N,N,N′,N′-tetra(diphenylphosphinomethyl)pyridine-2,6-diamine/palladium catalyzed Suzuki-Miyaura coupling of aryl and heteroaryl halides

Article abstract of DOI:10.1016/j.catcom.2015.03.028

An easily synthesized tetraphosphine N,N,N′,N′-tetra(diphenylphosphinomethyl)-pyridine-2,6-diamine (TPPDA) in combination with PdCl₂ was proved to be a highly efficient catalyst for Suzuki-Miyaura cross-coupling. This system could catalyze a variety of aryl halide substrates with a wide range of functional groups as well as heteroaryl halides. A high turnover number (TON) up to 3,350,000 was reached for 3-bromochlorobenzene.

Full text of DOI:10.1016/j.catcom.2015.03.028

Catalysis Communications 66 (2015) 87–90
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
N,N,N′,N′-tetra(diphenylphosphinomethyl)pyridine-2,6-diamine/
palladium catalyzed Suzuki–Miyaura coupling of aryl and
heteroaryl halides
⁎
Fei-chen Guo, Rong Zhou, Zhi-jie Jiang, Wei Wang, Hai-yan Fu, Xue-li Zheng, Hua Chen, Rui-xiang Li
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, Sichuan, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An easily synthesized tetraphosphine N,N,N′,N′-tetra(diphenylphosphinomethyl)-pyridine-2,6-diamine (TPPDA)
in combination with PdCl2 was proved to be a highly efficient catalyst for Suzuki–Miyaura cross-coupling. This
system could catalyze a variety of aryl halide substrates with a wide range of functional groups as well as
heteroaryl halides. A high turnover number (TON) up to 3,350,000 was reached for 3-bromochlorobenzene.
© 2015 Elsevier B.V. All rights reserved.
Received 17 February 2015
Received in revised form 17 March 2015
Accepted 19 March 2015
Available online 21 March 2015
Keywords:
Suzuki–Miyaura coupling
Palladium
Tetraphosphine
Aryl halide
1. Introduction
the coordination of the ligand to the metal and stabilize the active
species. An extremely high TON of 28,000,000 was obtained for
Being one of the most efficient techniques to synthesize biaryl com-
pounds, palladium-catalyzed Suzuki–Miyaura coupling is playing an in-
creasing role in the pharmaceutical and chemical industries [1–4]. Many
efficient catalytic systems were developed in the past decades [5–7].
The classic Pd/phosphine systems which are widely explored usually re-
quire relatively high catalyst loading (1–5 mol%). The difficult separa-
tion and recycling of palladium cause the high catalyst cost and make
modern homogeneous catalysts unattractive with respect to heteroge-
neous ones. However, if the reaction conditions allow the use of less
than 1000 ppm of metal (TON ≥ 1000), recycling is generally unneces-
sary and the cost of the product can be greatly reduced [8,9]. Hence
much attention is recently focused on decreasing palladium loading
with the purpose of making the reaction more practical and economical
[10–12].
The use of various multidentate phosphines is an efficient proto-
col to resolve the problem because the chelating effect of multiple
phosphorus atoms in multidentate phosphines can efficiently im-
prove the stability of the catalytic species and avoid the agglomera-
tion of the metal [13–16]. Consequently, the longevity of the catalyst
system is extended and the catalyst loading is lowered immensely.
Tedicyp, a cyclopentane alkyl backbone tetraphosphine, has four
diphenylphosphinoalkyl groups stereospecifically bound to the
same face of the cyclopentane ring, which may be the key to control
Suzuki reaction of 4-bromobenzophenone [17–20]. Similarly, a
ferrocenyl tetraphosphine Fc(P)t4Bu reported by J.-C. Hierso and co-
workers has a Pd complex that could catalyze the coupling of
the electron-rich substrate 4-bromoanisole in the presence of
0.001 mol% of catalyst and give the coupling products in a yield of
77% [21]. Especially, a cyclodextrin based tetraphosphine α-Cytep
has a Pd complex which displayed a spectacularly high TON of up
to 3.4 × 1011 for Suzuki reaction [22].
In spite of their high efficiency, the long synthetic routes to above-
mentioned ligands and their air-sensitivity limit their applications [17,
21,22]. Our group has recently reported the synthesis and applications
of two easily prepared tetraphosphine ligands TPPDA and N,N,N′,N′-
tetra(diphenylphosphinomethyl)-1,2-ethylenediamine (L) (Scheme 1)
[23,24]. L showed excellent properties in Heck, Suzuki and Sonogashira
reactions [23,25–27]. TPPDA showed even better catalytic performance
for Sonogashira reaction than L [24]. In this paper we further report the
efficiency of TPPDA for the Suzuki–Miyaura coupling of aryl and
heteroaryl halides.
2. Experimental
2.1. General procedure of Suzuki coupling reactions
K3PO4 (212 mg, 1 mmol), aryl halides (0.5 mmol) and phenylboronic
acid (0.75 mmol) were added successively into a dried Schlenk tube
with a magnetic bar under nitrogen. Then a N,N-dimethylacetamide
⁎
Corresponding author.
E-mail address: liruixiang@scu.edu.cn (R. Li).
http://dx.doi.org/10.1016/j.catcom.2015.03.028
1566-7367/© 2015 Elsevier B.V. All rights reserved.

88
F. Guo et al. / Catalysis Communications 66 (2015) 87–90
key role in improving the activity of Pd catalyst. A yield of only 33%
was obtained when L was used as ligand in the same conditions,
which proved the better catalytic performance of TPPDA-Pd system
than L-Pd system (Table 1, entry 11).
Subsequently, the effect of solvents and bases on the reaction was in-
vestigated (Table 2). With K3PO4 as the base, the reaction of 4-
trifluoromethyl-2-nitrochlorobenzene with phenylboronic acid was
performed in the presence of 0.1 mol% catalyst in different solvents, in-
cluding toluene, o-xylene, N,N-dimethylformamide (DMF), DMA and
dioxane. The best 98% yield of coupling product was given in o-xylene,
followed by a yield of 81% in toluene (Table 2, entries 1–2). However,
the reaction did not proceed smoothly in the other solvents (Table 2, en-
tries 3–5). The effect of various bases on the reaction was investigated in
o-xylene. Trace desired product was formed when strong base KOH,
NaOH or t-BuOK was used (Table 2, entries 8–9, 13). The highest con-
version was obtained in the presence of K3PO4 (Table 2, entry 2).
Thus, o-xylene and K3PO4 were adopted as solvent and base,
respectively.
With the optimum reaction conditions, the scope of the halide sub-
strates for Suzuki–Miyaura coupling was explored (Table 3). As shown
in Table 3, the established PdCl2/TPPDA catalytic system displayed
high activity in this cross-coupling reaction at 90 °C. A variety of aryl
bromides, regardless of their electron-rich or electron-poor characteris-
tics, could react with phenylboronic acid efficiently in the presence of
0.01 mol% PdCl2 (Table 3, entries 1–3, 6–21). Additionally, the system
was proved to be compatible with a wide range of functional groups,
such as –CF3, –CN, –NO2, –CHO, –COCH3, –F, –Cl, –OCH3, etc. 2-
Bromobenzonitrile and 2-bromonitrobenzene gave 4 and 5 in lower
yields of 26% and 14%, respectively, due to steric hindrance (Table 3,
entries 4–5). However, when the catalyst loading was increased to
0.1 mol%, good yields of 97% and 94% could be achieved, respectively.
Bromobenzene, 3-bromobenzotrifluoride, 4-bromobenzotrifluoride, 3-
bromobenzaldehyde and 4-bromobenzaldehyde were almost
completely converted into the desired products in the presence of
0.001 mol% of TPPDA–palladium complex (Table 3, entries 1–3, 8–9).
Even when the catalyst loading was decreased to 0.0001 mol%, a yield
of 65% could still be achieved for 4-bromobenzaldehyde after 96 h and
the TON reached up to 650,000 (Table 3, entry 9). The phenyldihalides
such as 4-bromofluorobenzene, 3-bromochlorobenzene and 4-
bromochlorobenzene also gave the target compounds in yields of 78%,
86% and 93%, respectively, with a S/C of 100,000 (Table 3, entries
12–14). It was worth noting that although there were two different
kinds of halogen atoms in each substrate, only one kind of coupling
product could be observed in each reaction. The lowest limitation of
Scheme 1. Structures of TPPDA and L.
(DMA 0.05 mL) solution of tetraphosphine TPPDA (0.0005 mmol) and
PdCl2 (0.0005 mmol), which was reacted at 100 °C for 1 h prior to use,
was added into the mixture. Afterwards, o-xylene (3 ml) was added
with syringe. After being stirred for the required time in the preset con-
ditions, the reaction mixture was cooled to room temperature. The mix-
ture solution was extracted with ethyl acetate (3 × 5 mL). Combined
organic phase was washed with brine (3 × 5 mL) and dried over anhy-
drous MgSO4. The dried solution was filtered and purified by silica gel
chromatography (petroleum ether 60–90 °C) to give a corresponding
product.
3. Results and discussion
To optimize conditions, the effect of various reaction parameters
(palladium precursor, solvent, base) on the coupling reaction of 4-
trifluoromethyl-2-nitrochlorobenzene with phenylboronic acid was ex-
plored at 120 °C. First of all, the catalytic performances of various palla-
dium precursors with ligand TPPDA were investigated (Table 1). It was
found that both Pd(COD)Cl2 and PdCl2 gave satisfying results which
were much better than those of the others (Table 1, entries 1–5).
When the molar ratio of substrate to catalyst (S/C) was increased to
5000, the advantage of PdCl2 over Pd(COD)Cl2 could be obviously seen
(Table 1, entries 6–7). The molar ratio of PdCl2 to tetraphosphine
TPPDA also had a great influence on the reaction. The ratio of 1/1 was
optimum and an 82% yield of desired product was obtained (Table 1,
entry 7). If the ratio was higher or lower than that, lower yields were
given (Table 1, entries 8–9) because too little ligand could not stabilize
the catalytic species efficiently and too much ligand made the active
sites occupied. A low yield of 5% was obtained in the absence of ligand
TPPDA (Table 1, entry 10). It is evident that ligand TPPDA played a
Table 1
Effect of palladium precursors on the Suzuki–Miyaura coupling reaction.a
Table 2
Effect of bases and solvents on the Suzuki–Miyaura coupling reaction.a
Entry
Pd source
S/C
Yield (%)
1
2
3
4
5
6
7
Pd2(dba)3
Pd(OAc)2
[Pd(η3-C3H5)Cl]2
Pd(COD)Cl2
PdCl2
Pd(COD)Cl2
PdCl2
PdCl2
1000
1000
1000
1000
1000
5000
5000
5000
5000
5000
5000
8
12
48
99
98
72
82
15b
17c
5d
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
Toluene
o-Xylene
DMF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Na2CO3
KOH
NaOH
NaHCO3
NaOAc
Et3N
81
98
3
7
9
84
57
8
45
24
50
18
3
DMA
Dioxane
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
8
9
10
11
PdCl2
PdCl2
PdCl2
33e
9
10
11
12
13
a
Reaction condition: 4-trifluoromethyl-2-nitrochlorobenzene 0.5 mmol, phenylboronic
acid 0.75 mmol, K3PO4 1.0 mmol, o-xylene 3 mL, catalyst [Pd]/TPPDA = 1/1, 120 °C, 1 h, un-
der nitrogen, GC yields.
t-BuOK
b
Catalyst PdCl2/TPPDA = 2/1.
Catalyst PdCl2/TPPDA = 2/3.
c
a
Reaction condition: 4-trifluoromethyl-2-nitrochlorobenzene 0.5 mmol, phenylboronic
acid 0.75 mmol, base 1.0 mmol, solvent 3 mL, PdCl2 5 × 10−4 mmol, ligand TPPDA 5 × 10−4
mmol, 120 °C, 1 h, under nitrogen, GC yields.
d
No ligand.
L as ligand.
e

F. Guo et al. / Catalysis Communications 66 (2015) 87–90
Table 3 (continued)
89
Table 3
PdCl2/TPPDA-catalyzed Suzuki–Miyaura coupling reaction of aryl halides.a
Entry
Substrate
S/C
Time (h)
Product
Yield (%)
1000
1000
10,000
1
1
72
24
98 (91)b,d
72
99d
Entry
1
Substrate
S/C
10,000
Time (h)
Product
Yield (%)
a
Reaction condition: aryl halides 0.5 mmol, phenylboronic acid 0.75 mmol, K3PO4 1.0
100 (97)b
92
mmol, o-xylene 3 mL, catalyst PdCl2/TPPDA = 1/1, 90 °C, under nitrogen, GC yields.
2
24
1
b
Isolated yields.
Toluene as solvent.
Temperature 120 °C.
100,000
c
2
3
4
5
10,000
100,000
2
24
2
3
4
5
100 (95)b,c
d
98c
10,000
100,000
2
24
100 (96)b,c
100c
the catalyst loading was further tested. The temperature was raised
to 120 °C in order to shorten the reaction time in the condition of high
S/C ratios. For 3-bromochlorobenzene, yields of 93% were achieved in
the presence of 0.0001 mol% catalyst after 96 h (Table 3, entry 13).
When the S/C was increased to 5,000,000, 55% conversion of 3-
bromochlorobenzene was obtained after 120 h. When the reaction
time was extended to 160 h, the conversion of 67% (TON of 3,350,000)
was achieved. These results indicated that the catalyst was not
deactivated during the long reaction period and the catalyst system
had a good longevity. This could be attributed to the good stabilizing ef-
fect of the tetraphosphine upon active palladium species. The results
also demonstrated that the use of multidentate ligands could be one
of the most effective ways to explore ultra-low catalyst loadings.
Turnover numbers of 64,000, 94,000 and 82,000 were achieved with
this catalyst for 2-bromoanisole, 3-bromoanisole and 4-bromoanisole,
respectively (Table 3, entries 15–17). The differences among these cou-
pling reactions might be on account of the effect of steric hindrance.
Similar trend could be observed in the reactions of 2-bromotoluene
and 4-bromotoluene (Table 3, entries 18–19). Moreover, a high TON
of 620,000 was obtained for 3-bromoanisole after 96 h at 120 °C
(Table 3, entry 16). The results proved the good catalytic activity for
the coupling of electron-rich substrates.
Subsequently, various aryl chlorides were examined in this catalytic
system. Aryl chlorides are usually cheaper but less active than aryl bro-
mides. Their reluctance to perform the oxidative addition to palladium
makes the coupling procedure difficult [28,29]. Thus the reaction temper-
ature was raised to 120 °C and the catalyst loading was increased to
0.1 mol% in order to improve the reactivity of aryl chlorides. 2-
Chlorobenzaldehyde, 4-chlorobenzotrifluoride and 4-chlorobenzonitrile
were transformed into products 22, 3 and 6 in moderate yields
of 41–56%,while 2-chloroacetophenone, 2-chloronitrobenzene and 4-
chloronitrobenzene afforded the corresponding coupling products in
relatively high isolated yields of 78%, 87% and 76%, respectively (Table 3,
entries 22–27). When the more electron-deficient 4-trifluoromethyl-2-
nitrochlorobenzene was employed, the product 24 was obtained in 72%
yield at a mild temperature of 90 °C after 1 h (Table 3, entry 28). When
the S/C was increased to 10,000, a yield of 99% was obtained in 72 h. A
yield of 29% was obtained for 4-chloronitrobenzene at 90 °C after 20 h
(Table 3, entry 27), while a yield of only 10% was given in the same con-
ditions in the presence of L [25]. Compared with ligand L, the molecular
backbone of TPPDA is more rigid. The more sufficient steric factor in
tetraphosphine TPPDA may accelerate the reductive elimination step.
This may be the key to the better results in the catalysis of aryl chlorides.
Furthermore, several heteroaryl bromides were also investigated
using this catalytic system (Table 4). When we used 2-bromofuran, 3-
bromofuran, 2-bromothiophene and 3-bromothiophene in the pres-
ence of 0.1 mol% catalyst nearly complete conversions were observed
after 24 h (Table 4, entries 1–4). Turnover numbers of 4950, 3800 and
1960 were achieved in this catalyst system for 2-bromofuran, 3-
bromofuran and 2-bromothiophene, respectively (Table 4, entries
1–3). We observed higher TON for the coupling with 3-bromopyridine
(9200) than with 2-bromopyridine (600) (Table 4, entries 5–6). This
was generally assumed to be an interaction between hetero atom and
palladium complex which decelerated the reaction rate [20].
1000
10,000
1
2
100 (97) b
26
1000
10,000
1
2
100 (94) b
14
6
7
10,000
2
6
7
100 (98)b
10,000
2
100 (97)b
8
9
10,000
100,000
2
24
8
9
100 (93)b
97
100 (96)b
100
10,000
100,000
1000,000
10,000
2
24
96
2
65
10
11
12
13
10
11
12
13
100 (95)b
10,000
2
100 (96)b
10,000
100,000
2
24
96 (90)b,c
78c
10,000
100,000
1000,000
5000,000
5000,000
10,000
2
24
96
120
160
2
100 (97)b
86
93d
55d
67d
14
15
14
15
100 (95)b
93
100,000
24
10,000
100,000
6
24
96 (89)b
64
16
17
10,000
100,000
1,000,000
10,000
6
24
96
6
16
17
100 (97)b
94
62d
100 (93)b
82
100,000
24
18
19
20
21
10,000
100,000
6
24
18
19
20
21
100 (92)b
48
100 (97)b
97
10,000
100,000
6
24
10,000
10,000
6
6
95 (90)b
88 (83)b
22
23
24
25
1,000
1000
1000
1000
72
72
72
72
22
3
60 (56)b,d
52 (45)b,d
45 (41)b,d
82 (78)b,d
6
23
26
27
1000
72
5
7
93 (87)b,d
1000
1000
72
20
81 (76)b,d
29

90
F. Guo et al. / Catalysis Communications 66 (2015) 87–90
Table 4
References
PdCl2/TPPDA-catalyzed Suzuki–Miyaura coupling reaction of heteroaryl bromides.a
[1] N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457–2483.
[2] R. Capdeville, E. Buchdunger, J. Zimmermann, A. Matter, Nat. Rev. Drug Discov. 1
(2002) 493–502.
[3] J. Magano, J.R. Dunetz, Chem. Rev. 111 (2011) 2177–2250.
[4] P. Lin, Chem. Rev. 98 (1998) 2405–2494.
[5] E.A.B. Kantchev, C.J. O'Brien, M.G. Organ, Angew. Chem. Int. Ed. 46 (2007)
2768–2813.
[6] H. Bonin, E. Fouquet, F.X. Felpin, Adv. Synth. Catal. 353 (2011) 3063–3084.
[7] A. Fihri, M. Bouhrara, B. Nekoueishahraki, J.M. Basset, V. Polshettiwar, Chem. Soc.
Rev. 40 (2011) 5181–5203.
[8] V. Farina, Adv. Synth. Catal. 346 (2004) 1553–1582.
[9] J.P. Corbet, G. Mignani, Chem. Rev. 106 (2006) 2651–2710.
[10] D.A. Albisson, R.B. Bedford, S.E. Lawrence, P.N. Scully, Chem. Commun. (1998)
2095–2096.
[11] A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. Int. Ed. 39 (2000) 4153–4155.
[12] D. Yuan, H.V. Huynh, Organometallics 29 (2010) 6020–6027.
[13] C. Bianchini, H.M. Lee, A. Meli, W. Oberhauser, F. Vizza, P. Brüggeller, H.B. Rainer, C.
Langes, Chem. Commun. 2000 (2000) 777–778.
[14] P. Nair, G.K. Anderson, N.P. Rath, Organometallics 22 (2003) 1494–1502.
[15] T. Imamoto, K. Yashio, K.V.L. Crépy, K. Katagiri, H. Takahashi, M. Kouchi, I.D. Gridnev,
Organometallics 25 (2006) 908–914.
[16] L.D. Field, B.A. Messerle, R.J. Smernik, T.W. Hambley, P. Turner, Inorg. Chem. 36
(1997) 2884–2892.
[17] D. Laurenti, M. Feuerstein, G. Pèpe, H. Doucet, M. Santelli, J. Org. Chem. 66 (2001)
1633–1637.
Entry
1
Substrate
S/C
1000
5000
1000
5000
1000
2000
1000
Time (h)
Product
Yield (%)
24
24
24
24
24
24
24
25
100 (93)b
99
2
3
26
27
100 (94)b
76
100 (92)b,c
98c
4
5
28
29
96 (90)b,c
1000
24
65 (60)b
6
5000
10,000
24
24
30
100 (97)b
92
a
Reaction condition: heteroaryl bromides 0.5 mmol, phenylboronic acid 0.75 mmol,
K3PO4 1.0 mmol, o-xylene 3 mL, catalyst PdCl2/TPPDA = 1/1, 90 °C, under nitrogen,
GC yields.
b
Isolated yields.
Toluene as solvent.
c
[18] M. Feuerstein, D. Laurenti, C. Bougeant, H. Doucet, M. Santelli, Chem. Commun. 2001
(2001) 325–326.
[19] M. Feuerstein, H. Doucet, M. Santelli, Synlett 9 (2001) 1458–1460.
[20] M. Feuerstein, H. Doucet, M. Santelli, Tetrahedron Lett. 42 (2001) 5659–5662.
[21] J.-C. Hierso, A. Fihri, R. Amardeil, P. Meunier, H. Doucet, M. Santelli, B. Donnadieu,
Organometallics 22 (2003) 4490–4499.
[22] E. Zaborova, J. Deschamp, S. Guieu, Y. Bleriot, G. Poli, M. Menand, D. Madec, G.
Prestat, M. Sollogoub, Chem. Commun. 47 (2011) 9206–9208.
[23] X.J. Yu, R. Zhou, Y. Zhang, H.Y. Fu, R.X. Li, H. Chen, X.J. Li, Catal. Commun. 12 (2010)
222–225.
[24] R. Zhou, W. Wang, Z.J. Jiang, H.Y. Fu, X.L. Zheng, C.C. Zhang, H. Chen, R.X. Li, Catal. Sci.
Technol. 4 (2014) 746–751.
4. Conclusion
In summary, PdCl2 associated with TPPDA is an efficient catalytic
system for Suzuki cross coupling reaction, which can be employed in
mild conditions for the coupling reaction of aryl and heteroaryl halides.
A wide range of substrates could be coupled with phenylboronic acid to
afford the desired products in good to excellent yields at low catalyst
loadings.
[25] K. Wang, T. Yi, X.J. Yu, X.L. Zheng, H.Y. Fu, H. Chen, R.X. Li, Appl. Organomet. Chem.
26 (2012) 342–346.
[26] K. Wang, Q. Fu, R. Zhou, X.L. Zheng, H.Y. Fu, H. Chen, R.X. Li, Appl. Organomet. Chem.
27 (2013) 232–238.
[27] T. Yi, M. Mo, H.Y. Fu, R.X. Li, H. Chen, X.J. Li, Catal. Lett. 142 (2012) 594–600.
[28] J.P. Heiskanen, O.E.O. Hormi, Tetrahedron 65 (2009) 518–524.
[29] S. Mohanty, D. Suresh, M.S. Balakrishna, J.T. Mague, Tetrahedron 64 (2008)
240–247.
Acknowledgments
This project was supported by the National Natural Science
Foundation of China (No. 21202104).