Pyrrole-2-carboxylic acid as a ligand for the Cu-catalyzed reactions of primary anilines with aryl halides

Article abstract of DOI:10.1021/jo8008676

(Chemical Equation Presented) Pyrrole 2-carboxylic acid (L5) was found to be an effective ligand for the Cu-catalyzed monoarylation of anilines with aryl iodides and bromides. Under the reported conditions (10% CuI/20% L5/DMSO/K ₃PO₄

Full text of DOI:10.1021/jo8008676

In recent years, Cu-catalyzed C-N bond-forming reactions
have evolved as reliable alternatives to Pd-catalyzed reactions.2
However, Cu-based catalyst systems for the synthesis of diaryl
amines are less general and useful than the Pd-based protocols.4
The Cu-catalyzed reactions of anilines with aryl halides are slow
enough that a wide variety of N-H and O-H nucleophiles,
including amides, nitrogen heterocycles, aliphatic, benzylic and
allylic amines, as well as aliphatic and benzylic alcohols are
selectively arylated in the presence of an anilino-NH2 group.5
In the absence of a competing reactant, the poor nucleophilicity
of the aniline, when employing Cu-based catalysts, further
manifests itself in the need to use high catalyst loadings (>20%
Cu),4a,f long reaction times (>30 h),4b,c,e strong bases that
preclude the presence of many common functional groups,4g
and/or anilines with strong electron-withdrawing groups in the
para-position.4b Further, the few examples of Cu-catalyzed
reactions of anilines with ortho-substituted aryl halides require
even higher catalyst loadings (35-50% Cu).4f Finally, when
employing Cu-based catalysts, the propensity of the diaryl amine
product to undergo further N-arylation to form a triarylamine
provides an added level of complexity to developing a suitable
catalyst system.6
Pyrrole-2-carboxylic Acid as a Ligand for the
Cu-Catalyzed Reactions of Primary Anilines with
Aryl Halides
Ryan A. Altman, Kevin W. Anderson, and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed April 21, 2008
We began our investigation into the Cu-catalyzed reactions
of aromatic amines with aryl iodides by evaluating previously
reported catalysts for this transformation.4 Since the more
successful systems employed proline-type ligands,4b–e we sought
to evaluate the use of new ligands that would provide a more
active and generally applicable catalyst for the reaction of aniline
with an aryl iodide (Table 1). While several heterocyclic-2-
carboxylic acids, including some previously reported as ligands
for Cu-catalyzed and -mediated nucleophilic substitution reac-
tions of aryl halides,7 provided poor results for this transforma-
tion (entries 1-4), pyrrole-2-carboxylic acid, L5 (Figure 1),
manifested good catalytic activity (entry 5). Both the N-H and
carboxylate functional groups of this ligand are important to
the activity of the catalysts derived from it. This can be seen as
modification of these groups provided less-active catalysts
(entries 6-8). Benzannulated analogues L9 and L10 also
provided less-active catalysts (entries 9 and 10), presumably
because they are too hindered. Finally, L5 provided a more
active catalyst system than those derived from commercially
Pyrrole 2-carboxylic acid (L5) was found to be an effective
ligand for the Cu-catalyzed monoarylation of anilines with
aryl iodides and bromides. Under the reported conditions
(10% CuI/20% L5/DMSO/K3PO4/80-100 °C/20-24 h), a
variety of useful functional groups were tolerated, and
moderate to good yields of the diaryl amine products were
obtained.
The diaryl amine moiety can be found in a variety of
biologically active pharmaceuticals, natural products, and
materials. Metal-catalyzed cross-coupling reactions of anilines
with aryl halides are among the foremost methods for as-
sembling this substructure.1,2 For reactions of poorly nucleo-
philic primary anilines with aryl halides, Pd-based catalyst
systems are highly efficient.1 This is due, in great part, to the
rapid transmetalation of anilines to Pd(II), a phenomenon that
arises from the large increase in acidity of the nucleophile when
coordinated to Pd(II).3 The complementary nature of Pd- and
Cu-catalyzed C-N bond-forming processes, and the issues
involving removal of the trace Pd from the products encourage
the development of Cu-based catalyst systems for the preparation
of diaryl amines.
(4) (a) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001,
42, 4791. (b) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(c) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70, 8107. (d) Guo,
X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. AdV. Synth. Catal. 2006, 348, 2197. (e)
Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636. (f)
Liu, Y.; Bai, Y.; Zhang, J.; Li, Y.; Jiao, J.; Qi, X. Eur. J. Org. Chem. 2007,
6084. (g) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397.
(5) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Klapars, A.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (c) Altman, R. A.;
Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190. (d) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (e) Shafir,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (f) Shafir, A.; Lichtor,
P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490. (g) Altman, R. A.;
Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73,
284.
(1) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, Manuscript
accepted for publication. (b) Jiang, L.; Buchwald, S. L. Palladium-Catalyzed
Aromatic Carbon-Nitrogen Bond Formation. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; pp 699-760.
(6) (a) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670. (b) Kelkar,
A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron Lett. 2002, 43, 7143. (c)
Patil, N. M.; Kelkar, A. A.; Chaudhari, R. V. J. Mol. Catal. A: Chem. 2004,
223, 45.
(2) (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(3) Biscoe, M. B.; Barder, T. E.; Bucwhald, S. L. Angew. Chem., Int. Ed.
2007, 46, 7232.
(7) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.
10.1021/jo8008676 CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5167–5169 5167

TABLE 1. Cu-Catalyzed Reaction of Aniline with Iodobenzenea
TABLE 2. Cu-Catalyzed Reactions of Anilines with Aryl Iodidesa
entry
ligand
GC conversion (%)
GC yield (%)
1
2
3
4
L1
L2
L3
L4
58
46
47
0
35
27
27
0
5
6
7
8
L5
L6
L7
L8
94
57
55
66
62
60
64
64
48
64
51
68
37
22
0
26
22
34
29
15
19
30
9
L9
10
11
12
13
14
15
L10
L11
L12
L13
L14
L15
a Reaction conditions: 1.0 mmol of ArNH2, 0.5 mmol of ArI, 1.0
mmol of K3PO4, 0.050 mmol of CuI, 0.10 mmol of ligand, 0.25 mL of
DMSO, at 80 °C in a sealed tube under an N2 atmosphere for 17 h.
a Reaction conditions: 2.0 mmol of ArNH2, 1.0 mmol of ArI, 2.0
mmol of K3PO4, 0.10 mmol of CuI, 0.20 mmol of L5, 0.5 mL of
DMSO, in a sealed tube under an N2 atmosphere for 24 h. b Yields
reported are the average of at least two runs determined to be >95%
pure by elemental analysis or 1H NMR. c 5% of CuI, 10% of L5, 1.5
mmol of ArNH2.
FIGURE 1. Ligands examined for N-arylation reactions of aniline.
available ligands previously reported for this transformation
(entries 11-14).4a,b,d,f
electron-donating substituent at the para position. Substrates
containing base-sensitive functional groups such as benzoic
esters and benzonitriles, which do not tolerate heating in the
presence of hydroxide,5c were transformed to the desired product
in respectable yields (entries 2 and 3). In addition, the presence
of an ortho substituent on the aryl halide was tolerated (entry
4). Using the standard conditions, reactions of anilines contain-
ing strongly electron-withdrawing substituents at the 4-position
provided the diaryl amine product in lower yields (entries 5-7).
In these reactions, significant quantities of triarylamine byprod-
ucts were observed.4d The reaction of 4-nitroaniline with an aryl
iodide provided the undesired triarylamine as the major product.
However, an aryl halide could be coupled with N-(4-aminophe-
nyl)acetamide to provide a product with a similar substitution
pattern (entry 8). As previously noted, the Cu-catalyzed coupling
of an anilino-NH2 group in the presence of an amide is unusual
for a Cu-catalyzed reaction of this type.6a,b In this case, the
observed chemoselectivity is likely due to the slow reaction of
secondary amides.9 In contrast to this result, the reaction of
4-aminobenzamide with 4-iodoanisole provided a complex
mixture of products. Last, the Cu/L5-catalyzed reaction of
Further optimization of the reaction conditions with L5
revealed that the base/solvent combination of K3PO4/DMSO
typically provided a superior system than combinations involv-
ing K2CO3, Cs2CO3, KOH, and NaOt-Bu in DMF, 1,4-dioxane,
toluene, and acetonitrile. Since diaryl ether and phenolic
products (up to 20% of ArX consumption) were frequently
produced under the reaction conditions and observed by GC/
MS,8 the base was flame-dried under reduced pressure then
cooled under a positive pressure of N2 prior to use.
The reaction conditions we developed (1.0 equiv of ArX/2.0
equiv of ArNH2/10% CuI/20% L5/K3PO4/DMSO/80-90 °C)
could be used to couple aryl iodides with anilines in moderate
to good yields (Table 2). For the reaction of p-anisidine with
4-chloroiodobenzene, the catalyst loading and reaction temper-
ature could be reduced to 5% CuI and 70 °C, respectively (entry
1). Attempts to reduce the catalyst loading down to 2 mol %,
however, were unsuccessful. For this example, the lower catalyst
loading employed can be attributed to the increased nucleophi-
licity of p-anisidine relative to anilines that lack a strong
(8) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer, M.
Org. Lett. 2004, 6, 913.
(9) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421.
5168 J. Org. Chem. Vol. 73, No. 13, 2008

TABLE 3. Cu-Catalyzed Reactions of Anilines with Aryl
Bromidesa
products. Electron-donating and -withdrawing substituents were
tolerated on both the nucleophile and electrophile (entries 1-4).
In addition, anilines and aryl bromides containing ortho sub-
stituents were effectively combined (entries 5-8). When
employing 3-bromoquinoline as a substrate, a significant
quantity of reduced heteroarene was observed (entry 9). The
formation of this byproduct is common for Cu-catalyzed
reactions of heteroaryl halides with amines.5c
In conclusion, pyrrole 2-carboxylic acid was employed as a
suitable ligand for the Cu-catalyzed monoarylation of anilines
with aryl iodides and bromides. Anilines and aryl halides
possessing diverse electronic properties and useful functional
groups were all tolerated. In many cases, the relatively low
catalyst loading (10% Cu), the breadth of functional groups
tolerated by the catalyst system, and the cost and commercial
availability of the metal and ligand might offset the required
use of 2 equiv of amine and the moderate yields obtained. We
are continuing our investigations to develop newer and more
active Cu-based catalyst systems for this transformation.
Experimental Section
General Procedure for the Cu-Catalyzed Cross-Coupling
of Anilines with Aryl Halides. An oven-dried screw-cap test tube
was charged with K3PO4 (424 mg, 2.0 mmol). The tube was sealed
and the base was flame-dried under vacuum and cooled under a
purge of N2. CuI (19 mg, 0.10 mmol), pyrrole 2-carboxylic acid
(22 mg, 0.20 mmol), aryl halide (1.0 mmol, if solid), amine (2.0
mmol, if solid) and a magnetic stir bar were added to the cooled
vessel. The tube was then evacuated and back-filled with nitrogen.
The evacuation/backfill sequence was repeated two additional times.
Aryl halide (1.0 mmol, if liquid), amine (2.0 mmol, if liquid), and
DMSO (0.50 mL) were then added by syringe. The vessel was
immersed in a preheated oil bath and the reaction mixture was
stirred vigorously until TLC and/or GC analysis of the crude
reaction mixture indicated that the aryl halide had been completely
consumed. The reaction mixture was cooled to room temperature.
Ethyl acetate (15 mL), NH4Cl(aq) (2 mL), and H2O (1 mL) were
added and the mixture was stirred. The organic layer was separated
and filtered through a plug of silica. The aqueous layer was extracted
twice more with ethyl acetate (10 mL), and each extract was
sequentially filtered through the pad of silica gel. The filtrate was
concentrated and the resulting residue was purified by flash
chromatography (hexanes/ethyl acetate, gradient elution) to provide
the desired product.
a Reaction conditions: 2.0 mmol of ArNH2, 1.0 mmol of ArBr, 2.0
mmol of K3PO4, 0.10 mmol of CuI, 0.20 mmol of L5, 0.5 mL of
DMSO, in a sealed tube under an N2 atm for 24 h. b Yields reported are
the average of at least two runs determined to be >95% pure by
elemental analysis or 1H NMR. c 20% of L15 employed as a ligand in
DMF at 110 °C. d 30 h.
2-aminobenzothiazole with 4-iodoanisole arylated the hetero-
cyclic nitrogen as opposed to the anilino-NH2 (entry 9).10 This
result is noteworthy, since the Pd-catalyzed reactions of this
nucleophile with aryl bromides selectively react at the anilino-
NH2 position.11
Aryl bromides were also successfully coupled by using the
CuI/L catalyst system (Table 3), although higher temperatures
were required (100 °C). Increasing the reaction temperature to
110 °C provided significant quantities of N-arylated and
decarboxylated pyrrole, and low yields of the diarylamine
Acknowledgment. We thank the National Institutes of
Health (GM58160 and GM46059) for financial support for this
project. R.A.A. is grateful to the National Institutes of Health
(F31GM081905) for a predoctoral fellowship. We thank Merck
for additional unrestricted funding. The NMR instruments used
for this publication were furnished by funds from the National
Science Foundation (CHE 9808061 and DBI 9729592).
Supporting Information Available: Experimental proce-
dures and characterization data for all new and known
compounds and kinetic and computational data for complexes.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Authentic N-(4-methoxyphenyl)benzo[d]thiazol-2-amine was indepen-
dently prepared from the reaction of 2-chlorobenzothiazole and p-anisidine
according to the procedure in: Cossey, H. D.; Judd, J.; Stephens, F. F. J. Chem.
Soc. 1965, 954. The product of this uncatalyzed reaction was found to be different
than the product obtained from the reaction described in Table 2, entry 9.
(11) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett.
2002, 4, 3481.
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J. Org. Chem. Vol. 73, No. 13, 2008 5169