Palladium- and copper-catalyzed site selective monoamination of dibromobenzoic acid

Article abstract of DOI:10.1002/adsc.201000800

The carboxylate anion has been used as a directing group in the aromatic amination of electronically equivalent aryl bromides to afford selective ortho-substituted derivatives (> 99:1 selectivity; 60-80% yield) in the case of copper(I) catalysis. The solvent, base and equivalents of base were important factors in the success of this reaction. Complementary selectivity was achieved with palladium catalysis where the para-substituted derivatives were produced selectively (> 99% selectivity, 70-80% yield).

Full text of DOI:10.1002/adsc.201000800

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DOI: 10.1002/adsc.201000800
Palladium- and Copper-Catalyzed Site Selective Monoamination
of Dibromobenzoic Acid
Ioannis N. Houpis,a,* Koen Weerts,a Ulrike Nettekoven,b Martine Canters,a
Hongyu Tan,c Renmao Liu,c and Youchu Wangc
a
Janssen Pharmaceutica, API Development, Turnhoutseweg 30, 2340 Beerse, Belgium
Fax : (+32)-14-605-755; e-mail: yhoupis@its.jnj.com
Solvias A.G., Synthesis and Catalysis, Mattenstr.22, 4002 Basel, Switzerland
WuxiApptec, Process Chemistry, 288 Fute Zhong Road, Shanghai 200131, Peopleꢀs Republic of China
b
c
Received: October 23, 2010; Published online: March 2, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000800.
À
Abstract: The carboxylate anion has been used as a
directing group in the aromatic amination of elec-
tronically equivalent aryl bromides to afford selec-
tive ortho-substituted derivatives (>99:1 selectivity;
60–80% yield) in the case of copper(I) catalysis.
The solvent, base and equivalents of base were im-
portant factors in the success of this reaction. Com-
plementary selectivity was achieved with palladium
catalysis where the para-substituted derivatives
were produced selectively (>99% selectivity, 70–
80% yield).
boxylate anion in C H activation processes, followed
by further functionalizations,[2] while we have demon-
strated the selective Kumada and Suzuki coupling of
electronically similar halides (such as 1).[3]
In the Suzuki coupling, we have shown that 2,4-di-
bromobenzoic acid (1) can be selectively coupled at
the 2- or 4-positions depending on the choice of li-
gands [Scheme 1, Eq. (1)]. Thus in the presence of
Pd2dba3 (0.5 mol%), in the absence of phosphine li-
gands, the 2-substituted product (II) can be obtained
with >99:1 selectivity while addition of DPEphos (8)
afforded the 4-substituted analogue (I) in >10:1 se-
lectivity (Scheme 1).
In our attempt to extend the scope of the directing
effect of the carboxylate in Pd-catalyzed amination
reactions, we examined the amination of benzoic acid
derivatives bearing reactive halides in the electroni-
cally comparable ortho and para positions.[4] In this
preliminary report we describe the reactions of 2,4-di-
Keywords: carboxylate directed aminations;
copper; 2,4-dibromobenzoic acid; palladium; selec-
tive aromatic aminations
Selective transformations and in particular directed bromobenzoic acid 1 with electronically and stericaly
processes have been in the focus of synthetic chemists diverse amines. Other dihalide derivatives are being
for many decades. Such processes include directed examined and will be reported in due course. In this
À
ortho-metallation reactions, directed C H activations work complementary regioselectivity could not be
and directed hydrogenations, to name a few.
achieved by varying the palladium ligand (dibenzyli-
ACHTUNGTRENdNGNU ineacetone vs. phopshine) however, complementary
The carboxylate anion has not featured as promi-
nently as, for example, amide and carbamate function- reactivity could be obtained by employing Cu for
alities in such directed processes due to its low “di- ortho substitution[5] while Pd afforded para substitu-
recting” power.[1] However, several research groups tion with the appropriate choice of ligands.
have shown recently the directing effect of the car-
Scheme 1. Carboxylate-directed Suzuki coupling.
538
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Adv. Synth. Catal. 2011, 353, 538 – 544

Palladium- and Copper-Catalyzed Site Selective Monoamination of Dibromobenzoic Acid
Figure 1. Ligand screen in the Pd-catalyzed amination of 1 with benzylamine.
As in our previous work, we began by reacting 1 [Figure 1, Eq. (2)], however no reaction was ob-
with benzylamine (2) in the presence of Pd2dba3,[3b] served. In an attempt to effect this transformation, we
under a variety of combinations of solvent and base initiated a screening exercise in two phases. A pre-
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539

Ioannis N. Houpis et al.
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Table 1. Initial base and solvent screening for the coupling
of l with benzylamine.
of ligands in a 96-well plate, using the best solvent
and base combination identified in the preliminary
screening, and finally the results from this screening
were confirmed by scaling up the most promising re-
actions (Figure 1). The results exhibit some interest-
ing trends.
First, all the catalyst systems that were investigated
preferentially give the para-product 3, which is consis-
tent with our previous results.[3b] Second, popular li-
gands for aromatic amination reactions failed to give
any product, and the same is true of imidazolinium
carbene-based catalysts.[6,7]
Third, the best results were obtained with ferrocen-
yl ligands (e.g., 6, Figure 1)[8] while XantPhos[9] 7 also
gave promising results as expected from our prelimi-
nary screen (Figure 1 and entry 2, Table 1). Last, the
optimal base was t-BuOÀ (Table 1) with the counter-
ion playing a significant role (entries 2 and 4,
Table 1). Thus, we decided to optimize the reaction,
using the conditions shown in Eq. (3) (Table 2), with
ligands 6 and 7 and examine its scope.
Entry L[a]
Base
Solvent[b] Conversion Ratio[c]
[%]
3:4
1
2
3
4
5
6
7
8
9
BINAP t-BuONa DME
51
98
38
34
20
0
0
0
50
3
7:1
7
dppf
7
5
7
7
t-BuONa DME
t-BuONa DME
t-BuOK DME
t-BuONa DME
20:1
n.d.
n.d.
10:1
n.d.
n.d.
n.d.
30:1
n.d.
Cs2CO3
DME
LiHMDS DME
A
8
8
t-BuONa DME
10
LiOH
DME
[a]
PdACHTUNGTRENNUNG(OAc)2 (3 mol%) was used as the Pd source (Pd:L=
1:2 for monedentate, 1:1 for bidentate ligands).
Toluene, THF and Me-THF gave inferior results.
The ratio was determined by NMR integration.
[b]
[c]
liminary screening of ligands, base and solvent was in-
We confirmed that DME was the preferred solvent
itiated to identify reasonable base and solvent combi- for both Xant-Phos (7), as shown before, and the fer-
nations (Table 1) followed by a more thorough screen rocenyl ligand 6 and that t-BuONa was the optimal
Table 2. Optimization and scope of the Pd-catalyzed amination of 1 with various amines.
Entry
Amine
Base [equiv.]
Temperature [oC]
L (% Pd)
Conversion [%]
17/18
Yield [%]
1
2
3
4
5
6
7
8
9
9
9
2
3
2
3
3
3
3
3
3
3
3
3
80
60
80
60
80
60
60
80
60
60
80
60
6 (5)
6 (5)
7 (3)
6 (5)
7 (3)
6 (1)
6 (5)
7 (5)
6 (5)
6 (5)
7 (5)
6 (5)
62
95
95
95
60
95
70
100
50
50
90
0
5
100
20
100
7
100
100
100
100
100
30
–
79
58
82
–
78
–
59
15
27
75
–
10
10
10
11
11
12
13
12
14–16
9
10
11
12
–
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Palladium- and Copper-Catalyzed Site Selective Monoamination of Dibromobenzoic Acid
Table 3. Optimization of the Cu-catalyzed cross coupling of 1 with BuNH2 in DMA.
Entry
Cu(I) (mol%)
Base (equiv.)
Temperature/Time
Conversion
4
4a
1
2
3
4
5
6
7
8
9
10
CuI (10%)
CuI (10%)
CuI (5%)
CuI (20%)
K2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K3PO4 (2)
K3PO4 (2)
258C/16 h
258C/16 h
258C/16 h
258C/16 h
258C/16 h
258C/16 h
508C/16 h
708C/16 h
708C/16 h
708C/16 h
70%
85%
25%
98%
7%
20%
95%
95%
100%
100%
53%
57%
18%
70%
–
14%
80%
86%
92%
94%
13%
22%
–
25%
–
CuACHTUNGTRENNUNG(acac)2 (10%)
CuBr (10%)
CuI (10%)
CuI (10%)
Cu2O (10%)
Cu2O (5%)
–
9%
4%
2%
<1%
base. Finally, the equivalents of base, catalyst load cleophiles by Hartley.[10] Although several subsequent
and amine structure were examined, and the results studies have demonstrated the ortho-directing effect
are shown in Table 2. The data showed that the reac- of the carboxylate in dihalobenzoic acid derivatives,
tion was almost completely para-selective with both the examples found in the literature use halides of dif-
ferrocenyl catalyst 6 and Xant-phos 7 albeit the selec- ferent reactivity (e.g., F vs. Cl) to obtain the desired
tivity of the former is higher. The equivalents of base selectivity. Wolf et al. have studied[5b] the amination of
are critical to the success of the reaction, in both reac- 2,5-dibromobenzoic acid obtaining the expected ortho
tivity and selectivity. However unlike our previously coupling product. To the best of our knowledge, elec-
reported Suzuki coupling reactions, where 2 equiva- tronically comparable halides have not been studied
lents of base were optimal, the amination rection re- to date.
quired 3 equivalents of base to achieve nearly 100%
Our investigation started with the reaction of ben-
para-selectivity (entries 1 and 2, Table 2).
zylamine with 1 using the Wolf protocol (1308C; 2-
Catalyst 6 performed well with unhindered alkyl- ethoxyethanol)[5b] developed for 2,5-dibromobenzoic
ACHTUNGTRENNUNG
load while ca. 3% is required for the latter. It should
be noted that no diamination products were identified that would exclude nucleophilic solvents and, in a
in any of the reactions. brief study, focused on polar aprotic solvents such as
As a consequence we sought to develop conditions
Unfortunately, we were not successful in effecting N-methylpyrrolidinone, N,N-dimethyl formamide and
the cross-coupling of secondary amines with a variety dimethyl acetamide (DMA).
of substrates (entry 12, Table 2).
Since we found no substantial difference between
Having accomplished para-substitution selectively these three solvents, we chose DMA for further opti-
we then turned our attention to devising an ortho-se- mization, and the most relevant results are outlined in
lective process. Indeed, one of the earliest carboxyl- Table 3.
ate-directed cross-coupling reactions is the Cu-cata-
Surprisingly, the reaction progressed well even at
lyzed amination of 2-halobenzoic acids where signifi- room temperature, giving up to 85% conversion when
cant rate acceleration is observed by the presence of Cs2CO3 was used as the base (Table 3, entries 1 and
the carboxylate ion ortho to the halogen.
2). Only the ortho-product 4 was observed. However,
This process, pioneered by Ullmann, was shown to the aminophenol 4a was still formed in substantial
be catalytic by Goldberg and extended to carbon nu- amounts. CuI initially appeared to be the best cata-
Adv. Synth. Catal. 2011, 353, 538 – 544
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Ioannis N. Houpis et al.
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mides as shown in the case of 2,4-dibromobenzoic
acid.[12] We have further shown that this amination re-
action can be induced to give selectively the ortho or
para product by simply tuning the catalyst system
from palladium to copper.
Experimental Section
Representative Experimental Procedures for the
Preparation of Compounds 17–9 to 17–13 (RNH2 =9–
13)
2,4-Dibromobenzoic acid (0.227 g, 1 mmol), BnNH2 (0.161 g,
1.5 mmol) and t-BuONa (0.28 g, 3 mmol) were added under
nitrogen into a Schleck tube followed by dimethoxyethane
(2.0 mL). The mixture was degassed thoroughly by bubbling
nitrogen for 30 min. 1,1-Bis(diisopropylphosphino)ferrocene
(0.024 g, 0.05 mmol) and PdACHTNUTRGNENG(U OAc)2 (0.011 g, 0.05 mmol)
were added in sequence under nitrogen. The mixture was
heated to 608C and stirred for 16 h at that temperature until
LC-MS showed the complete consumption of 2,4-dibromo-
benzoic acid. The mixture was cooled to 08C and 2NHCl
was added to pH 4~5. The mixture was concentrate to
remove solvent and water (10.0 mL) was added followed by
EtOAc (20.0 mLꢂ2). The combined organic layer was
washed with brine (20 mLꢂ2), dried over Na2SO4, filtered
and concentrated to afford a yellow residue which was puri-
fied by chromatography on silica gel using EtOAc/heptane
(v/v 1.3/1) as eluent.1H NMR (CDCl3, 400 MHz): d=4.29
(2H, s, CH2), 6.52 (1H, dd, J1 =2.0 Hz, J2 =8.8 Hz, Ar), 6.83
(1H, d, J=2.0 Hz, Ar), 7.17–7.28 (5H, m, Ar), 7.70 (1H, d,
J=8.4 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d=109.9,
116.7, 116.9, 123.6, 126.5, 126.6, 128.0, 133.3, 138.5, 152.4,
167.5; HR-MS: m/z=306.0116, calcd. for C14H12BrNO2 [M+
H]+: 306.1456.
Figure 2. Scope of the Cu-catalyzed ortho-amination of 1a.
lyst, but up to 20% was needed for complete conver-
sion (Table 3, entries 2–4).
Other Cu sources were not useful (Table 3, entries 5
and 6) and, even more surprisingly, commonly used
Cu-amine-derived catalysts were also unsuccessful.[11]
Finally, when the reaction was performed at a higher
temperature (Table 3, entry 7), the reaction proceed-
ed to ca. 95% conversion with reasonable catalyst
2-Bromo-4-n-hexylaminobenzoic acid: 1H NMR (CDCl3,
400 MHz): d=0.9 (3H, triplet, J=6.8 Hz, CH3), 1.23–1.39
load (10%) while forming only 9% of 4a as compared (6H, m, CH2), 1.58–1.62 (2H, m, CH2), 3.12 (2H, triplet, J=
6.8 Hz, CH2), 6.46 (1H, dd, J1 =2.4 Hz, J2 =8.8 Hz, Ar),
6.81(1H, d, J=2.0 Hz, Ar), 7.92(1H, d, J=8.4 Hz, Ar);
13C NMR (CDCl3, 100 MHz): d=14.0, 22.5, 26.6, 29.1, 31.4,
43.2, 110.4, 110.6, 116.2, 117.3, 117.5, 125.3, 134.7, 152.3,
169.9; HR-MS: m/z=300.0584, calcd. for C13H18BrNO2 [M+
H]+: 300.1915.
to 22% at room temperature (Table 3; entries 7 versus
2). Finally, our screen revealed that Cu2O and K3PO4
was the ideal combination of catalyst and base
(Table 3, entry 10), giving 94% of the desired product
4 with only traces of the aminophenol 4a.
We examined the scope of the reaction using these
optimized conditions and the results are shown in
Figure 2. The reaction appears to be general with pri-
mary alkylamines to afford ortho-aminated benzoic
2-Bromo-4-cyclohexylaminobenzoic
acid:
1H NMR
(CDCl3, 400 MHz): d=1.16–1.42 (5H, m, CH2), 1.64–1.78
(3H, m, CH2), 2.01–2.04 (2H, m, CH2), 3.27–3.32 (1H, m,
CH2), 6.42 (1H, dd, J1 =2.0 Hz, J2 =8.8 Hz, Ar), 6.80 (1H, s,
acids (4, 19 and 20) in good isolated yield. Aniline is Ar), 7.91 (1H, d, J=8.8 Hz, Ar); 13C NMR (CDCl3,
100 MHz): d=24.7, 25.5, 29.6, 32.9, 51.2, 110.7, 115.8, 117.7,
125.3, 134.8, 151.2, 169.1; HR-MS: m/z=298.0428, calcd. for
C13H16BrNO2 [M+H]+: 298.1756.
not a good substrate, affording the desired adduct
(21) in low yield, however, electron-rich anilines do
give useful yields of the desired ortho-product (e.g.,
22). Amines 14–16 again fail to react under our reac-
tion conditions as was the case in the Pd-catalyzed re-
action. We are actively investigating conditions that
will effect the reaction with secondary amines.
2-Bromo-4-phenylaminobenzoic acid: 1H NMR (CDCl3,
400 MHz): d=6.96 (1H, dd, J1=2.4 Hz, J2=8.8 Hz, Ar),
7.02 (1H, triplet, J=7.2 Hz, Ar), 7.16 (2.0H, d, J=7.6 Hz,
Ar), 7.24 (1H, d, J=2.4 Hz, Ar), 7.31 (2H, dd, J1 =7.2 Hz,
J2 =8.4 Hz, Ar), 7.81 (1H, d, J=8.4 Hz, Ar); 13C NMR
(CDCl3, 100 MHz): d=112.2, 119.3, 119.8, 120.1, 122.6,
123.5, 129.0, 133.3, 140.8, 149.0, 167.4; HR-MS; m/z=
In summary, we have demonstrated that the carbox-
ylate ion can have a pronounced effect in aromatic
amination of electronically similar aromatic bis-bro- 291.9958, calcd. for C13H10BrNO2 [M+H]+: 292.1280.
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Palladium- and Copper-Catalyzed Site Selective Monoamination of Dibromobenzoic Acid
2-Bromo-4-(4-methoxyphenylamino)-benzoic
acid:
(1H, dd, J1 =1.6 Hz, J2 =8.8 Hz, Ar), 6.87 (2H, d, J=8.8 Hz,
Ar), 6.97 (1H, d, J=1.6 Hz, Ar), 7.09 (2H, d, J=9.2 Hz,
Ar), 7.76 (1H, d, J=8.4 Hz, Ar); 13C NMR (DMSO-d6,
100 MHz): d=55.5, 114.9, 115.9, 119.5, 126.7, 130.5, 132.0,
133.7, 151.2, 157.5, HR-MS: m/z=322.0062, calcd. for
C14H12BrNO3 [M+H]+: 322.1540.
1H NMR (CDCl3, 400 MHz): d=3.77 (3H, s, CH3), 6.88–
6.92 (2H, m, Ar), 7.06–7.11 (3H, m, Ar), 7.77 (2H, d, J=
8.8 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d=54.5, 111.2,
114.2, 118.2, 118.5, 123.6, 123.7, 133.3, 133.5, 150.5, 156.4,
167.5; HR-MS: m/z=322.0064, calcd. for C14H12BrNO3 [M+
H]+: 322.1540.
References
Representative Experimental Procedures for the
Preparation of Compounds 4 and 19–22
[1] Directed ortho-metallation eactions: a) E. J.-G. Anctil,
V. Snieckus, J. Organomet. Chem. 2002, 653, 150;
b) E. J.-G. Anctil, V. Snieckus, in: Metal-Catalyzed
Cross Couping Reactions, 2nd edn., (Eds.: F. Diederich,
A. De Meijere), Wiley, New York, 2004, pp 761–814;
c) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak,
Angew. Chem. 2004, 116, 2256; Angew. Chem. Int. Ed.
2004, 43, 2206. Directed hydrogenations: d) R. H.
Crabtree, M. W. Davies, J. Org. Chem. 1986, 51, 2655.
[2] Reviews: a) A. R. Dick, M. S. Sanford, Tetrahedron
2006, 62, 2439; b) J.-Q. Yu, R. Giri, X. Chen, Org.
Biomol. Chem. 2006, 4, 4041.
[3] a) I. N. Houpis, C. Huang, U. Nettekoven, J. G. Chen,
R. Liu, M. Canters, Org. Lett. 2008, 10, 5601; b) I. N.
Houpis, J.-P. Van Hoeck, U. Tilstam, Synlett 2007, 14,
2179; c) I. N. Houpis, R. Liu, Y. Wu, Y. Yuan, Y. Wang,
U. Nettekoven, J. Org. Chem. 2010, 75, 6965.
[4] Selected reports of the carboxylate directing effect see:
a) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org.
Lett. 2008, 10, 1159; b) K. Ueura, T. Satoh, M. Miura,
Org. Lett. 2007, 9, 1407; c) D. Tanaka, S. P. Stuart,
A. G. Myers, J. Am. Chem. Soc. 2005, 127, 10323; d) R.
Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano,
L. B. Saunders, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129,
3510; e) T.-S. Mei, R. Giri, N. Maugel, J.-Q. Yu, Angew.
Chem. 2008, 120, 5293; Angew. Chem. Int. Ed. 2008, 47,
5215; f) H. A. Chiong, Q.-N. Pham, O. J. Daugulis, J.
Am. Chem. Soc. 2007, 129, 9879; g) N. Boudet, S. Sase,
P. Sinha, C.-Y. Liu, A. Krasovskiy, P. Knochel, J. Am.
Chem. Soc. 2007, 129, 12358; h) A. V. Kalinin, J. F.
Bower, P. Riebel, V. Snieckus, J. Org. Chem. 1999, 64,
2986; i) review: B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett
2008, 949.
[5] Significant information is available in the literature.
Some recent examples: a) X. Liu, H. Fu, Y. Jiang, Y.
Zhao, Angew. Chem. 2009, 121, 354; Angew. Chem. Int.
Ed. 2009, 48, 348; b) S. Liu, J.-P. C. Pestano, C. Wolf,
Synthesis 2007, 3519; c) M. L. Docampo, R. F. Pellon,
A. Estevez-Broen, A. G. Ravelo, Eur. J. Org. Chem.
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Synlett 2003, 2428.
Solid 2,4-dibromobenzoic acid (0.455 g, 2 mmmol), BnNH2
(0.321 g, 3 mmol) and K3PO4 (0.848 g, 4 mmol) were placed
in a Schlenck tube under nitrogen and N,N-dimethylacet-
ACHTUNGTRENNUNGamide was added (4.0 mL). The mixture was degassed by
bubbling nitrogen for 30 min. Cu2O (0.014 g, 0.1 mmol) was
added under nitrogen and the mixture was heated to 708C
and stirred at that temperature for 16 h. Upon completion
(LC-MS showed that 2,4-dibromobenzoic acid had been
consumed completely) the mixture was cooled to 258C and
filtered through Celite to remove the solids. Water
(20.0 mL) was added to the mixture at 258C, the pH was ad-
justed to 4–5 by addition of 2N HCl and the mixture was
extracted with EtOAc (25.0 mLꢂ2). The combined organic
layer was washed with brine (30 mLꢂ2), dried over Na2SO4,
filtered and concentrated to afford a solid residue which was
purified by chromatography on silica gel using EtOAc/hep-
1
tane (v/v 1.5/1) as eluent. H NMR (CDCl3, 400 MHz): d=
4.42 (2H, s, CH2), 6.74 (1H, dd, J1 =1.6 Hz, J2 =8.4 Hz, Ar),
6.81 (1H, d, J=1.6 Hz, Ar),7.26–7.37 (5H, m, Ar), 7.81
(1H, d, J=8.8 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d=
46.9, 107.8, 114.5, 118.5, 127.0, 127.5, 128.8, 131.0, 133.8,
137.8, 152.1, 172.9; HR-MS: m/z=306.0116, calcd. for
C14H12BrNO2 [M+H]+: 306.1456.
4-Bromo-2-n-hexylaminobenzoic acid: 1H NMR (CDCl3,
400 MHz): d=0.90 (3H, triplet, J=7.2 Hz,CH3), 1.31–1.33
(4H, m, CH2), 1.37–1.42 (2H, m, CH2), 1.63–1.70 (2H, m,
CH2), 3.15 (2H, triplet, J=7.2 Hz, CH2), 6.68 (1H, dd, J1 =
2.0 Hz, J2 =8.8 Hz, Ar), 6.81 (1H, d, J=1.6 Hz, Ar), 7.77
(1H, d, J=8.4 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d=
13.9, 22.5, 26.7, 28.8, 31.4, 42.8, 107.1, 114.1, 117.6, 130.9,
133.8, 152.3, 172.8; HR-MS: m/z=300.0586, calcd. for
C13H18BrNO2 [M+H]+: 300.1915.
4-Bromo-2-cyclohexylaminobenzoic
acid:
1H NMR
(CDCl3, 400 MHz): d=1.22–1.45 (5H, m, CH2), 1.61–1.64
(1H, m, CH2), 1.74–1.78 (2H, m, CH2), 1.97–2.03 (2H, m,
CH2), 3.31–3.36 (1H, m, CH), 6.65 (1H, dd, J1 =1.6 Hz, J2 =
8.8 Hz, Ar), 6.82 (1H, d, J=1.6 Hz, Ar), 7.76(1H, d, J=
8.8 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d=24.5, 25.6,
32.6, 50.6, 107.0, 114.3, 117.36, 117.37, 130.8, 134.0, 151.4,
172.7; HR-MS: m/z=298.0429, calcd. for C13H16BrNO2 [M+
H]+: 298.1756.
[6] E. A. B. Kantchev, C. J. O’Brien, M. G. Organ, Angew.
Chem. 2007, 119, 2842; Angew. Chem. Int. Ed. 2007, 46,
2768.
4-Bromo-2-phenylaminobenzoic acid: 1H NMR (CDCl3,
400 MHz): d=6.78 (1H, dd, J1 =2.0 Hz, J2 =8.8 Hz, Ar),
7.12 (1H, triplet, J=7.2 Hz Ar), 7.24 (1H, s, Ar), 7.26(1H,
s, Ar),7.31 (1H, d, J=1.6 Hz, Ar), 7.40 (2H, triplet, J1=
8.0 Hz, J2=7.6 Hz, Ar), 7.87 (1H, d, J=8.4 Hz, Ar);
13C NMR (CDCl3, 100 MHz): d=108.9, 116.3, 120.3, 123.7,
124.9, 129.7, 130.5, 133.7, 139.4, 149.8, 172.3; HR-MS: m/z=
291.9959, calcd. for C13H10BrNO2 [M+H]+: 292.1280.
[7] For a thorough review of modern Pd-catalyzed amina-
tion reaction of aryl halides and amines and references
for the use of biaryl phosphine ligands in several metal
catalyzed reactions see: a) D. S. Surry, S. L. Buchwald,
Angew. Chem. 2008, 120, 6438; Angew. Chem. Int. Ed.
2008, 47, 6338; b) A. R. Mucci, S. L. Buchwald, Top.
Curr. Chem. 2002, 219, 131; c) J. F. Hartwig, in: Hand-
book of Organoaplladium Chemistry in Organic Syn-
4-Bromo-2-(4-methoxyphenylamino)-benzoic
acid:
1H NMR (DMSO-d6, 400 MHz): d=3.77 (3H, s, CH3), 6.72
Adv. Synth. Catal. 2011, 353, 538 – 544
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
543

Ioannis N. Houpis et al.
COMMUNICATIONS
thesis, (Ed.: E. Negishi), Wiley-Interscience, New York,
2002, Vol. 1, p 1051.
[8] Ferrocenyl-based ligands have been successfully used
to effect amination reactions: a) M. S. Driver, J. F.
Hartwig, J. Am. Chem. Soc. 1996, 118, 7217; b) B. C.
Hamann, J. F. Hartwig, J. Am. Chem. Soc. 1998, 120,
7369.
[9] Y. Guari, D. S. Van Es, J. N. H. Reek, P. C. J. Kamer, P.
Van Leeuwen, Tetrahedron Lett. 1999, 40, 3789.
[10] For a thorough review, see: J. Lindley, Tetrahedron
1984, 40, 1433.
the selectivity is determined by the formation of the
Cu-metallacycle A. In the case of Pd, in the absence of
phosphine ligands, we have rationalized previously
(I. N. Houpis, R. Liu, Y. Wu, Y. Yuan, Y. Wang, U. Net-
tekoven, J. Org. Chem. 2010, 75, 6965) that a similar
palladacycle B is formed in the case of the Suzuki reac-
tion . In the presence of phophines, steric effects direct
the oxidative addition to the less hindered para-posi-
tion (C).
[11] A number of such ligands were investigated with no
success; a) A. Shafir, S. L. Buchwald, J. Am. Chem.
Soc. 2006, 128, 8742 and references cited therein;
b) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115,
5558; Angew. Chem. Int. Ed. 2003, 42, 5400; c) K.
Kunz, U. Scholz, D. Ganzer, Synlett 2003, 2428.
[12] A thorough mechanistic investigation has not been un-
dertaken, however we believe that in the case of Cu
544
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 538 – 544