3-(Diphenylphosphino)propanoic acid: An efficient ligand for Cu-catalyzed N-arylations of indoles and aryl amines

Article abstract of DOI:10.14233/ajchem.2015.18258

3-(Diphenylphosphino)propanoic acid (L2) was found to be an efficient ligand for the copper-catalyzed N-arylations of indoles and arylamines with aryl iodides, the C-N coupling reactions catalyzed by CuCl/L2 were smoothly carried out in DMSO at 120 °C and give the corresponding products with the yields of 25-98 %.

Full text of DOI:10.14233/ajchem.2015.18258

Asian Journal of Chemistry; Vol. 27, No. 3 (2015), 1075-1078
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18258
3-(Diphenylphosphino)propanoic Acid: An Efficient Ligand
for Cu-Catalyzed N-Arylations of Indoles and Aryl Amines
*
Y.S. LIU, N.N GU, Y. LIU, X.W. MA, P. LIU and J.W. XIE
School of Chemistry and Chemical Engineering, The Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,
Shihezi University, Shihezi City, P.R. China
*
Corresponding author: Fax: +86 993 2057270; Tel: +86 993 2057213; E-mail: liuping1979112@aliyun.com
Received: 5 June 2014; Accepted: 11 September 2014; Published online: 19 January 2015;
AJC-16728
3-(Diphenylphosphino)propanoic acid (L2) was found to be an efficient ligand for the copper-catalyzed N-arylations of indoles and
arylamines with aryl iodides, the C-N coupling reactions catalyzed by CuCl/L2 were smoothly carried out in DMSO at 120 ºC and give
the corresponding products with the yields of 25-98 %.
Keywords: P, O ligands, N-arylation, Cu catalyzed, Indoles, Arylamines.
bring about steric properties to the phosphorus coordinating
INTRODUCTION
47-49
atom . So we assumed that they might be a class of efficient
ligands for the copper catalyzed C-N coupling reactions. Based
N-Arylheterocycles are prevalent in chemical pharma-
1
ceutical and materials industries . So the development of
practical methods to synthesize such compounds has attracted
considerable attention. Among them, transition metal-
catalyzed C-N coupling reactions have proved to be an efficient
50-52
on previous research works , herein we report our results
on CuCl-catalyzed N-arylation of indoles and arylamines by
using 3-(diphenylphosphino)propanoic acid (Fig. 1).
2
-8
strategy . In particular, the lower cost of copper-based cata-
lytic systems makes them suitable for large-scale industrial
applications and has challenged synthetic chemists to devise
milder synthetic methods. The design of new ligands structures
for copper-catalyzed cross-coupling protocols constitutes an
area of considerable interest. Recently, a series of novel mono-
and bidentate ligands for Cu-based C-N coupling were
EXPERIMENTAL
All the reactions were carried out under air using magnetic
1
stirring unless otherwise noted. H NMR spectral data were
recorded on a Bruker DPX-400 spectrometers using TMS as
an internal standard and CDCl as solvent. EI-Mass spectra
3
were measured on a LC/Q-TOF MS (Micromass, England).
All other reagents were of analytical grade quality purchased
commercially and used.
H NMR spectral data were recorded on a Bruker DPX-
400 spectrometers using TMS as internal standard and CDCl
9
-11
discovered, such as organic phosphanes ligands , N,N-
1
2-21
22-29
bidentate ligands , O,O-bidentate ligands , and N,O-
3
0-41
1
bidentate ligands . In spite of the significant progress made,
it is still necessary to search more efficient, air stable and low-
cost ligands or metal-complexes to facilitate these coupling
reactions under relatively milder conditions.
3
as solvent. Mass spectra were recorded on GC-MS (Agilent
7890A/5975C) instrument under EI model.
The bidentate derivatives containing phosphorus and
oxygen are well-known ligands for organic reactions catalyzed
by transition metals, such as the oligomerization and poly-
merization of ethylene , C-C coupling reactions , etc.
However, investigations on the copper catalyzed C-N coupling
reactions in the presence of phosphorus and oxygen chelating
ligands were less reported. As we known, the phosphorus and
oxygen chelating ligands can provide additional coordination
sites for the catalytic metal center and thus enhance its effi-
ciency, because they not only confer suitable electron, but also
General procedure: To a 5 mL of sealed tube was added
CuCl (0.04 mmol), 3-(diphenylphosphino)propanoic acid (L2)
(0.08 mmol), aryl iodide (0.5 mmol), 1H-indole (0.75 mmol),
NaOH (1 mmol) and DMSO (1 mL). The mixture was stirred
at 120 ºC for the certain time. After cooling to room tempe-
4
2
43-47
rature, the mixture was quenched with 10 mL H
with EtOAc (3 × 20 mL). The combined EtOAc extracts were
dried with anhydrous Na SO , filtrated and the solvent was
2
O and extracted
2
4
removed under reduced pressure and the residue was purified
by flash column chromatography on silica gel with PE/EtOAc

1
076 Liu et al.
Asian J. Chem.
7
.03 (m, 4H), 6.89 (m, 1H), 6.67 (s, 1H), 3.82 (s, 3H). GC/
MS: m/z 223.
Compound 5i: H NMR (400 MHz, CDCl
m, 3H), 7.66-7.57 (m, 5H), 7.50-7.46 (m, 2H), 7.41-7.36 (m,
H), 7.25 (s, 1H), 7.21-7.16 (m, 1H), 6.71 (m, 1H). GC/MS:
m/z 269.
Compound 5j: H NMR (400 MHz, CDCl
m, 2H), 7.10-7.06 (m, 2H), 7.04-6.98 (m, 4H), 6.91-6.85 (m,
1
P
P
3
): δ 7.75-7.69
(
2
COOH
2
CH CO OH
1
2
Fig. 1. Structures of ligands 1 and 2
1
3
): δ 7.26-7.21
(
as the eluent to afford the desired products. All N-arylation
products reported herein are known compounds and were
characterized by H NMR and GC-MS.
Compound 5b: H NMR (400 MHz, CDCl
m, 1H), 7.57-7.54 (m, 1H), 7.48 (dd, J = 5.6, 2.3 Hz, 4H),
.35-7.30 (m, 2H), 7.24-7.13 (m, 2H), 6.67 (dd, J = 3.3, 0.7
1
H), 2.30 (s, 3H). GC/MS: m/z 183.
1
1
Compound 5k: H NMR (400 MHz, CDCl
3
): δ 7.25-7.18
1
(m, 4H), 7.13 (t, J = 6.9 Hz, 1H), 6.96-6.89 (m, 4H), 2.25 (s,
3
): δ 7.70-7.66
3
H). GC/MS: m/z 183.
(
7
1
Compound 5l: H NMR (400 MHz, CDCl
3
): δ 7.29-7.27
(
m, 1H), 7.24 (td, J = 2.0, 1.1 Hz, 2H), 7.09-7.05 (m, 5H),
Hz, 1H). GC/MS: m/z 193.
1
6.94-6.90 (m, 2H). GC/MS: m/z 169.
Compound 5c: H NMR (400 MHz, CDCl
3
): δ 7.68 (ddd,
J = 7.6, 1.3, 0.8 Hz, 1H), 7.51-7.42 (m, 5H), 7.28 (d, J = 3.3
Hz, 1H), 7.23-7.15 (m, 2H), 6.68 (dd, J = 3.3, 0.8 Hz, 1H).
RESULTS AND DISCUSSION
GC/MS: m/z 229.
Ligands 1 and 2 were synthesized by the literature
methods . To optimize the reaction conditions, a series of
1
53,54
Compound 5d: H NMR (400 MHz, CDCl
3
): δ 7.69-7.66
(
m, 1H), 7.63-7.59 (m, 2H), 7.52-7.49 (m, 1H), 7.38-7.35 (m,
reactions between 4-iodotoluene (3a) and 1H-indole (4a) was
performed in the presence of base and solvent to evaluate the
roles of various ligands and copper sources for the N-arylation
process. As shown in Table-1, among the explored different
ligands and copper sources, L2 (3-(diphenylphosphino)prop-
anoic acid) exhibited the highest catalytic activity with 40 %
yield (Table-1, entries 1 and 2). Solvent is another important
factor of the catalysis, it was found that DMSO was much
better than DMF (Table-1, entry 5). Meanwhile, both toluene
and 1,4-dioxane were not suitable to work as reaction solvents
(Table-1, entries 3 and 4). The base screening results suggested
2
3
H), 7.27 (t, J = 3.2 Hz, 1H), 7.23-7.15 (m, 2H), 6.68 (dd, J =
.3, 0.9 Hz, 1H). GC/MS: m/z 271.
1
Compound 5f: H NMR (400 MHz, CDCl
J = 7.6, 1.4, 0.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.38-7.34 (m,
3
): δ 7.67 (ddd,
2
6
1
H), 7.24 (dd, J = 5.1, 2.2 Hz, 1H), 7.21-7.12 (m, 2H), 7.01-
.96 (m, 2H), 6.65-6.62 (m, 1H), 4.05 (q, J = 7.0 Hz, 2H),
.44 (dd, J = 8.2, 5.8 Hz, 3H). GC/MS: m/z 237.
1
Compound 5g: H NMR (400 MHz, CDCl
3
): δ 7.71-7.67
(
1
m, 1H), 7.37-7.30 (m, 4H), 7.17-7.14 (m, 3H), 7.05-7.02 (m,
H), 6.67 (dt, J = 2.4, 1.2 Hz, 1H), 2.06 (d, J = 2.1 Hz, 3H).
GC/MS: m/z 207.
Compound 5h: H NMR (400 MHz, CDCl
m, 2H), 7.43-7.37 (m, 1H), 7.33 (t, J = 2.6 Hz, 1H), 7.24-
that NaOH was the best, Na
2
CO
3
, K
3
PO
4
, Et N gave lower
3
1
3
): δ 7.69-7.58
yields (Table-1, entries 6-8). The comparison of different
copper sources indicated that CuCl was superior to other
(
TABLE-1
OPTIMIZATION OF THE REACTION CONDITIONS
a
I
[Cu]/Ligand
+
base, solvent
temp, time
N
N
H C
H
3
H C
3
3a
4a
5a
b
Entry
[Cu] (mol %)
CuCl/4
CuCl/4
CuCl/4
CuCl/4
CuCl/4
CuCl/4
CuCl/4
CuCl/4
Ligand (mol %)
Base
Solvent
DMSO
DMSO
1,4-Dioxane
Toluene
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yield (%)
29
40
10
Trace
20
21
1
2
3
4
5
6
7
8
9
1/8
2/8
2/8
2/8
2/8
2/8
2/8
2/8
2/8
2/8
2/8
2/16
2/16
2/16
NaOH
NaOH
NaOH
NaOH
NaOH
Na CO3
2
K PO4
18
10
31
28
32
67
82
90
3
Et N
3
Cu(OAc) /4
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
2
1
1
1
0
1
2
CuSO /4
4
Cu power/4
CuCl/8
CuCl/8
c
13
d
14
CuCl/8
a
c
b
Reaction conditions: 4-ioidotoluene (0.5 mmol), 1H-indole (1 mmol), base (1 mmol), and solvent (1 mL), reaction time 12 h; Isolated yields;
d
Temperature 120 ºC. Temperature 120 ºC, reaction time 24 h

Vol. 27, No. 3 (2015)
3-(Diphenylphosphino)propanoic Acid: An Efficient Ligand for Cu-Catalyzed N-Arylations 1077
TABLE-2
a
N-ARYLATION OF INDOLES AND ARYL AMINES CATALYZED BY CuCl/L2
I
N-Het
CuCl/Ligand 2
R
+
Het-NH
R
DMSO, NaOH
1
00°C
3
4
5
b
Entry
R (3)
H (3b)
4-Cl (3c)
4-Br (3d)
4-CN (3e)
4-OEt (3f)
Het-NH
Product
Yield (%)
98
85
66
Trace
90
25
1
2
3
4
5
6
7
8
9
1H-indole (4a)
5b
5c
5d
5e
5f
5g
5h
5i
4a
4a
4a
4a
4a
4a
4a
2-CH (3g)
3
3-OMe (3h)
4-C H (3i)
69
96
38
6
5
3a
Aniline (4c)
5j
1
1
0
1
2-CH (3g)
4c
4c
5k
5l
58
50
3
3b
a
Reaction conditions: aryl halides (0.5 mmol), Het-NH (1 mmol), CuCl (8 mol %), Ligand 2 (16 mol %), NaOH (1 mmol), DMSO (1 mL), 120 °C,
reaction time 24 h; Isolated yields
b
sources, including Cu(OAc)
2
, CuSO
4
and Cu power (Table-1,
system is efficient for the coupling of indoles and aryl amines
with aryl iodides to give moderate to excellent yields. The
easily availability of the catalyst, mild reaction conditions,
experimental simplicity and broad substrate scope are the
features of the catalytic method presented in the current paper.
The application scope expansion of the catalytic system is
currently studied in our laboratory.
entries 9-11). The amount of Cu resource/ligand was another
important factor of the reaction. When the amount of CuCl/
L2 was increased from 4 mol %/8 mol % to 8 mol %/16 mol %,
the isolated yield of the product (5a) was increased to 67 %
(
1
Table-1, entry 12). Increasing the reaction temperature from
00 to 120 °C and prolonging reaction time from 12 to 24 h
improved the yield from 82 to 90 % (Table-1, entries 13 and
4). So the combination of CuCl (8 mol %)/L2 (16 mol %),
ACKNOWLEDGEMENTS
1
NaOH (2 equiv.) at 120 °C for 24 h in DMSO was chosen as
the optimal conditions for N-arylation of 1H-indoles with
The authors gratefully acknowledge the financial support
of this work by the National Basic Research Program of China
4
-iodotoluene.
(
2
973 Program: 2012CB722603), the NSFC (Nos. 21103114,
1463022); Shihezi University Training Programme for
The role of the CuCl/L2 system for general N-arylation
of indoles with various aryl halides was further evaluated and
summarized in Table-2. Iodobenzene as a substrate reacted
with 1H-indole and 98 % yield was obtained (Table-2, entry
DistinguishedYouth Scholars (No. 2014ZRKXJQ05) and the
Doctor Foundation of Xinjiang Bingtuan (No. 2012BB010).
1
). The electron-poor aryl bromides, such as 1-chloro-4-iodo-
REFERENCES
benzene and 1-bromo-4-iodobenzene led to the N-arylated
products in 85 and 66 % yields, respectively (Table-2, entries
1
.
N.R. Candeias, L.C. Branco, P.M. P. Gois, C.A.M. Afonso and A.F.
Trindade, Chem. Rev., 109, 2703 (2009).
2
and 3). However, N-arylation product was not observed under
2. J.F. Hartwig, in ed:A. Ricci, ModernAmination Methods, Wiley-VCH,
Weinheim, p. 195 (2000).
the experimental condition, when 4-iodobenzonitrile was used
as the substrate (Table-2, entry 4). The electron-rich aryl
bromide, such as 1-ethoxy-4-iodobenzene, gave 90 % yield at
the same condition (Table-2, entry 5). Notably, sterically
demanding ortho substituents, such as 1-iodo-2-methyl-
benzene, did not hamper the N-arylation reaction (25 %,
Table-2, entry 6). Both 1-iodo-3-methoxybenzene and 4-
iodobiphenyl reacted with the 1H-indole and the corresponding
products with moderate to excellent yields were obtained
3
4
5
.
.
.
J.P. Wolfe and S.L. Buchwald, J. Am. Chem. Soc., 119, 6054 (1997).
C. Desmarets, R. Schneider andY. Fort, J. Org. Chem., 67, 3029 (2002).
S. Tasler and B.H. Lipshutz, J. Org. Chem., 68, 1190 (2003).
6. F. Monnier and M. Taillefer, Angew. Chem. Int. Ed., 48, 6954 (2009).
7
8
9
.
.
.
M.G. Boswell, F.G. Yeung and C. Wolf, Synlett, 1240 (2012).
Y.-C. Teo, F.-F.Yong and G.S. Lim, Tetrahedron Lett., 52, 7171 (2011).
R.K. Gujadhur, D. Venkataraman and J.T. Kintigh, Tetrahedron Lett.,
4
2, 4791 (2001).
10. R.K. Gujadhur, C.G. Bates and D. Venkataraman, Org. Lett., 3, 4315
2001).
(
1
1
1. M. Yang and F. Liu, J. Org. Chem., 72, 8969 (2007).
2. A. Kiyomori, J.-F. Marcoux and S.L. Buchwald, Tetrahedron Lett., 40,
(
Table-2, entries 7 and 8). In addition, the reactions of aryl
iodides such as 1-iodo-4-methylbenzene, 1-iodo-2-methyl-
benzene and iodobenzene with aniline were also successful
and provided the desired products in moderate yields (Table-2,
entries 9-11).
2
657 (1999).
13. L. Liu, M. Frohn, N. Xi, C. Dominguez, R. Hungate and P.J. Reider, J.
Org. Chem., 70, 10135 (2005).
1
4. A.A. Kelkar, N.M. Patil and R.V. Chaudhari, Tetrahedron Lett., 43,
143 (2002).
15. Y.-H. Liu, C. Chen and L.-M.Yang, Tetrahedron Lett., 47, 9275 (2006).
6. J.C. Antilla,A. Klapars and S.L. Buchwald, J. Am. Chem. Soc., 124, 11684
2002).
17. A. Klapars, X. Huang and S.L. Buchwald, J. Am. Chem. Soc., 124, 7421
2002).
7
Conclusion
1
In summary, we have developed a novel and general
catalytic method for N-arylations of indoles and aryl amines
promoted by CuCl/3-(diphenylphosphino)propanoic acid. The
(
(

1
078 Liu et al.
Asian J. Chem.
1
1
2
2
8. B. Mallesham, B.M. Rajesh, P.R. Reddy, D. Srinivas and S. Trehan,
Org. Lett., 5, 963 (2003).
9. P.-S. Wang, C.-K. Liang and M.-K. Leung, Tetrahedron, 61, 2931
36. Q. Cai, W. Zhu, H. Zhang, Y. Zhang and D. Ma, Synthesis, 496 (2005).
37. H. Zhang, Q. Cai and D. Ma, J. Org. Chem., 70, 5164 (2005).
38. X. Lv, Z. Wang and W. Bao, Tetrahedron, 62, 4756 (2006).
39. Z. Lu, R.J. Twieg and S.D. Huang, Tetrahedron Lett., 44, 6289 (2003).
40. Z. Lu and R. Twieg, Tetrahedron Lett., 46, 2997 (2005).
41. H. Rao, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 70, 8107 (2005).
42. W. Keim, Chem. Ing. Techn., 56, 850 (1984).
(
2005).
0. E. Alcalde, I. Dinares, S. Rodriguez and C. Garcia de Miguel, Eur. J.
Org. Chem., 1637 (2005).
1. P.E. Maligres, S.W. Krska and P.G. Dormer, J. Org. Chem., 77, 7646
(
2012).
43. X. Du, X.J. Feng, Y. Liu, R. He and M. Bao, Chin. Chem. Lett., 21, 641
(2010).
44. L. Zhou, Q. Miao, R. He, X.J. Feng and M. Bao, Tetrahedron Lett., 48,
7899 (2007).
45. M.P. Guo, F.F. Jian and R. He, J. Fluor. Chem., 127, 177 (2006).
46. M.P. Guo, F.F. Jian and R. He, Tetrahedron Lett., 46, 9017 (2005).
47. E. Ullah, J. McNulty and A. Robertson, Tetrahedron Lett., 50, 5599
(2009).
48. A. Bader and E. Lindner, Coord. Chem. Rev., 108, 27 (1991).
49. G.J.P. Britovsek, W. Keim, S. Mecking, D. Sainz and T. Wagner, J.
Chem. Soc. Chem. Commun., 1632 (1993).
2
2
2
2
2
2
2
2. F.Y. Kwong, A. Klapars and S.L. Buchwald, Org. Lett., 4, 581 (2002).
3. Y.-J. Chen and H.-H. Chen, Org. Lett., 8, 5609 (2006).
4. D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 72, 672 (2007).
5. F.Y. Kwong and S.L. Buchwald, Org. Lett., 5, 793 (2003).
6. A. Shafir and S.L. Buchwald, J. Am. Chem. Soc., 128, 8742 (2006).
7. Z. Xi, F. Liu, Y. Zhou and W. Chen, Tetrahedron, 64, 4254 (2008).
8. X.H. Zhu, L. Su, L.Y. Huang, G. Chen, J.L. Wang, H.C. Song andY.Q.
Wan, Eur. J. Org. Chem., 635 (2009).
2
3
9. X. Lv and W. Bao, J. Org. Chem., 72, 3863 (2007).
0. H.-J. Cristau, P.P. Cellier, J.-F. Spindler and M. Taillefer, Chem. Eur. J.,
1
0, 5607 (2004).
50. Y. Liu, W. Liu, Q. Zhang, P. Liu, J.-W. Xie and B. Dai, J. Chem. Res.,
37, 636 (2013).
51. Y. Liu, Q. Zhang, X.-W. Ma, P. Liu, J.-W. Xie, B. Dai and Z.-Y. Liu,
Int. J. Org. Chem., 3, 185 (2013).
52. Y.-S. Liu, Y. Liu, X.-W. Ma, P. Liu, J.-W. Xie and B. Dai, Chin. Chem.
Lett., 25, 775 (2014).
3
3
3
1. Z.Q. Wu, Z.Q. Jiang, D. Wu, H.F. Xiang and X.G. Zhou, Eur. J. Org.
Chem., 2010, 1854 (2010).
2. Z.Q. Wu, L. Zhou, Z.Q. Jiang, D. Wu, Z.K. Li and X.G. Zhou, Eur. J.
Org. Chem., 2010, 4971 (2010).
3. Y. Wang, Z. Wu, L.X. Wang, Z.K. Li and X.G. Zhou, Chem. Eur. J., 15,
8
971 (2009).
53. K. Issleib and G. Thomas, Z. Anorg. Allg. Chem., 330, 295 (1964).
54. K. Issleib and G. Thomas, Chem. Ber., 93, 803 (1960).
3
3
4. D. Ma, Q. Cai and H. Zhang, Org. Lett., 5, 2453 (2003).
5. D. Ma and Q. Cai, Synlett, 128 (2004).