Gold complex-catalyzed CP bond formation by Kabachnik-Fields reactions

Article abstract of DOI:10.1016/j.catcom.2012.08.001

CP bond formation was realized through the three-component reaction of an amine, an aldehyde and a dialkylphosphite catalyzed by gold complex. The corresponding α-aminophosphonates were afforded in one-pot reaction with high yields under mild conditions.

Full text of DOI:10.1016/j.catcom.2012.08.001

Catalysis Communications 28 (2012) 134–137
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Gold complex-catalyzed C\P bond formation by Kabachnik–Fields reactions
Yan Zhang a,b, Chengjian Zhu a,
⁎
a
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
School of Medicine and Pharmaceuticals, Jiangnan University, Wuxi 214122, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2012
Received in revised form 1 August 2012
Accepted 1 August 2012
Available online 29 August 2012
C\P bond formation was realized through the three-component reaction of an amine, an aldehyde and a
dialkylphosphite catalyzed by gold complex. The corresponding α-aminophosphonates were afforded in
one-pot reaction with high yields under mild conditions.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Gold complex
Formation of C\P bonds
Kabachnik–Fields reactions
α-Aminophosphonate
Dialkylphosphite
1. Introduction
Gold catalysis has rapidly become a hot topic in chemistry in the past
decade [26]. Gold species are equally effective as heterogeneous or
Aminophosphonate is an important class of biologically active com-
pounds [1] and the synthesis has received a considerable amount of
interest because of their structural analogy to α-amino acids. α-Amino
phosphonic acids, as well as their phosphonate esters and short peptides
incorporating this unit, are excellent inhibitors of a wide range of pro-
teolytic enzymes [2]. They also act as antibiotics [3], herbicides [4], phar-
macological agents [5] and enzyme inhibitors [6]. There are two main
pathways for the synthesis of α-aminophosphonates: (a) Pudovik reac-
tion, where dialkylphosphites are added to imines using either a base
[7–9] or a Lewis acid such as AlCl3 [10], SnCl4 [11], BF3·OEt2 [12], ZnCl2
and MgBr2 [13]. These reactions cannot be carried out in a one-pot oper-
ation because the amines and water that exist during imine formation
can decompose or deactivate the Lewis acids [14]. (b) Kabachnik–Fields
three-component reaction in which an amine, an aldehyde and a di-
or tri-alkylphosphite react in a one-pot fashion by use of either Lewis
acids or Bronsted acids, such as Zn(OAc)2, Cd(ClO4)2, Bi(CF3SO3)3,
Mg(ClO4)2, HClO4–SiO2, and CeO2 [15–25]. Although these procedures
do not require the isolation of unstable imines prior to the reactions,
their application was limited due to harsh reaction conditions, air
sensitivities, and the use of stoichiometric and/or toxic, relatively expen-
sive reagents or catalysts. Since α-amino phosphate derivatives are in-
creasingly useful and important in many fields such as pharmaceutical
industry; the development of simple, eco-benign, low cost protocols is
still desirable.
homogeneous catalyst [27,28], which showed excellent results in diver-
sified reactions [29,30]. Gold complexes have been employed as a high-
ly efficient catalyst for the formation of C\C, C\O, C\N, C\S and C\F
bonds starting from alkenes and alkynes [31,32]. Phosphorous–carbon
formation has attracted growing attention because of its application in
organic synthesis and bioorganic chemistry. We recently reported the
formation of C\C, C\O and C\N bonds catalyzed by gold catalysts
under mild conditions [33,34]. Inspired by our previously reported
results, we were searching for a convenient, efficient, and general gold
complex/oxidant system to form C\P bond selectively. Fortunately, an
excellent gold–bipy system has been developed for the three component
reaction of aldehyde, amine and dialkylphosphite.
2. Experiment
2.1. General
All reactions were carried out in the open air. 1H NMR spectra
were recorded on a 300 MHz NMR spectrometer. Chemical shifts
were expressed in parts per million (ppm) either downfield from
tetramethylsilane or refer to the solvents signals. Abbreviations for
signal couplings are: s, singlet; d, doublet; t, triplet; and m, multiplet.
2.2. Preparation of catalysts
Gold complex 1 [AubpyCl2]Cl [35] was synthesized by reported
methods. Thus, dipyridine (312 mg, 2 mmol) in water (20 mL) was
added slowly to a stirred solution of sodium tetrachloroaurate (III)
⁎
Corresponding author. Tel.: +86 25 83594886; fax: +86 25 83317761.
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2012.08.001

Y. Zhang, C. Zhu / Catalysis Communications 28 (2012) 134–137
135
Table 1
hydrate (398 mg, 1 mmol) in 20 mL of water. After 3 h, the resulting
Optimization of reaction conditions including catalyst, temperature and solvent.a
solution was filtered through celite. The yellow precipitate was rinsed
with water (15 mL) and eluted with CH3CN. Concentration in vacuo
provided the desired gold (III) complex 1 as a yellow powder.
Gold complex 2 [AuPy2Cl2]Cl [36] and gold complex 3 PicAuCl2
[37] were prepared using the same procedure (Fig. 1).
2.3. Characterization of catalysts
Entry
Catalyst
(mol%)
Solvent
Temp
(°C)
Time
(h)
Yieldb
(%)
Commercially available reagents and solvents were used without
further purification. [AubpyCl2]Cl 1H NMR (300 MHz, CH3CN-d3) δ
9.45–9.44 (m, 2H), 8.66–8.60 (m, 4H), 8.09–8.06 (m, 2H). [AuPy2Cl2]
Cl 1H NMR (300 MHz, CH3CN-d3) δ 8.55–8.51(m, 4H), 7.84–7.76 (m,
2H), 7.42–7.36 (m, 4H). PicAuCl2 1H NMR (300 MHz, acetone-d6) δ
9.30–9.28 (m, 1H), 8.71–8.66 (m, 1H), 8.27–8.23 (m, 1H), 8.20–8.17
(m, 1H).
1
2
3
4
5
6
7
8
Yb(OTf)3
Sc(OTf)3
HAuCl4 (10)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
60
40
40
12
10
24
12
10
10
10
24
24
24
24
24
24
5
68
60
30
75
90
80
83
0
Bu4NAuCl4 (10)
[AubpyCl2]Cl (10)
[AuPy2Cl2]Cl (10)
PicAuCl2 (10)
AuClPPh3 (10)
none
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (10)
[AubpyCl2]Cl (5)
[AubpyCl2]Cl (1)
9
0
10
11
12
13
14
15
16
17
70
55
62
52
96
96
92
86
2.4. General procedure for the preparation of α-aminophosphonate cata-
lyzed by gold complex
THF
CH2Cl2
toluene
CH3CN
CH3CN
CH3CN
CH3CN
A 25 mL round-bottom flask equipped with magnetic stirrer, was
charged with aldehyde (1 mmol), amine (1.1 mmol), diethylphosphite
(1.5 mmol) and gold complex 1 (5 mol%). The resulting mixture was
continuously stirred at 40 °C. At the end of the reaction, which was
determined by TLC, the mixture was added into water and extracted
with ethyl acetate (3–10 mL). The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography. The fraction was collected and concentrated to give
the desired product.
5
5
5
a
Reaction conditions: benzaldehyde (1 mmol) was treated with aniline (1.1 mmol) and
diethyl phosphate (1.5 mmol) in the presence of the catalyst.
b
Isolated yields.
and 15). Further studies indicated that the catalyst loading of gold–bipy
complex can be reduced to as few as 5 mol% (entries 16–17). Conse-
quently, the following Kabachnik–Fields reactions were carried out
under the standard conditions: 5 mol% gold–bipy as the catalyst and
acetonitrile as the solvent at 40 °C. It is noteworthy that this reaction
could be run under air without loss of efficiency.
3. Results and discussions
3.1. Optimization of reaction conditions
In search for an effective catalyst and the best operative experimental
conditions, the three-component reaction of benzaldehyde, aniline, and
diethylphosphite was chosen as a model reaction. Various Lewis acids
were screened and the results are listed in Table 1. We found that the
desired α-aminophosphate could be obtained in excellent yield when
gold(III) complexes were used in CH3CN at room temperature; while
lower yield was obtained when Yb(OTf)3 or Sc(OTf)3 was employed as
the catalyst under the same reaction condition (entries 1–2). Among
the gold catalysts screened, gold–bipy complex (1) showed the best
catalytic activity. Although other gold complexes show moderate catalyt-
ic activity, the reactions need a relatively longer time to reach reasonable
yields (entries 3–7). The utilization of AuClPPh3 instead of a AuIII catalyst
results in the formation of only trace amount of product (entry 8). The
necessity to use the catalyst was realized by the observations that poor
yields were obtained when the reaction was carried out in the absence
of any catalyst (entry 9). The effect of solvents was also investigated.
Acetonitrile was found to be the most effective solvent, due to the good
solubility of gold complexes. On the other hand, the use of ethanol,
THF, CH2Cl2 and toluene required longer time to produce the comparable
yields (entries 10–13). In addition, the temperature was also investigated.
The optimal temperature was found to be 40 °C (compare entries 5 to 14
Table 2
Kabachnik–Fields reactions with different substrates catalyzed by gold catalyst.a
Entry
R
R′
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
C6H5
C6H5
C6H5
4-ClC6H4
2-Furaldehyde
CH3CH2
H
5
4
4
4
5
3
6
5
4
7
6
5
5
6
10
10
90
91
95
90
90
92
80
87
89
85
92
90
91
92
72
Trace
CH3
CH3O
H
CH3
CH3O
H
CH3
CH3O
H
H
OCH3
Cl
H
H
9
10
11
12
13
14
15
16
H
a
Reaction conditions: aldehyde (1 mmol) was treated with amine (1.1 mmol) and
diethyl phosphate (1.5 mmol) in the presence of 5 mol% gold catalyst at 40 °C.
b
Fig. 1. Gold catalysts 1, 2, and 3.
Isolated yields.

136
Y. Zhang, C. Zhu / Catalysis Communications 28 (2012) 134–137
in the construction of biologically important compounds. Cleaner con-
version, higher yields, avoidance of the tedious work-up as well as the
simplicity of operation are some of the advantages of the protocol. Re-
search is currently underway to apply the principle to other catalytic
systems.
Acknowledgment
We gratefully acknowledge the National Natural Science Foundation
of China (20832001, 20972065, and 21172106) and the National Basic
Research Program of China (2010CB92330) for their financial support.
Fig. 2. Reaction of imine and diethyl phosphite under the standard condition.
3.2. Investigation of the scope of the reaction
References
To demonstrate the generality of this method, we next investigated
the scope of this reaction under the optimized conditions and the results
are summarized in Table 2. As shown in Table 2, all reactions proceeded
smoothly to give the corresponding α-aminophosphates. Reactions of
various aromatic and heteroaromatic aldehydes containing electron do-
nating and electron withdrawing functional groups with various aromat-
ic amines all produced the desired product with good to excellent yields.
No desired products were isolated with aliphatic aldehydes. This may be
contributed to the slow formation and unstable nature of the imine
formed from the aliphatic aldehydes examined.
[1] A. Bogomilova, G. Haegele, K. Troev, E. Wagner, M. Guenther, Phosphorus Sulfur
Silicon and the Related Elements 187 (2012) 165.
[2] C.R. Reddy, C.R. Rani, G.C.S. Reddy, C.N. Raju, Pharmaceutical Letter 3 (2011) 134.
[3] A. Alcaine, E. Marques-Lopez, P. Merino, T. Tejero, R.P. Herrera, Organic and Bio-
molecular Chemistry 9 (2011) 2777.
[4] G.C.S. Reddy, S. Annar, K.U.M. Rao, A. Balakrishna, C.S. Reddy, Pharmacy and
Chemistry 2 (2010) 177.
[5] A. Arizpe, F.J. Sayago, A.I. Jimenez, M. Ordonez, C. Cativiela, European Journal of
Organic Chemistry 16 (2011) 3074.
[6] M. Sienczyk, J. Oleksyszyn, Current Medicinal Chemistry 16 (2009) 1673.
[7] A. Balakrishna, K.K. Chiruvella, M.V.N. Reddy, R. Reddy, S.K. Nayak, S.C. Raghavan,
C.S. Reddy, Letters in Drug Design & Discovery 7 (2010) 250.
[8] B. Lejczak, P. Kafarski, Topics in Heterocyclic Chemistry 20 (2009) 31.
[9] A. Klepacz, A. Zwierzak, Tetrahedron Letters 43 (2002) 1079.
[10] A. Manjula, V. Rao, P. Neelakanthan, Synthetic Communications 33 (2003) 2963.
[11] S. Laschat, H. Kunz, Synthesis (1992) 90.
3.3. Proposed mechanism
[12] I. Schlemminger, A. Willecke, W. Maison, R. Koch, A. Lutzen, J. Martens, Journal of
the Chemical Society, Perkin Transactions 1 (2001) 2804.
[13] J. Zon, Polish Journal of Chemistry 55 (1981) 643.
There have been two possible pathways reported for the formation of
α-aminophosphonate [38]. One pathway is through the imine formation
followed the nucleophilic attack by the phosphite [39]. Another is the
nucleophilic displacement of the hydroxyl group of the initially formed
α-hydroxyphosphonate [40]. In order to study the mechanism of the
gold catalyzed reaction, we carried out some separate reactions. Thus,
imine was synthesized from benzaldehyde and aniline as a light yellow
solid, and was treated with diethyl phosphate in the same condition
(Fig. 2). A similar yield was obtained compared to the three-component
reaction. Based on the above experiments, a plausible mechanism of the
reaction was proposed on the basis of formation of an activated imine,
which was followed by the nucleophilic attack of phosphate on imino car-
bon, subsequent shifting of hydrogen atom leads to the formation of
α-aminophosphates (Fig. 3).
[14] J.S. Yadav, B.V.S. Reddy, K. Sarita Raj, K. Bhaskar Reddy, Synthesis (2001) 2277.
[15] U.R.S. Arigala, C. Matcha, K.R. Yoon, Heteroatom Chemistry 23 (2012) 160.
[16] S.D. Dindulkar, M.V. Reddy, Y.T. Jeong, Catalysis Communications 17 (2012) 114.
[17] A. Banik, S. Batta, D. Bandyopadhyay, B.K. Banik, Molecules 15 (2010) 8205.
[18] K. Ando, T. Egami, Heteroatom Chemistry 22 (2011) 358.
[19] M.V. Reddy, S.D. Dindulkar, Y.T. Jeong, Tetrahedron Letters 52 (2011) 4764.
[20] M. Rostamizadeh, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-khorassani, S.S.
Sajadikhah, N. Maleki, Z. Shahkarami, Letters in Organic Chemistry 7 (2010) 542.
[21] S.M. Agawane, J.M. Nagarkar, Tetrahedron Letters 52 (2011) 3499.
[22] J.T. Hou, J.W. Gao, Z.H. Zhang, Applied Organometallic Chemistry 25 (2011) 47.
[23] K.P. Boroujeni, A.N. Shirazi, Heteroatom Chemistry 21 (2010) 418.
[24] B.V.S. Reddy, A.S. Krishna, A.V. Ganesh, G.G.K.S.N. Kumar, Tetrahedron Letters 52
(2011) 1359.
[25] J. Tang, L.M. Wang, W.B. Wang, L. Zhang, S.Y. Wu, D. Mao, Journal of Fluorine
Chemistry 132 (2011) 102.
[26] L.P. Liu, G.B. Hammond, Chemical Society Reviews 41 (2012) 3129.
[27] A.S.K. Hashmi, L. Schwarz, J.H. Choi, T.M. Frost, Angewandte Chemie International
Edition 39 (2000) 2285.
4. Conclusions
[28] A.S.K. Hashmi, G.J. Hutchings, Angewandte Chemie International Edition 45 (2006)
7896.
[29] W.B. Wang, G.B. Hammond, B. Xu, Journal of the American Chemical Society 134
(2012) 5697.
[30] L. Guczi, A. Beck, Z. Paszti, Catalysis Today 181 (2012) 26.
[31] A.S.K. Hashmi, A.M. Schuster, S. Litters, F. Rominger, M. Pernpointner, Chemistry
A European Journal 17 (2011) 5661.
In summary, we have demonstrated the novel C\P bond formation
through a three-component one-pot reaction catalyzed by gold catalyst
in good to excellent yields. The reaction proceeds with high efficiency to
give the corresponding amino phosphates which are extremely useful
Fig. 3. Mechanism of synthesis of α-amino phosphates catalyzed by gold.

Y. Zhang, C. Zhu / Catalysis Communications 28 (2012) 134–137
137
[32] M.N. Hopkinson, A.D. Gee, V. Gouverneur, Chemistry A European Journal 17 (2011)
[36] P. Bourosh, O. Bologa, Y. Simonov, N. Gerbeleu, J. Lipkowski, M. Gdaniec, Inorganica
Chimica Acta 360 (2007) 3250.
8248.
[33] J. Xie, H.M. Li, J.C. Zhou, Y.X. Cheng, C.J. Zhu, Angewandte Chemie 124 (2012) 1278.
[34] Y. Zhang, H. Peng, M. Zhang, Y.X. Cheng, C.J. Zhu, Chemical Communications
(2011) 2354.
[37] A.S.K. Hashmi, J.P. Weyrauch, M. Rudolph, E. Kurpejovic, Angewandte Chemie In-
ternational Edition 43 (2004) 6545.
[38] R. Gancarz, Tetrahedron 51 (1995) 10627.
[35] R. Hayoun, D.K. Zhong, A.L. Rheingold, L.H. Doerrer, Inorganic Chemistry 45
(2006) 6120.
[39] J.S. Yadav, B.V.S. Reddy, K.S. Raj, K.B. Reddy, A.R. Prasad, Synthesis (2001) 2277.
[40] B. Kaboudin, Tetrahedron Letters 44 (2003) 1051.