heterocycles
Hui Zhang,† Qian Cai,‡ and Dawei Ma*,‡
Department of Chemistry, Fudan University, Shanghai 200433, China, and State Key Laboratory of
Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
Received March 8, 2005
CuI-catalyzed coupling reaction of electron-deficient aryl iodides with aliphatic primary amines
occurs at 40 °C under the promotion of N-methylglycine. Using L-proline as the promoter, coupling
reaction of aryl iodides or aryl bromides with aliphatic primary amines, aliphatic cyclic secondary
amines, or electron-rich primary arylamines proceeds at 60-90 °C; an intramolecular coupling
reaction between aryl chloride and primary amine moieties gives indoline at 70 °C; coupling reaction
of aryl iodides with indole, pyrrole, carbazole, imidazole, or pyrazole can be carried out at 75-90
°C; and coupling reaction of electron-deficient aryl bromides with imidazole or pyrazole occurs at
60-90 °C to provide the corresponding N-aryl products in good to excellent yields. In addition,
N,N-dimethylglycine promotes the coupling reaction of electron-rich aryl bromides with imidazole
or pyrazole to afford the corresponding N-aryl imidazoles or pyrazoles at 110 °C. The possible action
of amino acids in these coupling reactions is discussed.
Introduction
could not be tolerated, and therefore their usage was
greatly limited.4 In addition, these reactions often require
the use of stoichiometric amounts of copper reagents,
which, on scale, leads to problems of waste disposal.4 To
overcome these drawbacks, several Pd-catalyzed C-N
formation methods have been discovered, which, upon
using some sterically hindered phosphine ligands, al-
lowed many coupling reactions of aryl halides with
N-containing compounds to proceed under relatively mild
conditions and low temperature.5 However, industrial use
of these methods is problematic in many cases due to the
air and moisture sensitivity, as well as the higher costs
of Pd catalysts and the relative ligands.
N-Arylamines, N-arylpyrroles, N-arylindoles, N-aryl-
imidazoles, and N-arylpyrazoles are prevalent in com-
pounds that are of biological, pharmaceutical, and ma-
terials interest.1-3 Copper-catalyzed Ullmann-type reac-
tions are traditional methods to assemble these com-
pounds.4 For a long time, these reactions had been carried
out at high temperatures and many functional groups
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Belfield, A.; Brown, G. R.; Foubister, A. J. Tetrahedron 1999,
55, 11399. (b) Hong, Y.; Senanayake, C. H.; Xiang, T.; Vandenbossche,
C. P.; Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998,
39, 3121. (c) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670.
(d) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
During the past years, we have witnessed great
progress on the modification of Ullmann-type coupling
reactions,6 which highly relied on the utilization of some
special bidentate additives such as aliphatic diamines,7
(2) (a) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton,
C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (b) Kundu, N. G.;
Mahanty, J. S.; Chowdhurry, C.; Dasgupta, S. K.; Das, B.; Spears, C.
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S.; Verheyde, B.; Hameurlaine, A.; Dehaen, W. J. Am. Chem. Soc. 2003,
125, 5356. (b) Paredes, E.; Kneeteman, M.; Gonzalez-Sierra, M.;
Mancini, P. M. E. Tetrahedron Lett. 2003, 44, 2943. (c) Jian H.; Tour,
J. M. J. Org. Chem. 2003, 68, 5091. (d) Finn, J.; Mattia, K.; Morytko,
M.; Ram, S.; Yang, Y.; Wu, X.; Mak, E.; Gallant, P.; Keith, D. Bioorg.
Med. Chem. Lett. 2003, 13, 2231. (e) Wang, X.; Tan, J.; Zhang, L. Org.
Lett. 2000, 2, 3107. (f) Smith, W. J.; Sawyer, J. S. Tetrahedron Lett.
1996, 37, 299 and references therein.
(4) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. For
reviews, see: (b) Lindley, J. Tetrahedron 1984, 40, 1433. (c) Hassan,
J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359.
(5) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J.
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10.1021/jo0504464 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/14/2005
5164
J. Org. Chem. 2005, 70, 5164-5173

CuI-Catalyzed C-N Bond Formation
ethylene glycol,8a diethylsalicylamide,8b 1,10-phenanthro-
line and its derivatives,9 oxime-type and Schiff base
ligands,10 thiophene-2-carboxylate,11 and amino acids.12
In a preliminary communication, we have reported that
N-methylglycine and L-proline were ideal promoters in
the CuI-catalyzed coupling reaction of aryl halides with
amines.12c Further exploration revealed this catalytic
system was applicable for coupling of aryl halides with
N-containing heterocycles.12e The majority of aryl halides
investigated were aryl iodides, and only a few examples
concerned aryl bromides. Because aryl bromides are
cheaper and more readily available than aryl iodides, we
further explored the scope of these coupling reactions
using aryl bromides. Herein, we wish to describe the
details.
limited to the coupling reaction below 60 °C. Thus,
L-proline, a less reactive promoter toward coupling with
aryl iodides, was studied. To our delight, CuI-catalyzed
reaction of 4-methylphenyl iodide with benzylamine at
60 °C gave 85% yield (entry 8). We next extended the
reaction conditions to the coupling of other iodides and
amines and found that, in all cases, satisfactory yields
were obtained (entries 8-10).
For less reactive aryl bromides, higher reaction tem-
peratures were required to ensure complete conversion
in comparison with the iodides. Thus, L-proline was
chosen as the promoter. We were pleased to find that
under its action, various aryl bromides efficiently coupled
with aliphatic primary amines (entries 13-22). Gener-
ally, the reaction proceeded at 80 °C to give the coupling
products in good to excellent yields (entries 13-18).
Sterically hindered bromides needed slightly high reac-
tion temperature (90 °C), although the yields were still
high (entries 20-22).
From Table 1, we noticed that a wide range of
functional groups were compatible with these reaction
conditions, which include nitro, carboxylate, ketone,
nitrile, aromatic amine, hydroxy, and olefin groups. This
advantage would allow this method to assemble anilines
with great structural diversity. In case of 4-bromobenz-
aldehyde, the coupling with benzylamine gave a complex
mixture, while coupling with 2-hydroxyethylamine pro-
vided the desired aniline 1m in 91% yield (entry 17). In
the latter case, the aldehyde moiety of 4-bromobenz-
aldehyde might form an oxazolidine with 2-hydroxy-
ethylamine in situ, which served as a protecting group
for aldehyde and was hydrolyzed during workup to afford
1m.
Coupling Reaction of Aryl Halides with Aliphatic
Secondary Amines. The steric hindrance of secondary
amines makes them more sluggish than primary amines
to couple with aryl halides. We were pleased to observe
that L-proline also served as a good promoter for the
Ullmann-type coupling. As summarized in Table 2, the
coupling reaction between iodobenzene with morpholine
or piperidine occurred at 90 °C (entries 1 and 2). When
the less bulky pyrrolidine, a secondary amine, was used,
the coupling with aryl iodides proceeded at 65 °C (entries
3 and 4). We next moved our attention to aryl bromides
and found that both electron-rich and electron-deficient
aryl bromides were coupled with pyrrolidine at 90 °C
using 10 mol % CuI and 20 mol % L-proline as a catalytic
system (entries 5-8). Noteworthy, this procedure worked
well for sterically hindered bromides as evidenced from
the coupling reaction of pyrrolidines with 2,4-dimethoxy-
1-bromobenzene, which gave aniline 2i in 86% yield
(entry 9). In addition, a good yield was also observed for
reaction of piperidine and 4-bromobenzonitrile (entry 10).
Although satisfactory results were obtained in cases
of cyclic secondary amines, poor coupling yields were
obtained for acyclic secondary amines (entries 11-13).
For dibenzylamine, increasing the reaction temperature
to 110 °C and using N,N-dimethylglycine still gave poor
conversion (entry 13). These results demonstrated that
the steric hindrance of secondary amines inhibited the
coupling reaction.
Results and Discussion
Coupling Reaction of Aryl Halides with Aliphatic
Primary Amines. Initially, we explored the scope for
CuI/amino acid-catalyzed reaction of aryl halides with
primary amines, and the results are summarized in Table
1. Because N-methylglycine was found as the most
powerful promoter for aryl amination reaction at 40 °C,12c
it was initially employed. Indeed, under its action, CuI-
catalyzed coupling reaction worked at 40 °C for all iodides
and a bromide tested (entries 1-4, 7, and 11). However,
only the iodides with electron-withdrawing groups pro-
vided the corresponding coupling products in good yields
(entries 1-3), while incomplete conversion was seen
when iodides bearing electron-donating groups were used
(entries 4 and 7). For 4-methylphenyl iodide, increasing
the reaction temperature to 60 °C gave the similar result
(compare entries 4 and 5). Because N-(4-methylphenyl)-
N-methylglycine was isolated in about 5% yield in this
case, we reasoned that the incomplete conversion might
result from the coupling of N-methylglycine with methyl-
phenyl iodide that consumed the promoter. This result
also indicated that, as a promoter, N-methylglycine was
(6) For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 15, 2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
Rev. 2004, 248, 2337. For other related studies, see: (d) Okano, K.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987. (e) Han, C.;
Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27. (f) Buck, E.;
Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J.
Org. Lett. 2002, 4, 1623.
(7) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (c) Antilla, J. C.; Baskin, J.
M.; Barder, T. E.; Bchwald, S. L. J. Org. Chem. 2004, 69, 5578.
(8) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
4, 581. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
(9) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett.
2001, 3, 4315. (b) van Allen, D.; Venkataraman, D. J. Org. Chem. 2003,
68, 4590.
(10) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Eur. J. Org. Chem. 2004, 695. (b) Cristau, H.-J.; Cellier, P. P.; Spindler,
J.-F.; Taillefer, M. Chem.-Eur. J. 2004, 10, 5607.
(11) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312.
(12) (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. (c)
Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (d) Ma, D.; Cai, Q.
Org. Lett. 2003, 5, 3799. (e) Ma, D.; Cai, Q. Synlett 2004, 1, 128. (f)
Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (g) Zhu, W.; Ma, D.
Chem. Commun. 2004, 888. (h) Ma, D.; Liu, F. Chem. Commun. 2004,
1934. (i) Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005,
496. For related work, see: (j) Deng, W.; Wang, Y.; Zou, W.; Liu, L.;
Guo, Q. Tetrahedron Lett. 2004, 45, 2311. (k) Deng, W.; Zou, Y.; Wang,
Y. F.; Liu, F.; Guo, Q. X. Synlett 2004, 1254.
Coupling of Bromopyridines or 1,3-Dibenzyl-5-
iodouracil with Amines. Because heteroaromatic ring
systems exist in numerous natural products and biologi-
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Zhang et al.
TABLE 1. CuI/Amino Acid-Catalyzed Coupling Reaction of Aryl Halides with Aliphatic Primary Aminesa
a Reaction conditions: CuI (0.5 mmol), amino acid (1 mmol), aryl halide (5 mmol), amine (7.5 mmol), K2CO3 (10 mmol, for aryl iodide)
or K3PO4 (10 mmol, for aryl bromide), 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. e 15 mmol of amines was utilized to avoid the low yields due to their evaporation at elevated
reaction temperatures.
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CuI-Catalyzed C-N Bond Formation
TABLE 2. CuI/Amino Acid-Catalyzed Coupling Reaction of Aryl Halides with Aliphatic Secondary Aminesa
a Reaction conditions: CuI (0.5 mmol), amino acid (1 mmol), aryl halide (5 mmol), amine (7.5 mmol), K2CO3 (10 mmol), DMSO (3 mL).
b B, L-proline; C, N,N-dimethylglycine. c Isolated yield. d 15 mmol of amines was added to avoid the low yields due to their evaporation
at elevated reaction temperatures.
cally active substances, cross-coupling reactions between
heteroaryl halides or their derivatives with amines have
recently received considerable attention.13 Consequently,
some heterocycle-embodied aryl or vinyl halides were
tested in our catalytic system. As indicated in Table 3,
coupling of 3-bromopyridine with several amines worked
well, providing the corresponding amination products in
excellent yields (entries 1-3). For 2,5-dibromopyridine,
amination occurred at the 2-position exclusively to deliver
4 as a single product in 81% yield (entry 4). This
regioselectivity was consistent with that observed previ-
ously in Pd-catalyzed aryl amination.13a In case of 1,3-
dibenzyl-5-iodouracil 5, coupling with morphline and
2-aminopyrimidine under our standard conditions pro-
duced 6 and 7 in 59% and 77% yields, respectively. These
results were comparable with those obtained with the
(CuOTf)2‚PhH/1,10-phenanthroline catalytic system.13b
Coupling Reaction of Aryl Halides with Anilines.
Although several mild conditions for CuI-catalyzed cou-
pling of aryl halides and aliphatic amines have been
reported in the literature, little attention has been
directed toward the further usages of these conditions
for forming diarylamines.8-12 Prior to our report,12c only
two examples were described by Venkataraman and co-
workers in which soluble copper(I) catalysts, Cu(PPh3)3Br14
and Cu(neocup)(PPh3)Br,9a were employed for elaborating
diaryl or triarylamines. We found that the combination
of CuI and L-proline could catalyze the coupling reaction
of iodobenzene with aniline at 90 °C to provide diphenyl-
amine in 66% yield (Table 4, entry 1). p-Anisidine gave
increased coupling yield (compare entries 1 and 2).
Further attempts indicated that good yields were ob-
(13) (a) Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611. (b)
Arterburn, J. B.; Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001,
42, 1425. (c) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M.
Org. Lett. 2002, 4, 3481. (d) Jonckers, T. H. M.; Maes, B. U. W.;
Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027.
(14) Gujadhur, R. K.; Venkataraman, D.; Kintigh, J. T. Tetrahedron
Lett. 2001, 42, 4791.
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Zhang et al.
TABLE 3. CuI/L-Proline-Catalyzed Coupling Reaction of Bromopyridines or 1,3-Dibenzyl-5-iodouracil with Aminesa
a Reaction conditions: CuI (0.5 mmol), L-proline (1 mmol), aryl halide (5 mmol), amine (7.5 mmol), K2CO3 (10 mmol), DMSO (3 mL).
b Isolated yield. c 15 mmol of amines was added to avoid the low yields due to their evaporation at elevated reaction temperatures.
tained when this amine was reacted with several aryl
bromides bearing either electron-donating or electron-
withdrawing groups (entries 4-7). However, poor conver-
sion was observed when bromobenzene was coupled with
aniline (entry 8), while trace coupling product was
isolated in case of methyl 4-aminobenzoate (entry 9).
These results demonstrated that the nucleophilicity of
arylamines was key in the present coupling reaction. The
poor conversion for nucleophilically weak arylamines
might result from that they could not compete with
L-proline in coupling with aryl halides, thereby decreas-
ing the reactivity of this catalytic system.
Coupling Reaction of Aryl Chlorides with Amines.
Reaction of chlorobenzene with benzylamine using the
catalysis CuI/L-proline gave trace coupling product
(Scheme 1). However, an intramolecular coupling reac-
tion between aryl chloride and amine moieties worked
at 70 °C to deliver indoline 10 in 70% yield.
Coupling Reaction of Aryl Halides with Imid-
azole, Benzoimidazole, or Pyrazole. As summarized
in Table 5, coupling reaction of 4-methoxyphenyl iodide
with imidazole or pyrazole catalyzed by CuI/L-proline
proceeded well at 90 °C to deliver the desired N-aryl
products 11a or 12a in excellent yields (entries 1 and 2).
In case an electron-deficient aryl iodide, this reaction
proceeded at lower temperature (entry 3). Further ex-
ploration revealed that electron-deficient aryl bromides
were compatible with these reaction conditions, giving
satisfactory conversion at 60-95 °C (entries 4-7, 12, and
13). However, for electron-rich aryl bromides, low conver-
sion was observed under the above standard conditions
(entry 8). After some experimentation, we found that this
problem could be solved by raising the reaction temper-
ature to 110 °C (entries 9, 10, and 14). At this time, N,N-
dimethylglycine was used as the additive to avoid the
severe self-coupling of L-proline with aryl bromides. The
new conditions also worked for sterically hindered sub-
strates as evidenced from the reaction of 2,4-dimeth-
oxyphenyl bromide with imidazole (entry 11). Further-
more, it was observed that the reaction of electron-
deficient aryl bromides with benzoimidazole produced
N-aryl benzoimidazoles in good yields (entries 15 and 16).
Coupling Reaction of Aryl Halides with Indoles,
Pyrrole, or Carbazole. Using 10 mol % CuI and 20 mol
% L-proline, the coupling reaction of indole with iodo-
benzene proceeded at 90 °C for 40 h to give N-phenyl-
indole 11a in 85% yield (Table 6, entry 1). For electron-
deficient aryl iodides, reaction temperature could be
lowered to 75-80 °C (entries 2-4). Sterically hindered
aryl iodides were compatible with these conditions as
evidenced from the reaction of 2-methoxyphenyl iodide
with indole to provide 14e in 79% yield (entry 5).
Furthermore, entries 6 and 7 illustrated that bulky indole
and carbazole also worked in this reaction. However,
when bromobenzene was used, low conversion was ob-
served. Although the coupling reaction of 4-methoxy-
phenyl iodide with pyrrole proceeded well, the corre-
sponding bromide gave poor conversion (compare entries
9 and 10). In this case, raising the reaction temperature
to 110 °C and employing N,N-dimethylglycine as the
additive only gave moderate conversion (entry 11). In-
deed, when 4-bromophenyl iodide was utilized, regio-
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CuI-Catalyzed C-N Bond Formation
TABLE 4. CuI/L-Proline-Catalyzed Coupling Reaction of Aryl Halides with Aryl Aminesa
a Reaction conditions: aryl halide (3 mmol), alkyl amine (2 mmol), K2CO3 (4 mmol), CuI (0.2 mmol), and L-proline (0.4 mmol) in 3 mL
of DMSO. b Isolated yield.
SCHEME 1
can form chelates with amino acids through the carboxyl
and amino groups,17 we put forward two possible catalytic
cycles for our reactions as depicted in Schemes 2 and 3.
In Scheme 2, the chelation of Cu(I) with an amino acid
makes Cu(I) species more reactive toward the oxidative
addition, or/and stabilize the oxidative addition inter-
mediates B, thereby promoting the coupling reaction.
Noteworthy, a similar four coordinated Cu(III) interme-
diate has been proposed by Liebeskind and co-workers
in their CuTC-catalyzed reactions.11 In Scheme 3, che-
lated Cu(I) might make the aromatic ring of the π-com-
plex D16 more electron-deficient, thereby facilitating the
nucleophilic attack of amines or nitrogen anions gener-
ated from N-containing heterocycles. The mechanism
outlined in Scheme 2 could be used to explain most of
the phenomena observed, for example, the order I > Br
> Cl for ease of halogen displacement from the aromatic
ring; and slightly better reactivity displayed by electron-
deficient aryl halides, while the mechanism showed in
Scheme 3 could be used to fully rationalize the substitu-
ent effect of aryl halides but had difficulty explaining the
reactivity order ArI > ArBr > ArCl. More detailed
selective product 15b was isolated in 80% yield (entry
12). These results indicated that the coupling reaction
of aryl bromides with indoles and pyrroles was unsuc-
cessful under our standard conditions. The low reactivity
displayed by pyrrole and indole in comparison with
imidazole and pyrazole for Ullmann-type coupling has
been noticed by Cristau and co-workers.10b
Plausible Mechanism. To date, three mechanisms for
Ullmann-type coupling reactions have been described in
the literatures:4b,6b,c (1) oxidative addition/reductive elimi-
nation mechanism proposed by Cohen in 1974;15 (2)
π-complex mechanism proposed by Paine in 1987;16 and
(3) radical or radical anion pathway.4b,18 On the basis of
the former two mechanisms and the fact that copper ions
(17) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids;
Wiley: New York, 1961; Vol. 3.
(18) Aalten, H. L.; Van Koten, G.; Grove, D. M.; Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45,
5565.
(15) Cohen, T.; Wood, J.; Dietz, A. G., Jr. Tetrahedron Lett. 1974,
15, 3555.
(16) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.
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Zhang et al.
TABLE 5. CuI/Amino Acid-Catalyzed Coupling Reaction of Aryl Halides with Imidazole, Benzoimidazole, or Pyrazolea
a Reaction conditions: CuI (0.2 mmol), L-proline (0.4 mmol), K2CO3 (4 mmol), aryl halide (2.2 mmol) and azole (2 mmol), DMSO (3 mL).
b B, L-proline; C, N,N-dimethylglycine. c Isolated yield.
mechanistic studies should be carried out to clarify these
issues.
methylglycine gave best results. However, when reaction
temperatures were up 60 °C, the coupling reaction of
secondary amino acids with aryl halides occurred, which
led to less reactive L-proline serving as a best additive.
In case of high temperatures (>95 °C), tertiary N,N-
dimethylglycine that is unable to proceed aryl amination
could be used as the additive.
In conclusion, we have demonstrated that some amino
acids are able to promote Ullmann-type C-N bond
formation reactions. The reactions showed excellent
functional group tolerance. Both the steric hindrance and
The above two mechanisms could also explain the
different behaves displayed by N-methylglycine, L-pro-
line, and N,N-dimethylglycine. Their capability for pro-
moting C-N formation reactions might be dependent on
their reactivity as the coupling agents and coordination
ability as bidentate additives. Based on their steric
hindrance, the order for coordination ability is N-methyl-
glycine > L-proline > N,N-dimethylglycine. Therefore,
when reaction temperatures were below 60 °C, N-
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CuI-Catalyzed C-N Bond Formation
TABLE 6. CuI/Amino Acid-Catalyzed Coupling Reaction of Aryl Halides with Indole, Pyrrole, or Carbazolea
a Reaction conditions: CuI (0.2 mmol), L-proline (0.4 mmol), and K2CO3 (4 mmol) for aryl iodide or Cs2CO3 (4 mmol) for aryl bromide,
aryl halide (2.2 mmol), and N-containing heterocycle (2 mmol), DMSO (3 mL). b Isolated yield. c N,N-Dimethylglycine was used as the
ligand.
SCHEME 2
ally displayed better reactivity than electron-rich aryl
halides. In most case, L-proline is a reliable promoter for
the following four types of reactions at relatively low
temperature: (1) coupling reaction of aryl iodides, and
aryl bromides with aliphatic primary amines, aliphatic
cyclic secondary amines, and electron-rich arylamines;
(2) intramolecular coupling reaction between aryl chloride
and primary amine moieties; (3) coupling reaction of aryl
iodides with indole, pyrrole, carbazole, imidazole, or
pyrazole; and (4) coupling reaction of electron-deficient
aryl bromides with imidazole or pyrazole. For coupling
reaction of electron-rich aryl bromides with imidazole or
pyrazole, N,N-dimethylglycine can serve as an efficient
the nucleophilicity of the amines are key in these
coupling reactions. Electron-deficient aryl halides gener-
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Zhang et al.
4-(N-Benzyl)aminoacetophenone 1k. White solid; mp
SCHEME 3
1
89-91 °C; H NMR (400 MHz, CDCl3) δ 7.82 (d, J ) 9.2 Hz,
2H), 7.30-7.38 (m, 5H), 6.60 (d, J ) 8.7 Hz, 2H), 4.61 (br s,
1H), 4.41 (d, J ) 4.6 Hz, 2H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 196.5, 152.1, 138.4, 130.9, 128.9, 127.7, 127.4, 127.0,
111.7, 47.7, 26.1; EI-MS m/z 226 (M + H)+, 225 (M+), 210, 92,
91, 77, 65, 43; ESI-HRMS for C15H16NO (M + H)+ requires
226.1226, found 226.1226.
4-[N-(2-Hydroxyethyl)]aminobenzaldehyde 1m. Pale
yellow solid; mp 46-48 °C; 1H NMR (400 MHz, CDCl3) δ 9.72
(s, 1H), 7.70 (m, 2H), 6.66 (m, 2H), 3.90 (t, J ) 5.3 Hz, 2H),
3.40 (t, J ) 5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 190.8,
153.7, 132.6, 126.3, 112.1, 60.8, 45.3; EI-MS m/z 165 (M+), 134,
105, 95, 79, 77, 51, 41; ESI-HRMS for C9H12NO2 (M + H)+
requires 166.0866, found 166.0863.
4-(N-Allyl)aminobenzonitrile 1n. Pale yellow oil; 1H
NMR (400 MHz, CDCl3) δ 7.41 (d, J ) 8.7 Hz, 2H), 6.57 (d, J
) 8.7 Hz, 2H), 5.85-5.95 (m, 1H), 5.19-5.30 (m, 2H), 4.44 (br
s, 1H), 3.80-3.84 (m, 2H); EI-MS m/z 158 (M+), 157, 131, 130,
129, 102, 41, 39.
N-Allyl Benzene-1,3-diamine 1o. Yellow oil; 1H NMR (400
MHz, CDCl3) δ 6.95 (t, J ) 7.8 Hz, 1H), 6.07 (m, 2H), 5.95 (m,
2H), 5.27 (m, 1H), 5.14 (m, 1H), 3.72 (m, 2H), 3.60 (br s, 3H);
EI-MS m/z 148 (M+), 147, 133, 121, 93, 80, 65, 39.
N-(2-Hydroxyethyl)-2,4-dimethoxyaniline 1r. Yellow oil;
1H NMR (400 MHz, CDCl3) δ 6.40-6.60 (m, 3H), 3.82-3.85
(m, 5H), 3.76 (s, 3H), 3.28 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 152.4, 148.5, 132.3, 111.1, 103.9, 99.3, 61.4, 55.8, 55.5, 46.9;
EI-MS m/z 197 (M+), 167, 166, 152, 151, 150, 136, 108; ESI-
HRMS for C10H16NO3 (M + H)+ requires 198.1132, found
198.1125.
promoter. Noteworthy is that these promoters are sig-
nificantly inexpensive and readily available. Moreover,
they can be easily removed from the crude products by
simply washing with water. Given these advantages, the
present reactions should find considerable applications
in organic synthesis.19
Experimental Section
N-(4-Acetylphenyl)pyrrolidine 2d. Pale yellow crystals;
mp 134-135 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J ) 9.2
Hz, 2H), 6.51 (d, J ) 9.2 Hz, 2H), 3.35-3.39 (m, 4H), 2.51 (s,
3H), 2.02-2.06 (m, 4H); EI-MS m/z 189 (M+), 188, 175, 174,
146, 91, 77, 43.
General Procedures. All reactions were carried out in
resealable tubes under nitrogen atmosphere. DMSO and DMF
were freshly distilled from CaH2. Commercial available CuI
must be washed with THF using a Soxhlet extractor before it
is used to ensure satisfactory catalytic activity.
1-(4-Chlorophenyl)pyrrolidine 2g. White solid; mp 84-
General Procedure for the Coupling Reaction of Aryl
Halides with Alkylamines Catalyzed by CuI and Amino
Acid. A mixture of aryl halide (5 mmol), alkylamine (7.5 mmol,
or 15 mmol for the amines with low boiling points), K2CO3 (10
mmol, for aryl iodide) or K3PO4 (10 mmol, for aryl bromide),
CuI (0.5 mmol), and the appropriate amino acid (1 mmol) in 3
mL of DMSO was heated at the indicated temperature. The
cooled mixture was partitioned between water and ethyl
acetate. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residual oil was loaded on a silica
gel column and eluted with 1/10 to 1/8 ethyl acetate/petroleum
ether to afford the corresponding aniline. The data for some
selected compounds are as follows.
1
85 °C; H NMR (400 MHz, CDCl3) δ 7.14 (d, J ) 8.7 Hz, 2H),
6.45 (d, J ) 8.7 Hz, 2H), 3.21-3.25 (m, 4H), 1.96-2.00 (m,
4H); EI-MS m/z 181 (M+), 180, 140, 127, 125, 111, 75.
4-Pyrrolidin-1-yl-benzonitrile 2h. Pale yellow solid; mp
1
88-90 °C; H NMR (400 MHz, CDCl3) δ 7.44 (d, J ) 8.7 Hz,
2H), 6.50 (d, J ) 8.7 Hz, 2H), 3.31-3.34 (m, 4H), 2.02-2.06
(m, 4H). EI-MS m/z 172 (M+), 171, 129, 116, 102, 75, 43, 41.
1
N-(2,4-Dimethoxyphenyl)pyrrolidine 2i. Yellow oil; H
NMR (400 MHz, CDCl3) δ 6.78 (d, J ) 8.2 Hz, 1H), 6.49 (d, J
) 2.7 Hz, 1H), 6.39-6.42 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H),
3.16-3.18 (m, 4H), 1.91-1.94 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 154.7, 152.3, 133.8, 116.2, 103.4, 100.1, 55.6, 55.4,
51.0, 24.3; EI-MS m/ z 207 (M+), 206, 193, 192, 164, 150, 149;
ESI-HRMS for C12H18NO2 (M + H)+ requires 208.1342, found
208.1332.
2-[(Phenylmethyl)amino]benzoic Acid 1b. White solid;
1
Benzyl-[3]pyridyl-amine 3a. Yellow solid; mp 86-88 °C;
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J ) 2.7 Hz, 1H), 7.96 (d,
J ) 4.6 Hz, 1H), 7.28-7.39 (m, 5H), 7.08-7.10 (m, 1H), 6.88-
6.90 (m, 1H), 4.34 (s, 2H); EI-MS m/z 184 (M+), 145, 91, 60,
45, 43, 42, 41.
N-Allyl-[3]pyridylamine 3b. Yellow oil; 1H NMR (400
MHz, CDCl3) δ 8.04 (d, J ) 2.7 Hz, 1H), 7.95 (d, J ) 4.1 Hz,
1H), 7.06-7.09 (m, 1H), 6.87-6.89 (m, 1H), 5.87-5.97 (m, 1H),
5.18-5.31 (m, 2H), 3.78-3.83 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 144.5, 138.8, 136.2, 134.6, 123.8, 118.9, 116.8, 46.1;
EI-MS m/z 134 (M+), 133, 107, 78, 51, 41, 39, 38; ESI-HRMS
for C8H11N2 (M + H)+ requires 135.0921, found 135.0917.
mp 174-176 °C; H NMR (400 MHz, CDCl3) δ 8.00 (m, 2H),
7.26-7.37 (m, 6H), 6.61-6.66 (m, 2H), 4.50 (s, 2H); EI-MS m/z
227 (M+), 208, 180, 132, 106, 91, 77, 65, 51, 43.
N-Benzyl-4-bromoaniline 1f. White solid; mp 52-53 °C;
1H NMR (400 MHz, CDCl3) δ 7.26-7.35 (m, 5H), 7.22 (d, J )
9.0 Hz, 2H), 6.49 (d, J ) 9.0 Hz, 2H), 4.30 (s, 2H), 4.08 (br s,
1H); EI-MS m/z 263 (M+, 81Br), 261 (M+, 79Br), 91, 77, 65, 63,
51, 41.
N-Benzyl-biphenyl-4-yl-amine 1h. White solid; mp 94-
1
95 °C; H NMR (400 MHz, CDCl3) δ 7.51 (d, J ) 8.1 Hz, 2H),
7.35-7.45 (m, 10H), 6.69 (d, J ) 8.1 Hz, 2H), 4.37 (s, 2H),
4.10 (br s, 1H); EI-MS m/z 257 (M+), 182, 168, 152, 141, 115,
91, 77, 65, 63, 51.
2-[N-(1,3-Dibenzyluracil-5-yl)]aminopyrimidine 7. White
1
solid; mp 151-152 °C; H NMR (400 MHz, CDCl3) δ 8.61 (s,
1H), 8.37 (d, J ) 4.6 Hz, 2H), 7.63 (s, 1H), 7.48-7.50 (m, 2H),
7.26-7.39 (m, 7H), 6.68-6.71 (m, 1H), 5.23 (s, 2H), 5.01 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 160.0, 159.4, 157.9, 149.8,
136.7, 135.9, 129.1, 128.6, 128.3, 128.1, 127.8, 126.0, 116.0,
112.7, 53.0, 45.3; EI-MS m/z 385 (M+), 384, 292, 158, 106, 91,
(19) For emerging applications of the present N-aromation meth-
odology, see: (a) Fletcher, S. P.; Clive, D. L. J.; Peng, J.; Wingert, D.
A. Org. Lett. 2005, 7, 23. (b) Jean, L.; Rouden, J.; Maddalauno, J.;
Lasne, M.-C. J. Org. Chem. 2004, 69, 8893. (c) Cuny, G.; Bois-Choussy,
M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475.
5172 J. Org. Chem., Vol. 70, No. 13, 2005

CuI-Catalyzed C-N Bond Formation
65; HRMS (ESI) for C22H20N5O2 (M + H)+ requires 386.1612,
found 386.1612.
1-(4-Biphenyl)-1H-imidazole 11f. White solid; mp 150-
1
152 °C; H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.68-7.71
(m, 2H), 7.60-7.62 (m, 2H), 7.46-7.49 (m, 5H), 7.35-7.41 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 140.5, 139.8, 136.6, 130.7,
129.1, 128.8, 128.6, 127.9, 127.1, 121.7, 118.2; EI-MS m/z 220
(M+), 193, 180, 166, 165, 152, 151; ESI-HRMS for C15H13N2
(M + H)+ requires 221.1082, found 221.1073.
General Procedure for the Coupling Reaction of Aryl
Halides with Anilines Catalyzed by CuI and L-Proline.
A mixture of aryl halide (3 mmol), aniline (2 mmol), K2CO3 (4
mmol), CuI (0.2 mmol), and L-proline (0.4 mmol) in 3 mL of
DMSO was heated at 90 °C for 27-40 h. The cooled mixture
was partitioned between water and ethyl acetate. The organic
layer was separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
residual oil was loaded on a silica gel column and eluted with
1/10 to 1/8 ethyl acetate/petroleum ether to afford the corre-
sponding aniline. The data for some selected compounds are
as follows.
N,N-Diphenylamine 8a. Yellow solid; mp 51-52 °C; 1H
NMR (400 MHz, CDCl3) δ 5.70 (br, 1H), 6.90-6.95 (m, 2H),
7.04-7.08 (m, 4H), 7.23-7.29 (m, 4H); EI-MS m/z 169 (M+),
77, 65, 51, 41.
N-Phenyl-p-anisidine 8b. Pale yellow solid; mp 102-103
°C; 1H NMR (400 MHz, CDCl3) δ 7.19-7.21 (m, 2H), 7.05-
7.09 (m, 2H), 6.77-6.91 (m, 5H), 5.49 (br s, 1H), 3.80 (s, 3H);
EI-MS m/z 199 (M+), 185, 184, 129, 128, 154, 77.
1-(2,4-Dimethoxyphenyl)-1H-imidazole 11g. Pale yellow
1
oil; H NMR (400 MHz, CDCl3) δ 7.61 (br s, 1H), 7.06 (d, J )
8.2 Hz, 3H), 6.48 (d, J ) 2.3 Hz, 1H), 6.41-6.43 (m, 1H), 3.73
(s, 3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 153.9,
126.5, 120.0, 104.5, 99.8, 55.8, 55.7; EI-MS m/z 204 (M+), 205,
177, 176, 164, 162, 149, 134; ESI-HRMS for C11H13N2O2 (M +
H)+ requires 205.0979, found 205.0972.
4-Benzoimidazol-1-yl-benzonitrile 13a. White solid; mp
1
132-133 °C; H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.90
(d, J ) 8.7 Hz, 3H), 7.69 (d, J ) 8.7 Hz, 2H), 7.57-7.60 (m,
1H), 7.38-7.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 144.5,
141.7, 140.2, 134.3, 132.9, 124.6, 124.0, 123.7, 121.2, 118.0,
111.6, 110.3; EI-MS m/z 219 (M+), 191, 164, 102, 91, 75; ESI-
HRMS for C14H10N3 (M + H)+ requires 220.0879, found
220.0869.
1-(4-Benzoimidazol-1-yl-phenyl)ethanone 13b. Pale yel-
1
low crystals; mp 136-138 °C; H NMR (400 MHz, CDCl3) δ
N-(4-Methylphenyl)-N-phenylamine 8g. White solid; mp
8.16-8.22 (m, 3H), 7.89-7.91 (m, 1H), 7.60-7.66 (m, 3H),
7.37-7.39 (m, 2H), 2.68 (s, 3H); EI-MS m/z 236 (M+), 222, 221,
193, 192, 166, 43.
1
86-87 °C; H NMR (400 MHz, CDCl3) δ 7.22-7.25 (m, 2H),
7.07-7.09 (m, 2H), 6.99-7.02 (m, 4H), 6.86-6.89 (m, 1H), 5.60
(br s, 1H), 2.30 (s, 3H); EI-MS m/z 183 (M+), 168, 167, 91, 77.
General Procedure for Coupling Reaction of Aryl
Halides with Indole, Pyrrole, or Carbazole Catalyzed by
CuI and Amino Acid. A resealable tube was charged with
CuI (0.2 mmol), L-proline or N,N-dimethylglycine (0.4 mmol),
and K2CO3 (4 mmol) for aryl iodide or Cs2CO3 (4 mmol) for
aryl bromide, aryl halide (2.2 mmol), and N-containing het-
erocycle (2 mmol), evacuated, and backfilled with nitrogen. To
this mixture was added 3 mL of DMSO by syringe at room
temperature under nitrogen. The mixture was heated at
indicated temperature before it was partitioned between water
and ethyl acetate. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residual oil was loaded on a silica
gel column and eluted with 1/10 to 1/8 ethyl acetate/petroleum
ether to afford the corresponding coupling product. The data
for some selected compounds are as follows.
1-(4-Methoxyphenyl)-2-methylindole 14f. Gray solid; mp
69-70 °C; 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 1H), 7.25
(m, 2H), 7.07 (m, 1H), 7.05 (m, 3H), 7.01 (m, 1H), 6.38 (s, 1H),
3.89 (s, 3H), 2.99 (s, 3H); EI-MS m/z 237 (M+), 222, 204, 194,
178, 167, 152, 129, 119, 102, 89, 77, 63, 51, 41.
9-(4-Methoxyphenyl)carbazole 14g. White solid; mp
155-156 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J ) 7.2
Hz, 2H), 7.45 (d, J ) 9.0 Hz, 2H), 7.35-7.41 (m, 4H), 7.26 (d,
J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz, 2H), 3.92 (s, 3H); EI-MS
m/z 273 (M+), 258, 241, 228, 202, 177, 137, 121, 114, 102, 88,
75, 69, 63, 57, 51.
N-(4-Methoxycarbonylphenyl)-N-(4-methylphenyl)-
1
amine 8h. Pale yellow solid; mp 106-108 °C; H NMR (400
MHz, CDCl3) δ 7.86 (d, J ) 8.7 Hz, 2H), 7.12 (d, J ) 8.2 Hz,
2H), 7.05 (d, J ) 8.2 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 5.93
(br s, 1H), 3.84 (s, 3H), 2.31 (s, 3H); EI-MS m/z 241 (M+), 210,
181, 180, 167.
Indoline 10. A resealable tube was charged with CuI (0.2
mmol), L-proline (0.4 mmol), and K2CO3 (4 mmol), evacuated,
and backfilled with nitrogen (two cycles). To this mixture were
added 2 mL of DMSO and 2-(2-chlorophenyl)ethylamine (2
mmol) by syringe at room temperature under nitrogen. The
sealed tube was put into an oil bath that was preheated to 70
°C, and the reaction mixture was stirred at the same temper-
ature for 45 h. The cooled mixture was partitioned between
water and ethyl acetate. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residual oil was loaded
on a silica gel column and eluted with 1/10 to 1/8 ethyl acetate/
petroleum ether to afford 170 mg (71%) of 10 as pale yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J ) 7.3 Hz, 1H),
7.00-7.04 (m, 1H), 6.69-6.73 (m, 1H), 6.64 (d, J ) 7.8 Hz,
1H), 3.53 (t, J ) 8.2 Hz, 2H), 3.02 (t, J ) 8.2 Hz, 2H); EI-MS
m/z 119 (M+), 91, 89, 65, 63, 39.
General Procedure for Coupling Reaction of Aryl
Halides with Pyrazole, Imidazole, or Benzimidazole
Catalyzed by CuI and Amino Acid. A resealable tube was
charged with CuI (0.2 mmol), L-proline or N,N-dimethylglycine
(0.4 mmol), K2CO3 (4 mmol), aryl halide (2.2 mmol), and azole
(2 mmol), evacuated, and backfilled with nitrogen. To this
mixture was added 3 mL of DMSO by syringe at room
temperature under nitrogen. The mixture was heated at
indicated temperature before it was partitioned between water
and ethyl acetate. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residual oil was loaded on a silica
gel column and eluted with 1/10 to 1/ 8 ethyl acetate/petroleum
ether to afford the corresponding coupling product. The data
for some selected compounds are as follows.
1-(4-Bromophenyl)pyrrole 15b. Yellow solid; mp 95-96
°C; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J ) 8.1 Hz, 2H),
7.26 (d, J ) 8.1 Hz, 2H), 7.05 (m, 2H), 6.35 (m, 2H); EI-MS
m/z 223 (M+, 81Br), 221 (M+, 79Br), 142, 115, 89, 76, 63, 50, 41.
Acknowledgment. We are grateful to the Chinese
Academy of Sciences, National Natural Science Founda-
tion of China (grants 20321202 and 20132030), and
Science and Technology Commission of Shanghai Mu-
nicipality (grants 02JC14032 and 03XD14001) for their
financial support.
JO0504464
J. Org. Chem, Vol. 70, No. 13, 2005 5173