2-Pyridinyl β-ketones as new ligands for roomerature CuI-catalysed C-N coupling reactions

Article abstract of DOI:10.1039/b821212k

2-Pyridinyl β-ketones were identified as new efficient ligands for CuI-catalysed N-arylation of aliphatic amines at room temperature with great selectivity and substrate scope tolerance.

Full text of DOI:10.1039/b821212k

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2-Pyridinyl b-ketones as new ligands for room-temperature
CuI-catalysed C–N coupling reactionsw
Deping Wangab and Ke Ding*a
Received (in Cambridge, UK) 26th November 2008, Accepted 20th January 2009
First published as an Advance Article on the web 20th February 2009
DOI: 10.1039/b821212k
2-Pyridinyl b-ketones were identified as new efficient ligands for
CuI-catalysed N-arylation of aliphatic amines at room tempera-
ture with great selectivity and substrate scope tolerance.
Ligand identification to improve the reaction efficiency and
generality is an important topic for copper-catalysed Ullmann
coupling reaction study.1 Recently, several classes of
mono- and bidentate chelators have been reported as effective
ancillary ligands for Ullmann coupling reaction under
Fig. 1 Structures of designed 2-pyridinyl b-ketone ligands.
moderate conditions.2–8 However, only few ligands reported
could promote Ullmann type C–N coupling at room
temperature.4h,7a,8f It is highly desirable to identify new ligands
to further improve the efficiency and generality of copper-
catalysed N-arylation. In this paper, we report the identification
of 2-pyridinyl b-ketones as new effective ligands for
CuI-catalysed Ullmann condensation at room temperature.
Structural feature analysis of previously reported ligands for
copper-catalysed Ullmann reaction clearly revealed that most
of them contained bidentate chelating centers consisting of
coordinating atoms such as O and/or N. The hetero atoms
(O or N etc.) might coordinate with copper ion to form a
transitional 5- or 6-membered ring, and the chelating inter-
action of coordinating atoms with copper ion might play a
crucial role in determining the efficiency of the catalyst
system.6a Based on this observation, 2-pyridinyl b-ketones,
in which the N(1) and O(20) atoms (ligands A–I, Fig. 1) might
provide ideal bidentate chelating centers, were designed as new
potential ancillary ligands to promote copper-catalysed C–N
coupling reaction.9
Table 1 2-Pyridinyl b-ketones as ligands for room-temperature
CuI-catalysed C–N coupling reactiona
Entry
Ligand
Yield (%)b
Entry
Ligand
Yield (%)b
21
1
2
3
4
5
—
A
B
C
D
N.R.
45
43
N.R.
60
6
7
8
9
10
E
F
G
H
I
o10
97
88
85
a
1a (1.0 mmol), 2a (1.5 mmol), 10 mol% CuI, 20 mol% ligand,
b
Cs2CO3 (2.0 mmol), DMF (0.5 mL), Ar, 25 1C, 12 h. Isolated yield.
group which decreased the coordinating potential of the
O(20) atom. Interestingly, 3-methyl-1-(pyridin-2-yl)butan-2-ol
(E) and N-(pyridin-2-yl)acetamide (F) showed much lower
efficiency, although they contained similar bidentate chelating
centers. The conformationally constrained 1-(5,6,7,8-tetrahydro-
quinolin-8-yl) ethanone analogues (G, H and I) displayed
significantly improved catalytic efficiency, which catalysed
the coupling reaction with yields of 97%, 88% and
85%, respectively. This might be due to the fact that the
conformationally restricted ligands (G, H and I) possess
favorable conformations for chelating the copper ion.
C-Arylation of the constrained ligands at the a-carbon
(ligand A) might be avoided because of the increased steric
hindrance.7e A brief screening revealed that the combination
of 10% CuI, 20% ligand G, Cs2CO3 in DMF was the optimal
condition.w
The catalytic activity of designed ligands was evaluated by
using the C–N coupling of 4-methoxy iodobenzene (1a) with
n-hexylamine (2a) at room temperature (25 1C) as a model
reaction. From Table 1, it was clear that 2-pyridinyl b-ketones
A, B and D successfully promoted the copper-catalysed
coupling reaction with moderate yields (45%, 43% and
60%, respectively) at room temperature. When 1,1,1-trifluoro-
3-(pyridin-2-yl)propan-2-one (ligand C) was utilized, almost
no desired product was detected. This might be due to the
presence of a strong electronic withdrawing trifluoromethyl
a Key Laboratory of Regenerative Biology and Institute of Chemical
Biology, Guangzhou Institute of Biomedicine and Health, Chinese
Academy of Sciences, International Business Incubator A-3,
Guangzhou Science Park, Guangzhou, 510663, China.
E-mail: ding_ke@gibh.ac.cn; Fax: (+)86-20-32290485;
Tel: (+) 86-20-32290425
The application of the CuI/Ligand G catalyst system was
explored with a wide range of substrate combinations under
the optimised conditions. As shown in Table 2, the coupling
reactions were performed well for most of the substrates
examined in 8 to 24 h with 83B98% yields at room temperature.
This catalyst system exhibited excellent functional group
b Graduate School of the Chinese Academy of Sciences, Chinese
Academy of Sciences, China
w Electronic supplementary information (ESI) available: Experimental
section, 1H NMR, 13C NMR and HRMS spectra of all new
compounds. See DOI: 10.1039/b821212k
ꢀc
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Table 2 Room-temperature amination of aryl iodidesa
catalyst system (3mB3o) at room temperature, but acyclic
secondary amines showed poor reactivity even if a high
temperature (65 1C) was applied (3s). The CuI/G-catalysed
Ullmann reaction was aslo successfully carried out on a
preparative scale (50 mmol) in a 92% isolated yield.w
The CuI/G catalyst system was further applied to the
coupling reaction of heterocyclic iodides with aliphatic amines
with great success. As shown in Table 3, all the examined
heteroaryl iodides coupled with primary or cyclic secondary
amines with excellent yields at room temperature.
Yield
Product
Time/h Yield (%)b Product
Time/h (%)b
12
10
97
97
16
19
80
86
Although the coupling of aryl bromides with aliphatic
amines difficultly occurred with poor conversion rate at room
temperature, the reaction was accelerated significantly at
elevated temperatures (Table 4). For example, only 10%
conversion was detected when 4-methoxy bromobenzene (7a)
was reacted with 4-methoxyl benzylamine after 24 h at room
temperature, but an 85% yield was obtained when the reaction
was carried out at 65 1C in 14 h (9a). The amination of other
aryl bromides were also successfully achieved at a moderate
temperature. In addition, electron-rich 4-methoxy bromobenzene
had been considered as a highly challenging substrate for
copper-catalysed amination with cyclic secondary amines.4c,7a
The CuI/G system was found to effectively catalyse the
coupling of piperidine with 1-bromo-3,4,5-trimethoxybenzene,
which possessed much higher electronic density than that of
4-methoxy bromobenzene, at a temperature of 95 1C (9d). This
highlighted the high efficiency of CuI/G catalyst system for the
coupling reaction of aryl halides with aliphatic amines.
However, the amination of less active 4-methyl chlorobenzene
3k
3b
3c
3d
3l
8
95
91
24
24
95
90
3m
12
3n
3e
10
13
15
92
91
85
15
11
12
83
89
85
3fc
3g
3o
3pc
Table 3 Room-temperature amination of heteroaryl iodidesa
3qc
3rd
3h
3i
8
98
93
20
20
92
7
Yield
Time/h (%)b Product
Yield
Time/h (%)b
Product
12
3se
3j
17
96
14
97
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), 10 mol% CuI,
b
20 mol% G, Cs2CO3 (2.0 mmol), DMF (0.5 mL), Ar, 25 1C. Isolated
yield. Cs2CO3 (3.0 mmol). CuI (20 mol%), G (40 mol%), NH4Cl
6a
6e
c
d
e
(2 equiv.), DMF (1 mL), H2O (50 mL). 65 1C.
24
19
20
88
87
95
19
24
14
87
83
90
6b
6c
6f
compatibility and high selectivity in the presence of multiple
potentially reactive groups (3i, 3j, 3p, 3q), which would favour
its potential application in the construction of complex
molecules. Of note, this procedure did not racemise the
chiral centres although a relatively strong base Cs2CO3 was
utilized (3p and 3q). The coupling of 2-iodobenzoic acid or
4-iodobenzenamine with the corresponding amine was
successfully achieved without protection (3f, 3k). The amination
of 40-iodoacetophenone with NH4Cl was also accomplished
with high yield (92%) at room temperature (3r). Cyclic
secondary amines displayed high reactivity under the CuI/G
6g
6d
6h
a
Reaction conditions: 4 (1.0 mmol), 5 (1.5 mmol), 10 mol% CuI,
b
20 mol% G, Cs2CO3 (2.0 mmol), DMF (0.5 mL), Ar, 25 1C. Isolated
yield.
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Table 4 CuI-catalysed amination of aryl bromidesa
M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire, Chem. Rev.,
2002, 102, 1359; (c) S. V. Ley and A. W. Thomas, Angew. Chem.,
Int. Ed., 2003, 42, 5400; (d) K. Kunz, U. Scholz and D. Ganzer,
Synlett, 2003, 15, 2428; (e) I. P. Beletskaya and A. V. Cheprakov,
Coord. Chem. Rev., 2004, 248, 2337; (f) F. Monnier and M. Taillefer,
Angew. Chem., Int. Ed., 2008, 47, 3096; (g) G. Evano, N. Blanchard
and M. Toumi, Chem. Rev., 2008, 108, 3054.
2 For diamines as the ligands on Cu-catalysed C–N coupling, see:
(a) J. C. Antila, J. M. Baskin, T. E. Barder and S. L. Buchwald,
J. Org. Chem., 2004, 69, 5578; (b) A. Klapars, J. C. Antila,
X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2001, 123,
7727; (c) J. C. Antila, A. Klapars and S. L. Buchwald, J. Am. Chem.
Soc., 2002, 124, 11684; (d) A. Klapars, X. Huang and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 7421.
3 For diols as the ligands on Cu-catalysed C–N coupling, see:
(a) F. Y. Kwong, A. Klapars and S. L. Buchwald, Org. Lett.,
2002, 4, 581; (b) G. E. Job and S. L. Buchwald, Org. Lett., 2002, 4,
3703.
Yield
Time/h (%)b Product
Yield
Time/h (%)b
Product
14
8
85
95
12
17
93
87
9a
9ed
4 For amino acids and amino alcohols as the ligands on Cu-catalysed
C–N coupling, see: (a) D. Ma, Y. Zhang, J. Yao, S. Wu and F. Tao,
J. Am. Chem. Soc., 1998, 120, 12459; (b) Q. Cai, W. Zhu, H. Zhang,
Y. Zhang and D. Ma, Synthesis, 2005, 5, 496; (c) H. Zhang, Q. Cai
and D. Ma, J. Org. Chem., 2005, 70, 5164; (d) D. Ma, Q. Cai and
H. Zhang, Org. Lett., 2003, 5, 2453; (e) D. Ma and C. Xia, Org.
Lett., 2001, 3, 2583; (f) Z. Wang, W. Bao and Y. Jiang, Chem.
Commun., 2005, 2849; (g) Z. Lu and R. J. Twieg, Tetrahedron,
2005, 61, 903; (h) J. Kim and S. Chang, Chem. Commun., 2008,
3052.
5 For oxime phosphines as the ligands on Cu-catalysed C–N coupling,
see: (a) L. Xu, J. Mao, D. Zhu, F. Wu, R. Wang and B. Wan,
Tetrahedron, 2006, 61, 6553; (b) D. Zhu, L. Xu, F. Wu and B. Wan,
Tetrahedron Lett., 2006, 47, 5781.
6 For salicylaldoximes as the ligands on Cu-catalysed C–N coupling,
see: (a) H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer,
Chem.–Eur. J., 2004, 10, 5607; (b) H.-J. Cristau, P. P. Cellier,
J.-F. Spindler and M. Taillefer, Eur. J. Org. Chem., 2004, 695;
(c) Q. Jiang, D. Jiang, Y. Jiang, H. Fu and Y. Zhao, Synlett, 2007,
1836.
9f
9b
18
20
83
80
18
17
92
90
9cc
9g
9h
9dc
a
Reaction conditions: 7 (1.0 mmol), 8 (1.5 mmol), 10 mol% CuI,
b
20 mol% G, Cs2CO3 (2.0 mmol), DMF (0.5 mL), Ar, 65 1C. Isolated
yield. At 95 1C. Cs2CO3 (3.0 mmol).
c
d
with n-hexylamine only gave a yield of 8% at 90 1C. No
significant improvement was observed with longer reaction
time or higher temperature.
7 For b-diketones and b-keto ester as the ligands on Cu-catalysed
C–N coupling, see: (a) A. Shafir and S. L. Buchwald, J. Am. Chem.
Soc., 2006, 128, 8742; (b) B. d. Lange, M. H. Lambers-Verstappen,
L. S. d. Vondervoort, N. Sereinig, R. d. Rijk, A. H. M. d. Vries and
J. G. d. Vries, Synlett, 2006, 18, 3105; (c) A. Shafir, P. A. Lichtor
and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129, 3490; (d) X. lv
and W. Bao, J. Org. Chem., 2007, 72, 3863; (e) N. Xia and
M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 337.
In summary, based on the structural feature analysis of
previously reported ligands, 2-pyridinyl b-ketones were
designed as new ligands for copper-catalysed Ullmann
reaction. One compound, 1-(5,6,7,8-tetrahydroquinolin-8-yl)
ethanone (ligand G), was identified as highly efficient supporting
ligand for copper-catalysed C–N coupling reaction at room
temperature. CuI/G effectively promoted the coupling of
aliphatic amines with phenyl or heteroaryl halides with
excellent functional group compatibility and high selectivity
in the presence of multiple potentially reactive groups at room
or moderate temperature. Investigations on the potential
application of these ligands in other types of copper-catalysed
coupling reactions are underway and will be reported in due
course.
8 For other ligands on Cu-catalysed C–N coupling, see:
(a) R. Gujadhur, D. Venkataraman and J. T. Kintigh, Tetrahedron
Lett., 2001, 42, 4791; (b) F. Y. Kwong and S. L. Buchwald, Org.
Lett., 2003, 5, 793; (c) Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chen
and B. Wan, Tetrahedron, 2006, 62, 4435; (d) A. S. Gajare,
K. Toyota, M. Yoshifuji and F. Ozawa, Chem. Commun., 2004,
1994; (e) M. Yang and F. Liu, J. Org. Chem., 2007, 72, 8969;
(f) D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 2007, 72,
672; (g) H. Rao, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 2005,
70, 8017; (h) H. Rao, Y. Jin, H. Fu, Y. Jiang and Y. Zhao,
Chem.–Eur. J., 2006, 12, 3636; (i) X. Zhu, Y. Ma, L. Su, H. Song,
G. Chen, D. Liang and Y. Wan, Synthesis, 2006, 23, 3955;
(j) M. Taillefer, N. Xia and A. Ouali, Angew. Chem., Int. Ed.,
2007, 46, 934; (k) J. Mao, J. Guo, H. Song and S. Ji, Tetrahedron,
2008, 64, 1383; (l) H. Wang, Y. Li, F. Sun, Y. Feng, K. Jin and
X. Wang, J. Org. Chem., 2008, 73, 8639; (m) P. Suresh and
K. Pitchumani, J. Org. Chem., 2008, 73, 9121; (n) K. L. Jones,
A. Porzelle, A. Hall, M. D. Woodrow and N. C. O. Tomkinson,
Org. Lett., 2008, 10, 797; (o) R. Ntaganda, B. Dhudshia, C. L.
B. Macdonald and A. N. Thadani, Chem. Commun., 2008, 6200.
9 For example of pyridine based ligands for Ullmann type coupling,
See P. J. Fagan, E. Hauptman, R. Shapiro and A. Casalnuovo,
J. Am. Chem. Soc., 2000, 122, 5043.
We thank the CAS (# KSCX2-YW-R-27), National Natural
Science Foundation (# 20802077, 90813033) and National
High Technology Research and Development Program
(863 program, # 2007AA02Z490) for their financial support.
Notes and references
1 Recent reviews on copper catalysed C–N bond formation, see:
(a) J. Lidley, Tetrahedron, 1984, 40, 1433; (b) J. Hassan,
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1891–1893 | 1893