Cu-catalyzed arylation of phosphinic amide facilitated

by (�)-trans-cyclohexane-1,2-diamine

Juan Li, Song Lin Zhang, Chuan Zhou Tao,Yao Fu *, Qing Xiang Guo *

Department of Chemistry, University of Science and Technology of China, Hefei 230026, China

Received 18 April 2007

Abstract

Cu-catalyzed cross coupling between phosphinic amides and aryl halides was accomplished for the first time by using (�)-trans-

cyclohexane-1,2-diamine as the ligand. This reaction provided a novel approach for synthesizing arylated phosphinic amides. Both

kinetic measurement and theoretical calculation indicated that phosphinic amides were much less reactive than amides by about 10

times in Cu-catalyzed cross coupling.

# 2007 Yao Fu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Phosphinic amide; Copper; Catalyst; Cross coupling

Phosphinic amides are interesting compounds in a number of fields ranging from medicinal chemistry to catalyst

design. Early studies by Rewcastle et al. [1] and Sartorelli et al. [2] showed that phosphinic amide derivatives of

anilinoacridine and 1-methyl-1-(4-tolylsulfonyl)hydrazine were potential antitumor and antineoplastic agents,

respectively. More recently Sorensen et al. reported that cyclic phosphinic amides were potent matrix

metalloproteinase inhibitors with antitumour activity [3]. The synthesis of phosphinic amides mostly relies on the

amidation of phosphinic chloride. This reaction, however, may not proceed smoothly with aromatic amines because of

their low reactivity. For instance, Shi et al. showed in 2004 that the synthesis of the phosphinic amide of a

binaphthyldiamine required the use of BuLi to activate the nitrogen. Thus, it is necessary to develop new methods to

synthesize aromatic phosphinic amides under milder conditions.

Here we report a novel method for the preparation of aryl phosphinic amides that is catalyzed by copper.

Related Cu-catalyzed reactions have been studied recently by us [4] and by several others [5,6] in the synthesis

of aryl amides and sulfonamides. To begin our study we firstly screened many combinations of ligands, bases,

and solvents for the Cu(I)-catalyzed cross coupling between P,P-diphenylphosphinic amide and iodobenzene to

find the optimal reaction conditions (Table 1). It was found that using N-methylglycine as the ligand the

coupling yield could only reach 10% (entry 1), whereas several other commonly utilized ligands for Cu

including tetramethyl ethylenediamine, N,N-dimethylglycine, L-proline, 2,20-bipyridine, N,N-dimethyl-b-alanine,

N-methyl-L-proline, and N,N0-dimethyl ethylenediamine also provided very low yields ranging from 17% to

www.elsevier.com/locate/cclet

Chinese Chemical Letters 18 (2007) 1033–1036

* Corresponding authors.

E-mail addresses: fuyao@ustc.edu.cn (Y. Fu), qxguo@ustc.edu.cn (Q.X. Guo).

1001-8417/$ – see front matter # 2007 Yao Fu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2007.07.028

65% (entries 2–9). Only when (�)-trans-cyclohexane-1,2-diamine was employed as the ligand could the

yield increase to 70% (entry 10). By using DMF as the solvent and extending the reaction time to 48 h, we

eventually obtained the best yield as high as 84% (entry 13), which was sufficient from the synthetic point of

view.

Having optimized the reaction conditions, we next examined the scope of the reaction by testing a number of

different aryl iodides [7]. It was found that the reaction could be applied to various aryl iodides with a reasonable

isolated yield ranging from about 50% to 90% (Table 2). Both the electron-rich (such as 1-iodo-4-

methoxybenzene) and electron-poor (1-iodo-4-nitrobenzene) aryl iodides could be well tolerated in the cross

coupling. Furthermore, sterically hindered substrates including 1-iodo-2-methylbenzene and 1-iodo-2-

methyoxybenzene could also be smoothly converted to the desired products under our reaction conditions.

Noteworthy, the yields in Table 2 were mostly around 70%. Although this was sufficient for synthetic purposes,

it was interesting to notice that the yields for Cu-catalyzed cross coupling between aryl halides and amides

were mostly over 90% as previously reported [6]. The comparison between amides and phosphinic amides

indicated that amides should be more reactive than phosphinic amides. To confirm this statement, we measured

the reaction kinetics of Cu(I)-catalyzed coupling of iodobenzene with benzamide and diphenylphosphinic

amide [8].

Fig. 1 showed the results of the kinetic study. Evidently benzamide was much more reactive than

diphenylphosphinic amide because the former required about 30 min completing the reaction whereas the latter

needs over 400 min. Furthermore, we used B3LYP/6-311 + G(d,p) to calculate the energy barrier for the oxidative

addition of phenyl iodide to the Cu(I) complex with benzamide and diphenylphosphinic amide (Fig. 1b). It was found

that the barrier for benzamide was +26.4 kcal/mol, whereas the barrier for diphenylphosphinic amide was +27.8 kcal/

mol. This meant that benzamide was more reactive than diphenylphosphinic amide by about 10-fold. Thus, both the

experiment and theory confirmed that amides should be more reactive than phosphinic amides in Cu-catalyzed cross

coupling reactions.

To summarize, Cu-catalyzed cross coupling between phosphinic amides and aryl halides was accomplished

by using (�)-trans-cyclohexane-1,2-diamine as the ligand. This reaction provided a novel approach for

synthesizing arylated phosphinic amides. Both kinetic measurement and theoretical calculation indicated

that phosphinic amides were much less reactive than amides by about 10 times in Cu-catalyzed cross

coupling.

J. Li et al. / Chinese Chemical Letters 18 (2007) 1033–10361034

Table 1

Cu(I)-catalyzed cross coupling between P,P-diphenylphosphinic amide and iodobenzenea

Entry CuI (mol%) Ligand Solvent Temperature (8C) Time (h) Isolated

yield (%)

1 5 N-Methylglycine DMF 100 24 10

2 5 N,N-Dimethylglycine DMF 100 24 40

3 5 L-Proline DMF 100 24 36

4 5 2,20-Bipyridine DMF 100 24 17

5 5 N,N-Dimethyl-b-alanine DMF 100 24 27

6 5 N-Methyl-L-proline DMF 100 24 53

7 20 N-Methyl-L-proline DMF 100 24 62

8 20 Tetramethyl ethylenediamine DMF 130 24 36

9 20 N,N0-Dimethyl ethylenediamine DMF 130 24 65

10 20 (�)-Trans-cyclohexane-1,2-diamine DMF 130 24 70

11 20 (�)-Trans-cyclohexane-1,2-diamine Toluene 110 24 43

12 20 (�)-Trans-cyclohexane-1,2-diamine Dioxane 110 24 45

13 20 (�)-Trans-cyclohexane-1,2-diamine DMF 130 48 84

a Condition: iodobenzene (1.0 mmol), diphenylphosphinic amide (1.2 mmol), K3PO4 (2.5 mmol), ligand (20 mol%), solvent (2 mL), under Ar.

J. Li et al. / Chinese Chemical Letters 18 (2007) 1033–1036 1035

Table 2

Cu(I)-catalyzed coupling between P,P-diphenylphosphinic amide and various aryl iodidesa

Entry Aryl iodide Product characterization Isolated

yield (%)

1 1H NMR: d 7.92–7.86 (m, 4H), 7.55–7.45 (m, 6H), 7.13 (t, 2H, J = 7.8 Hz),

6.98 (d, 2H, J = 7.8 Hz), 6.89 (t, 1H, J = 7.2 Hz), 5.47 (br, 1H); 13C NMR:

118.7, 122.0, 128.9, 129.4, 131.3, 132.2, 133.0, 140.5

84

2 1H NMR: d 7.90–7.83 (m, 4H), 7.75 (d, 2H, J = 8.7 Hz), 7.55–7.44 (m, 6H),

7.02 (d, 2H, J = 8.7 Hz), 5.82 (br, 1H), 2.47 (s, 3H); 13C NMR: 26.3, 117.8,

126.8, 129.1, 130.3, 131.0, 132.0, 132.7, 145.5, 196.9

88

3 1H NMR: d 7.92–7.85 (m, 4H), 7.54–7.42 (m, 6H), 6.94 (d, 2H, J = 8.4 Hz),

6.88 (d, 2H, J = 8.4 Hz), 5.28 (br, 1H), 2.21 (s, 3H); 13C NMR: 20.7, 118.9,

128.7, 128.9, 129.8, 131.4, 132.2, 133.2, 137.9

69

4 1H NMR: d 8.04 (d, 2H, J = 8.7 Hz), 7.90–7.83 (m, 4H), 7.59–7.49 (m, 6H),

7.07 (d, 2H, J = 8.7 Hz), 6.01 (br, 1H); 13C NMR: 117.7, 125.3, 129.0,

130.9, 131.6, 132.5, 140.6, 149.3

58

5 1H NMR: d 7.91–7.86 (m, 4H), 7.83 (d, 2H, J = 8.7 Hz), 7.58–7.45 (m, 6H),

7.01 (d, 2H, J = 8.7 Hz), 5.67 (br, 1H), 4.30 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H,

J = 7.2 Hz); 13C NMR: 14.4, 60.7, 117.7, 123.6, 129.0, 130.3, 131.2, 132.0,

132.5, 145.4, 166.4

70

6 1H NMR: d 7.90–7.83 (m, 4H), 7.57–7.43 (m, 6H), 7.23 (d, 2H, J = 8.7 Hz),

6.88 (d, 2H, J = 8.7 Hz), 5.48 (br, 1H); 13C NMR: 112.3, 120.2, 128.8,

131.6, 131.7, 132.1, 133.3, 141.5

48

7 1H NMR: d 7.92–7.86 (m, 4H), 7.54–7.42 (m, 6H), 6.97 (d, 2H, J = 8.7 Hz),

6.69 (d, 2H, J = 8.7 Hz), 5.19 (br, 1H), 3.68 (s, 3H); 13C NMR: 55.6, 114.7,

120.9, 128.8, 131.4, 132.2, 133.1, 133.5, 155.2

69

8 1H NMR: d 7.92–7.85 (m, 4H), 7.55–7.43 (m, 6H), 7.20 (d, 1H, J = 7.8 Hz),

7.11 (d, 1H, J = 7.2 Hz), 6.94 (t, 1H, J = 7.3 Hz), 6.83 (t, 1H, J = 7.1 Hz),

5.04 (br, 1H), 2.27 (s, 3H); 13C NMR: 17.8, 119.2, 122.2, 125.9, 127.0,

128.8, 130.5, 131.9, 132.2, 133.1, 138.7

67

9 1H NMR: d 7.92–7.86 (m, 4H), 7.56–7.46 (m, 6H), 7.11 (d, 1H, J = 7.8 Hz),

6.85–6.83 (m, 2H), 6.70 (d, 1H, J = 5.7 Hz), 5.87 (br, 1H), 3.86 (s, 3H); 13C NMR:

55.6, 110.2, 117.6, 121.0, 121.5, 128.8, 131.4, 131.8, 132.1, 133.1, 148.0

68

a Conditions: aryl iodide (1.0 mmol), diphenylphosphinic amide (1.2 mmol), K3PO4 (2.5 mmol), CuI (20 mol%), (�)-trans-cyclohexane-1,2-

diamine (20 mol%), DMF (2 mL), 130 8C, 48 h, under Ar.

Fig. 1. (a) Reaction kinetics of Cu(I)-catalyzed coupling of iodobenzene with benzamide and diphenylphosphinic amide. (b) Structures of the

complexes between Cu(I) and benzamide and diphenylphosphinic amide.

Acknowledgment

This research was supported by the NNSFC (No. 20472079).

References

[1] G.W. Rewcastle, B.C. Baguley, B.F. Cain, J. Med. Chem. 25 (1982) 1231.

[2] R.T. Hrubiec, K. Shyam, L.A. Cosby, R. Furubayashi, A.C. Sartorelli, J. Med. Chem. 29 (1986) 1299.

[3] M.D. Sorensen, L.K.A. Blahr, M.K. Christensen, T. Hoyer, S. Latini, P.-J.V. Hjarnaa, F. Bjorkling, Bioorg. Med. Chem. 11 (2003) 5461.

[4] Our recent studies:

(a) W. Deng, Y.F. Wang, Y. Zou, L. Liu, Q.X. Guo, Tetrahedron Lett. 45 (2004) 2311;

(b) W. Deng, Y. Zou, Y.F. Wang, L. Liu, Q.X. Guo, Synlett (2004) 1254;

(c) X.H. Tan, C.Z. Tao, Y.Q. Hou, L. Luo, L. Liu, Q.X. Guo, Chin. J. Chem. 23 (2005) 237;

(d) W. Deng, L. Liu, C. Zhang, M. Liu, Q.X. Guo, Tetrahedron Lett. 46 (2005) 7295;

(e) Y.F. Wang, W. Deng, L. Liu, Q.X. Guo, Chin. Chem. Lett. 16 (2005) 1197;

(f) S.L. Zhang, L. Liu, Y. Fu, Q.X. Guo, Theochem 757 (2005) 37;

(g) Y.F. Wang, Y. Zhou, J.R. Wang, Q.X. Guo, Chin. Chem. Lett. 17 (2006) 1283;

(h) W. Deng, Y.F. Wang, L. Liu, Q.X. Guo, Chin. Chem. Lett. 17 (2006) 595;

(i) W. Deng, Y.F. Wang, C. Zhang, L. Liu, Q.X. Guo, Chin. Chem. Lett. 17 (2006) 313;

(j) Y.F. Wang, Y. Zhou, J.R. Wang, L. Liu, Q.X. Guo, Chin. Chem. Lett. 18 (2007) 499;

(k) C.Z. Tao, X. Cui, J. Li, A.X. Liu, L. Liu, Q.X. Guo, Tetrahedron Lett. 48 (2007) 3525.

[5] Examples:

(a) D. Jiang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 72 (2007) 672;

(b) B. Lu, D. Ma, Org. Lett. 8 (2006) 6115;

(c) Y.-X. Xie, S.-F. Pi, J. Wang, D.-L. Yin, J.-H. Li, J. Org. Chem. 71 (2006) 8324;

(d) Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chen, B. Wan, Tetrahedron 62 (2006) 4435.

[6] Review:

W. Deng, L Liu, Q.-X. Guo, Chin. J. Org. Chem. 24 (2004) 150.

[7] Typical experimental procedure for Cu-catalyzed arylation of phosphinic amide: A Schlenk tube was charged with CuI (20 mol%),

diphenylphosphinic amide (1.2 mmol), and K3PO4 (2.5 mmol), evacuated, and backfilled with Ar. (�)-Trans-cyclohexane-1,2-diamine

(20 mol%), aryl iodide (1.0 mmol), and DMF (2 mL) were added under Ar. The reaction mixture was stirred at 130 8C for 48 h. The resulting

suspension was cooled to room temperature and the solvent was removed. The residue was filtered through a pad of silica gel eluting with ethyl

acetate. The filtrate was concentrated and the residue was purified by chromatography to afford pure product.

[8] Conditions for kinetic measurement: A Schlenk tube was charged with CuI (20 mol%), diphenylphosphinic amide (2.4 mmol), biphenyl

(0.75 mmol) and K3PO4 (5.0 mmol), evacuated, and backfilled with Ar. (�)-trans-cyclohexane-1,2-diamine (20 mol%), aryl iodide (2.0 mmol),

and DMF (4 mL) were added under Ar. The reaction mixture was stirred at 130 8C. Aliquots of 20 mL were withdrawn at 5, 10, 20, 30, 40, 60,

100, 190, 370 and 460 min and diluted in methanol. The samples were injected into the HPLC system and analyzed on a Cosmosil 5C18-MS-II

(2.0 mm � 150 mm) column using previously added biphenyl as internal standard at ambient temperature. AWaters HPLC system consisting of

a pump (Waters 1525) and a photodiode-array detector (Waters 2996) was used. The flow rate was 0.2 mL/min and the detection wavelength was

254 nm. The mobile phase consisted of methanol and water in a ratio of 70:30 (v/v).

J. Li et al. / Chinese Chemical Letters 18 (2007) 1033–10361036