Palladium-catalyzed Mizoroki-Heck coupling reactions using sterically bulky phosphite ligand

Article abstract of DOI:10.1016/j.inoche.2010.07.028

A new catalytic system based on palladium-phosphite for Mizoroki-Heck coupling reactions of aryl iodide and bromide is described. An air-stable phosphite ligand afforded the desired products with high yields in the palladium-catalyzed Mizoroki-Heck reacti

Full text of DOI:10.1016/j.inoche.2010.07.028

Inorganic Chemistry Communications 13 (2010) 1329–1331
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Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Palladium-catalyzed Mizoroki–Heck coupling reactions using sterically bulky
phosphite ligand
Eunhye Jung a, Kyungho Park a, Jaewook Kim b, Hee-Tae Jung b, Il-Kwon Oh c, Sunwoo Lee a,
⁎
a
Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
b
c
School of Mechanical Systems Engineering, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new catalytic system based on palladium-phosphite for Mizoroki–Heck coupling reactions of aryl iodide
and bromide is described. An air-stable phosphite ligand afforded the desired products with high yields in
the palladium-catalyzed Mizoroki–Heck reactions. The coupling of aryl iodides was optimized with 0.5 mol%
Pd(OAc)2, 1 mol% phosphite 2, and K2CO3 in DMF solvent. For the coupling of aryl bromides, 1 mol% Pd
(OAc)2 and 5 mol% phosphite 2 were required with Na2CO3 as base. As a coupling partner alkene, n-butyl
acrylate, t-butyl acrylate, styrene and N-t-butyl acrylamide all showed good yields.
Received 17 May 2010
Accepted 20 July 2010
Available online 29 July 2010
Keywords:
Mizoroki–Heck reactions
Phosphite
© 2010 Elsevier B.V. All rights reserved.
Palladium
Aryl halides
Alkenes
Coupling reactions
Palladium-catalyzed carbon–carbon bond forming reactions have
received much attention in research into organic synthesis for
decades [1]. The most general reaction types are Kumada [2,3],
Nigishi [4,5], Suzuki–Miyaura [6,7], Stille-Migita [8,9], Hiyama [10],
Sonogashira [11,12] and Mizoroki–Heck reactions [13–15], using
organometallic reagents such as Mg, Zn, B, Sn, Si and Cu as the
coupling partner, except for the Mizoroki–Heck reaction, which is the
coupling reaction of aryl and alkenyl halides with alkene derivatives.
Since the first report by Mizoroki and Heck, numerous studies have
investigated the development of this type of reaction. Like other type
of palladium-catalyst coupling reactions, Mizoroki–Heck reaction's
activity is also highly dependent on the nature of the ligand, for
example, its electronic and steric effect [16]. Therefore, most studies
have focused on the development of suitable ligand systems. Recently,
sterically bulky monodentate phosphine [17,18] and N-heterocycle
carbene [19,20] have been developed and afforded high activity.
However, alkyl phosphine ligands are not stable toward oxygen and
moisture, and most of the N-heterocyclic carbene ligands required a
cumbersome synthetic step. To overcome these problems, we have
examined sterically bulky phosphite ligands as shown in Fig. 1.
Whereas phosphite compound 1 has been employed as a ligand in the
palladium- or nickel-catalyzed reactions, including Mizoroki–Heck
reaction [21,22], phosphite 2 has received less attention. Recently, we
reported the Hiyama reaction [23] and homocoupling of aryl halides
[24] using palladium-phosphite 2 catalytic system. In order to expand
the scope of palladium-catalyzed coupling reaction using phosphite 2,
we attempted to apply phosphite 2 as a ligand in the Mizoroki–Heck
reaction.
To investigate the reactivity of phosphite as ligand, we first
employed 4-iodotoluene and n-butyl acrylate as the standard
substrates. Their coupling reactions were carried out under a variety
of palladium sources, bases and solvents. The results are summarized
in Table 1. Among the tested bases, potassium carbonate was the most
effective base for the coupled product (entry 1), while other bases
such as Cs2CO3, Na2CO3 and K3PO4 gave acceptable yields of 97%, 94%
and 90%, respectively (entries 2–4). Replacement of inorganic bases
by organic base such as DBU afforded low product yield (entry 5). All
the tested palladium sources showed good reactivities independent of
their oxidative state (entries 6–8). Polar solvents gave the desired
product in moderate to good yields (entries 9 and 10); however, no
coupled product was formed in nonpolar solvents such as p-xylene
(entry 11). As the reaction temperature was decreased to 80 °C, 4-
iodotoluene was not completely converted (entry 12). Therefore, the
optimized condition for the Mizoroki–Heck reaction of aryl iodide
substrate is 0.5 mol% Pd(OAc)2, 1.0 mol% phosphite 2, 1.5 eq. K2CO3
and DMF at 120 °C for 3 h. This optimized condition was then applied
to the aryl bromide substrate such as 4-bromotoluene. However, the
product yield was very low yield even at a palladium-catalyst loading
of 2.5 mol% and a reaction temperature of 140 °C (entry 13). To
increase the product yield, we investigated the reaction condition for
the aryl bromide substrates and found that the base is the most
important factor in the Mizoroki–Heck reaction of 4-bromotoluene
⁎
Corresponding author. Tel.: +82 62 530 3385; fax: +82 62 530 3389.
E-mail address: sunwoo@chonnam.ac.kr (S. Lee).
1387-7003/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2010.07.028

1330
E. Jung et al. / Inorganic Chemistry Communications 13 (2010) 1329–1331
Fig. 1. Phosphite compounds.
and n-butyl acrylate. Among the tested bases, only Na2CO3 showed an
acceptable product yield (64%) (entry 15), whereas the other
inorganic bases, which showed good reactivity for aryl iodide,
afforded low yields. To improve the reaction yield, we varied the
content of palladium and ligand and maximized the coupled product
yield at 81% with 1 mol% palladium and 5 mol% phosphate (entry 18).
Despite the doubling of the mole ratio of the catalyst, the yield was not
improved (entry 17). As expected, when the reaction was carried out
without the phosphite ligand, the desired product was formed with
very low yield (entry 19).
On the basis of the optimized conditions, we next carried out the
Heck coupling reactions with a variety of aryl iodides and alkene
derivatives (Table 2) [25]. The coupling reactions of n-butyl acrylate
and aryl iodides showed good yields (entries 1–7). The electron neutral
aryl iodide afforded the desired product with 94% yield (entry 1). In the
case of iodoanisole derivatives, sterically hindered 2-iodoanisole
showed a slightly lower yield than 4-iodoanisole (entries 3 and 4).
Aryl iodides having an electron withdrawing substituent gave the
coupled product in good yields, and showed chemoselectivity to iodide
(entry 6). The iodonaphthalene required a longer reaction time than
the other substrates, and afforded the desired product with 98% yield in
12 h. The coupling reactions of 4-iodotoluene and other alkene
derivatives such as t-butyl acrylate, N-t-butylacrylamide and styrene
showed good yields (entries 8, 9 and 10).
Next, a variety of aryl bromides was employed as coupling partner
with n-butyl acrylate in the Heck reaction using the palladium-
phosphite 2 catalytic system. The results are summarized in Table 3
[26]. Electron neutral aryl bromide, bromobenzene, gave the desired
coupled product in 70% yield (entry 1). Aryl bromides containing an
electron donating group produced the corresponding coupled product
in moderate yields (entries 2–7). Among the bromoanisole derivatives,
2-bromoanisole exhibited the lowest yield (entry 3). However, the
heteroaromatic bromides 3-bromopyridine and 2-bromothiophene
afforded the desired coupled product in good yield of 87% and 70%,
Table 2
The Mizoroki–Heck reaction of aryl iodides and alkene derivativesa.
Table 1
The optimized reaction condition for palladium-catalyzed Mizoroki–Heck reaction.a
Entry
X
Pd
Pd/L
(mol%)
Base
Solvent
DMF
Temp Conv. Yield
(%)b
(%)b
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
I
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
0.5/1
0.5/1
0.5/1
0.5/1
0.5/1
0.5/1
K2CO3
Cs2CO3 DMF
Na2CO3 DMF
K3PO4
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
120
120
120
120
120
120
120
120
120
120
120
80
140
140
140
140
140
140
140
100
100
100
94
99
97
94
90
21
98
99
98
72
94
0
87
15
25
64
9
DMF
DMF
DMF
DMF
30
100
100
100
77
97
3
90
35
37
75
Pd(CH3CN)2Cl2 0.5/1
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0.5/1
0.5/1
0.5/1
0.5/1
0.5/1
2.5/5
2.5/5
2.5/5
2.5/5
DMF
9
DMAc
DMSO
p-xylene
DMF
10
11
12
13
14
15
16
17
18
19
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
DMF
Cs2CO3 DMF
Na2CO3 DMF
K3PO4
DMF
16
2/10 Na2CO3 DMF
1/5
1/0
100
100
11
68
81
5
Na2CO3 DMF
Na2CO3 DMF
aReaction condition: ArI (3.0 mmol), alkene (4.0 mmol), Pd(OAc)2 (0.015 mmol),
phosphite
2 (0.03 mmol), K2CO3 (4.5 mmol) and DMF (15.0 mL) were stirred at
120 °C for 6 h. bAll compounds were characterized by comparing the results of gas
chromatography (GC) analysis, 1H and 13C NMR spectra with authentic samples or
literature data. cIsolated yield. dReaction time was 12 h.
a
Reaction condition: 4-halotoluene (0.3 mmol), n-butyl acrylate (0.4 mmol), base
(0.45 mmol), catalytic amount of palladium and phosphite 2 were reacted.
b
Determined by GC with internal standard (naphthalene).

E. Jung et al. / Inorganic Chemistry Communications 13 (2010) 1329–1331
1331
Table 3
yield. N-Butyl acrylate, t-butyl acrylate, N-t-butyl acrylamide and
styrene were used as alkene derivatives, and all showed good
reactivities. To the best of our knowledge, phosphite 2 has never
been reported as a ligand in Heck Coupling Reactions. This catalytic
system can be used without resort to dry reagents or anaerobic
conditions. In addition, considering given the very low cost of
arylphosphites as ligands, this method has a promising potential as
a convenient route for functionalizing aryl alkene compounds.
The Mizoroki–Heck reaction of Aryl bromides and n-butyl acrylatea,b
.
Acknowledgements
This work was supported by the Korea Science and Engineering
Foundation (KOSEF) NRL Program grant funded by Korea government
(MEST) (No. R0A-2008-000-20012-0) and Fundamental R&D Pro-
gram for Core Technology of Materials of Korean Ministry of
Knowledge Economy.
References
[1] A. de Meijer, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions 2nd ed., Vol.
1 and 2, Wiely-VCH, Weinheim, Germany, 2004.
[2] K. Tamao, K. Sumitani, M. Kumada, J. Am, Chem. Soc. 94 (1972) 4374–4376.
[3] K. Tamao, J. Organomet, Chem 653 (2002) 23–26.
[4] S. Baba, E-i. Negishi, J. Am. Chem. Soc. 98 (1976) 6729–6731.
[5] E.-i Negishi, Bull. Chem. Soc. Jpn 80 (2007) 233–257.
[6] N. Miyaura, T. Yanagi, A. Suzuki, Tetrahedron Lett. 20 (1979) 3437–3440.
[7] N. Miyaura, J. Organomet. Chem. 653 (2002) 54–57.
[8] M. Kosugi, Y. Shimizu, T. Migita, Chem. Lett. 6 (1977) 1423–1424.
[9] D. Milstein, J.K. Stille, J. Am. Chem. Soc. 100 (1978) 3636–3638.
[10] Y. Hatanaka, T. Hiyama, J. Org. Chem. 53 (1988) 918–920.
[11] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 50 (1975) 4467–4470.
[12] K. Sonogashira, J. Organomet. Chem. 653 (2002) 46–49.
aReaction condition: ArBr (3.0 mmol), n-butyl acrylate (4.0 mmol), Pd(OAc)2
(0.03 mmol), phosphite 2 (0.15 mmol), Na2CO3 (4.5 mmol) and DMF (15.0 mL) were
stirred at 140 °C for 12 h. bAll compounds were characterized by comparing the results
of gas chromatography (GC) analysis, 1H and 13C NMR spectra with authentic samples
or literature data. cIsolated yield.
[13] T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn 44 (1971) 581–584.
[14] R.F. Heck, J.P. Nolley Jr., J. Org. Chem. 37 (1972) 2320–2322.
[15] A. Zapf, M. Beller, Chem. Commun. (2005) 431–440.
[16] J.P. Knowles, A. Whiting, Org. Biomol. Chem. 5 (2007) 31–44.
[17] K.H. Shaughnessy, P. Kim, J.F. Hartwig, J. Am. Chem. Soc. 121 (1999) 2123-2332.
[18] A. Ehrentraut, A. Zapf, M. Beller, Synlett (2000) 1589–1592.
[19] W.A. Herrmann, Angew. Chem. Int. Ed. 41 (2002) 1290–1309.
[20] S. Roland, P. Mangeney, a, Jutand, Synlett, 2006 3088–3094.
[21] J. Ju, M. Jeong, J. Moon, H.M. Jung, S. Lee, Org. Lett. 9 (2007) 4615–4618.
[22] M. Beller, A, Zapf, Synlett, 1998 792–793.
[23] J. Ju, H. Nam, H.M. Jung, S. Lee, Tetrahedron Lett. 47 (2006) 8673–8676.
[24] J. Moon, H. Nam, J. Ju, M. Jeong, S. Lee, Chem. Lett. 36 (2007) 1432–1433.
[25] Typical Experimental Procedure: Pd(OAc)2 (3.4 mg, 0.015 mmol), phosphite 2
(19.0 mg, 0.030 mmol), aryl iodide (3.0 mmol) and alkene (4.0 mmol) were
combined with K2CO3 (622 mg, 4.5 mmol) in DMF (10.0 mL). The resulting
mixture was placed in an oil bath at 120 °C for 6 h. The reaction was poured into
20 mL of saturated aqueous ammonium chloride and extracted with Et2O
(3×20 mL). The combined ether extracts were washed with brine (60 mL),
dried over MgSO4, and filtered. The solvent was removed under vacuum. The
crude product was purified by flash chromatography (15% ethyl acetate in
hexane).
[26] Typical Experimental Procedure: Pd(OAc)2 (3.4 mg, 0.015 mmol), phosphite 2
(19.0 mg, 0.030 mmol), aryl bromide (3.0 mmol) and alkene (4.0 mmol) were
combined with Na2CO3 (477 mg, 4.5 mmol) in DMF (10.0 mL). The resulting
mixture was placed in an oil bath at 140 °C for 8 h. The reaction was poured into
20 mL of saturated aqueous ammonium chloride and extracted with Et2O
(3×20 mL). The combined ether extracts were washed with brine (60 mL),
dried over MgSO4, and filtered. The solvent was removed under vacuum. The
crude product was purified by flash chromatography (15% ethyl acetate in
hexane).
respectively (entries 8 and 9). Activated aryl bromides, which have an
electron donating group, showed good yields (entries 10–12). This
catalytic system showed good chemoselectivity. In the case of 4-
bromochlorobenzene, the coupling reaction occurred only at the
bromide site. All naphthyl bromides showed excellent yields (entries
13 and 14).
Based on the previous report, we suggested that the larger π-
acceptor ability of the phosphite moiety increases the reaction rates,
and the sterically bulky group in phoshite might give the positive
effect in the reductive elimination step [27]. To investigate the
coordination manner of phosphite 2 in the Mizoroki–Heck coupling
reaction, NMR experiment was carried out. When Pd(OAc)2 and
phosphite 2 were treated with the molar ratio of 1 to 2 in the mixture
of DMF-d7 and CDCl3, only one peak was observed and no free
phosphorus peak in 31P NMR [28]. Which means that phosphite 2
might coordinate to the palladium, and stabilize the complex. The
exact coordination manner is not identified at this point. Further
studies of coordination manner are in progress in our laboratory.
In conclusion, we first employed sterically bulky phosphite 2 as a
ligand in the Heck coupling reactions and investigated its catalytic
activity with palladium in the coupling of aryl iodides or bromides
with alkene derivatives. The coupling of aryl iodides was optimized
with 0.5 mol% Pd(OAc)2 and 1 mol% phosphite 2 and most of the
inorganic bases showed good reactivities. However, 1 mol% Pd(OAc)2
and 5 mol% phosphite 2 were needed for the coupling of aryl
bromides, and only Na2CO3 afforded the desired product in high
[27] G.P.F. van Strijdonck, M.D.K. Boele, P.C.J. Kamer, J.G. de Vries, P.W.N.M. van
Leeuwen, Eur. J. Inorg. Chem. (1999) 1073–1076.
[28] 31P NMR (DMF-d7/CDCl3) phosphite 2: δ124.83; The complex of Pd(OAc)2 and
phosphite 2: δ−9.23.