Homocoupling of heteroaryl/aryl/alkyl Grignard reagents: I2-promoted, or Ni- or Pd- or Cu- or nano-Fe-based salt catalyzed

Article abstract of DOI:10.1039/c6ra17859f

Five efficient processes for the homo-coupling of various Grignard reagents including aryl, heteroaryl and aliphatic ones in the presence of I₂, Pd(OAc)₂, Ni(OAc)₂, CuI, and nano-Fe₃O₄ were developed, respectively.

Full text of DOI:10.1039/c6ra17859f

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Homocoupling of heteroaryl/aryl/alkyl Grignard
reagents: I -promoted, or Ni- or Pd- or Cu- or
2
Cite this: RSC Adv., 2016, 6, 86998
nano-Fe-based salt catalyzed†
Received 13th July 2016
Accepted 7th September 2016
Xing Li,* Dongjun Li, Yingjun Li, Honghong Chang, Wenchao Gao and Wenlong Wei*
DOI: 10.1039/c6ra17859f
www.rsc.org/advances
Five efficient processes for the homo-coupling of various Grignard oxidative homo-coupling so far. Herein, we will report Pd(OAc)2-,
reagents including aryl, heteroaryl and aliphatic ones in the presence Ni(OAc) -, CuI-, and nano-Fe O -catalyzed, and I -promoted routes
2
3
4
2
of I
2
, Pd(OAc)
2
, Ni(OAc)
2
, CuI, and nano-Fe
3
O
4
were developed, to symmetrical biaryls from Grignard reagents.
First, when phenylmagnesium bromide was treated with
respectively.
ꢀ
0
.2 equiv. of I
obtained in 37% yield (Table 1, entry 1). The yield was improved
greatly by increasing the amount of I and the highest yield was
was used (Table 1, entry 4 vs. 2, 3
2
in toluene at 110 C, the desired product was
The symmetrical biaryl unit is found in a number of natural
products, pharmaceuticals, optical materials and functional
molecules. Oxidative homo-coupling reactions of Grignard
reagents have gained great attention as they provide an easy and
efficient access for the construction of such compounds. Several
kinds of transition metal promoters including cobalt salts, TlBr,
4
TiCl , vanadium salts, copper salts, etc. have been used in the
presence of a reoxidant to carry out the oxidative coupling process
in most cases. In these reactions, however, a stoichiometric or
excess amount of transition metal is used for smooth trans-
formation. Consequently, with the urgent demand for green
chemistry process and sustainable development, the exploration
of the suitable catalytic systems with efficient catalysts and inex-
pensive oxidants obviously becomes one of the most important
topics. On the other hand, some common and easily available
transition metal catalysts have been successfully used in the cross-
coupling reactions of Grignard reagents with organic electrophiles
and possessed the synthetic advantages such as high selectivity,
2
provided when 0.8 equiv. I
and 5).
2
1
With the promising results, the scope of Grignard reagents
was next investigated and the results are shown in Table 2. The
results indicated that a variety of Grignard reagents could also
be quickly transformed into the corresponding products in the
2
3
4
5
6
7
2
presence of I . Grignard reagents having electron-poor or -rich
8
groups on benzene ring underwent smoothly transformation to
give products in good to high yields (Table 2, entries 1–7). The
benzylmagnesium bromide could afford the corresponding
product in 54% yield, although a longer time and higher
temperature was required (Table 2, entry 8). Heteroaryl
Grignard reagents such as pyridylmagnesium bromide and
thienylmagnesium bromide were found be suitable substrates
Table 1 The optimization of the homocoupling of Grignard reagents
a
2
broad substrate scopes and mild reaction conditions in recent with I
years. In contrast, the catalyzed routes to symmetrical biaryls
9
from Grignard reagents about them have not received as much
attention although there have been several examples carried out
1
0
11
12
13
on manganese-, iron-, cobalt-, ruthenium- and copper-cata-
14
lyzed homo-coupling reactions. Therefore, we anticipate that
similar Pd- and Ni-catalyzed methods can also be realized under
certain conditions, and to the best of our knowledge, there have
b
Entry
I
2
(equiv.)
Yield (%)
1
2
3
4
5
0.2
0.4
0.6
0.8
0.9
37
65
80
96
92
2 3 4
been no reports on I -mediated, nano-Fe O - and CuI-catalyzed
Department of Chemistry and Chemical Engineering, Taiyuan University of
Technology, 79 West Yingze Street, Taiyuan 030024, People's Republic of China.
E-mail: lixing@tyut.edu.cn
a
2
Reaction conditions: phenylmagnesium bromide (0.3 mmol), I ,
ꢀ
b
toluene (1.5 mL), temperature (110 C), time (48 h). Isolated yield.
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c6ra17859f
1
86998 | RSC Adv., 2016, 6, 86998–87002
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
a
2
15
Table 2 The scope of the homocoupling of Grignard reagents with I
found that through the use of Pd(OAc)
,
a wide range of
2
Grignard reagents, including arylmagnesium bromide, hetero-
arylmagnesium bromide, and arylmagnesium chloride could be
effectively transformed in good to excellent yields in the pres-
16
ence of LiClO
zylmagnesium bromide also represented
substrate under the reux conditions (Table 3, entry 8).
To prove the generality of Ni(OAc) as a catalyst in the
4
(Table 3, entries 1–7 and 9–14). Finally, ben-
b
Entry
Grignard reagent
Product
t (h)
48
Yield (%)
a
compatible
1
2
96
83
2
homo-coupling of Grignard reagents, various substrates were
50
17
investigated. Optimized reaction conditions were next
3
4
48
48
88
92
Table 3 The scope of the homocoupling of Grignard reagents with
a
Pd(OAc)
2
5
6
7
48
50
50
86
84
91
b
Entry
Grignard reagent
Product
t (h)
15
Yield (%)
1
2
98
87
17
c
8
9
48
48
54
3
4
15
15
93
96
82
1
0
48
76
5
6
7
15
17
15
87
86
98
1
1
1
1
2
3
48
48
50
81
89
82
1
1
1
a
4
5
6
48
48
48
87
62
c
8
9
24
15
61
86
85
d
N.D.
10
15
Reaction conditions: Grignard reagent (0.3 mmol), I
2
(0.8 equiv.),
ꢀ
b
c
ꢀ
toluene (1.5 mL), temperature (110 C). Isolated yield. 140 C was
used. N.D. ¼ not detected.
d
1
1
1
1
2
3
15
15
16
88
92
86
to give the homo-coupled products in good yields (Table 2,
entries 9–11). Homo-couplings of arylmagnesium chloride also
proceeded well under similar conditions (Table 2, entries 12–
14). Excitedly, 1,4-diphenylbuta-1,3-diyne was provided in 62%
14
15
89
yield when (phenylethynyl)magnesium bromide was used as
a substrate (Table 2, entry 15). However, no product was
detected for styrylmagnesium bromide (Table 2, entry 16).
Subsequently, our studies focused on the Pd-catalyzed
homo-coupling of various types of Grignard reagents. It was
a
Reaction conditions: Grignard reagent (0.3 mmol), Pd(OAc)
2
(10
mol%), LiClO
4
(0.3 mmol, 1.0 equiv.), toluene (2.0 mL), temperature
ꢀ
b
c
ꢀ
(100 C). Isolated yield. 120 C was used.
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 86998–87002 | 86999

View Article Online
RSC Advances
Communication
applied to prepare a variety of homo-coupled products. For bromide with Ni(OAc)
2
as a catalyst provided somewhat lower
the aryl Grignard reagents having electron-poor or -rich yields than that with Pd(OAc) (Table 4, entries 9–11). Similar
2
groups on benzene ring (Table 4, entries 2–7), the coupling yields were obtained with arylmagnesium chloride (Table 4,
reactions provided high yields (85–97%). The steric entries 12–14).
hindrance also played an important role (Table 4, entries 4 vs.
To demonstrate the efficiency and scope of the method
1
8
2
and 7 vs. 6). The longer reaction time was required for the with CuI as a catalyst, we applied the catalytic system to
reaction with benzylmagnesium bromide, giving relatively a variety of Grignard reagents (Table 5). Various substrates
low yields (58%) (Table 4, entry 8). Heteroarylmagnesium including arylmagnesium bromide possessing methyl,
methoxy and uro groups, heteroarylmagnesium bromide,
and arylmagnesium chloride were smoothly converted to the
desired products in good to excellent yields (Table 5, entries
Table 4 The scope of the homocoupling of Grignard reagents with
a
Ni(OAc)
2
Table 5 The scope of the homocoupling of Grignard reagents with
a
CuI
b
Entry
Grignard reagent
Product
t (h)
18
Yield (%)
b
Entry
Grignard reagent
Product
t (h)
15
Yield (%)
c
1
2
95
1
2
95
95
20
90
93
97
18
3
4
18
18
3
4
15
15
95
96
5
6
7
17
20
18
90
85
92
5
6
7
15
18
18
95
86
98
8
9
24
18
58
82
c
8
9
24
15
57
88
82
1
0
18
77
10
15
1
1
1
1
2
3
18
18
18
81
83
86
1
1
1
1
2
3
15
15
16
87
89
79
1
4
18
90
1
4
16
84
a
Reaction conditions: Grignard reagent (0.3 mmol), Ni(OAc)
O (0.3 mmol, 1.0 equiv.), CH Cl (1.5 mL), temperature (25
C). Isolated yield. 13% yield was obtained in the absence of
Ni(OAc)
2
(10
mol%), Ag
2
2
2
ꢀ
b
c
a
Reaction conditions: Grignard reagent (0.3 mmol), CuI (15 mol%),
ꢀ
b
c
ꢀ
C
2
.
toluene (2.0 mL), temperature (100 C), air. Isolated yield. 120
was used.
87000 | RSC Adv., 2016, 6, 86998–87002
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
1
–7 and 9–14). Treatment of benzylmagnesium bromide also
To clarify the possible reaction mechanism I
homocoupling of iodobenzene with the I /toluene system, cross
2
2
-promoted, the
ꢀ
provided 57% yield at 120 C (Table 5, entry 8).
19
Nano Fe O was also found to be a good catalyst. Various coupling of iodobenzene with phenyl magnesium bromide in
3
4
Grignard reagents turned out to be suitable substrates and the presence of I , and phenyl magnesium bromide with
2
worked well (Table 6, entries 1–5 and 9–14) even though the PhI(OAc)
materials bearing electron-withdrawing groups (Table 6, entries experimental results showed that the reaction process may not
and 7). Benzylmagnesium bromide could afford the corre- involve the generation of an iodobenzene (eqn (1) and (2)). The
2
/toluene system were carried out (Scheme 1). The
6
sponding product in 50% yield (Table 6, entry 8).
fact that biphenyl was observed in 57% yield when PhI(OAc)
was used instead of I indicated that hypervalent iodine may
2
2
play an important role in this process, which suggested that
iodine serves not only as the promoter but also as the oxidant
(eqn (3)). On the basis of the observations and reported
Table 6 The scope of the homocoupling of Grignard reagents with
Fe O
3 4
a
20
literatures, a possible mechanism is postulated as follows
Scheme 2): partial iodine may be rst transformed into some
(
hypervalent iodine A in the reaction system. Then a low-valent
iodine species B is formed through reduction of A using the
Grignard reagent as a strong reducing agent. Subsequently, the
species B reacts with the Grignard reagent in the presence of I2
t
(h)
b
Entry
Grignard reagent
Product
Yield (%) as an oxidant to generate intermediate C, which gives the homo-
coupling product D by reductive elimination and releases A.
c
1
2
20
24
93
In conclusion, we have described the homo-coupling reac-
tions of various Grignard reagents in the presence of Pd(OAc)
Ni(OAC) , CuI, nano-Fe , and I , respectively. The ve
2
,
87
O
2
3
4
2
synthetic methods worked very well and were applicable to the
3
4
20
20
89
94
5
6
7
20
18
18
90
76
83
Scheme 1 Controlled experiments.
d
8
9
24
18
50
80
1
0
20
77
1
1
1
1
2
3
20
20
20
83
86
82
1
4
20
87
a
Reaction conditions: Grignard reagent (0.3 mmol), nano-sized Fe
3 4
O
(
10 mol%), AgNO
3
(0.36 mmol, 1.2c equiv.), toluene (2.0 mL),
ꢀ
b
temperature (100 C). Isolated yield. 9% yield was obtained in the
absence of Nano-Fe
d
ꢀ
O
4
.
120 C was used.
Scheme
2
A
proposed mechanism for the
2
I -promoted
3
homocoupling.
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 86998–87002 | 87001

View Article Online
RSC Advances
Communication
homo-coupling of various aryl and heteroaryl Grignard
reagents. Similar good yields were obtained regarding nano-
Fe O , and I . Pd-, Ni-, and Cu-based catalyst systems provided
higher yields than them. Notably, the rst two systems are more
green.
D. Flubacher and P. Knochel, J. Am. Chem. Soc., 2013, 135,
15346; (c) J. Terao and N. Kambe, Acc. Chem. Res., 2008, 41,
1545; (d) G. Cahiez, O. Gager and F. Lecomte, Org. Lett.,
2008, 10, 5255; (e) M. Nakamura, K. Matsuo, S. Ito and
E. Nakamura, J. Am. Chem. Soc., 2004, 126, 3686; (f)
J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu and
N. Kambe, J. Am. Chem. Soc., 2002, 124, 4222; (g)
T. Hatakeyama, S. Hashimoto, K. Ishizuka and
M. Nakamura, J. Am. Chem. Soc., 2009, 131, 11949; (h)
L. Ackermann, R. Born, J. H. Spatz and D. Meyer, Angew.
Chem., Int. Ed., 2005, 44, 7216.
3
4
2
Notes and references
1
(a) G. Bringmann, A. J. P. Mortimer, P. A. Keller,
M. J. Gresser, J. Garner and M. Breuning, Angew. Chem.,
Int. Ed., 2005, 44, 5384; (b) M. G. Organ, M. Abdel-Hadi,
S. Avola, N. Hadei, J. Nasielski, C. J. O'Brien and 10 (a) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111,
C. Valente, Chem.–Eur. J., 2006, 13, 150; (c) G. Bringmann,
T. Gulder, T. A. M. Gulder and M. Breuning, Chem. Rev.,
1780; (b) Z. Zhou and W. Xue, J. Organomet. Chem., 2009, 694,
599; (c) G. Cahiez, A. Moyeux, J. Buendia and C. Duplais, J.
Am. Chem. Soc., 2007, 129, 13788.
2011, 111, 563; (d) M. C. Kozlowski, B. J. Morgan and
E. C. Linton, Chem. Soc. Rev., 2009, 38, 3193; (e) J. Buter, 11 (a) T. Nagano and T. Hayashi, Org. Lett., 2005, 7, 491; (b)
D. Heijnen, C. Vila, V. Hornillos, E. Otten, M. Giannerini,
A. J. Minnaard and B. L. Feringa, Angew. Chem., Int. Ed.,
G. Cahiez, C. Chaboche, F. Mahuteau-Betzer and M. Ahr,
Org. Lett., 2005, 7, 1943; (c) W. Liu and A. Lei, Tetrahedron
Lett., 2008, 49, 610; (d) Y. Moglie, E. Mascar ´o , F. Nador,
C. Vitale and G. Radivoy, Synth. Commun., 2008, 38, 3861;
(e) J. Wu, W. Dai, J. H. Farnaby, N. Hazari, J. J. L. Roy,
V. Mereacre, M. Murugesu, A. K. Powellc and
M. K. Takasea, Dalton Trans., 2013, 42, 7404; (f) G. Kiefer,
L. Jeanbourquin and K. Severin, Angew. Chem., Int. Ed.,
2013, 52, 6302; (g) See ref. 10c.
2
016, 55, 3620.
(a) M. S. Kharasch and E. K. Fields, J. Am. Chem. Soc., 1941,
3, 2316; (b) H. Gilman and M. Lichtenwalter, J. Am. Chem.
2
3
6
Soc., 1939, 61, 957.
(a) A. McKillop, L. F. Elsom and E. C. Taylor, J. Am. Chem.
Soc., 1968, 90, 2423; (b) A. Mckillop, L. F. Elsom and
E. C. Taylor, Tetrahedron, 1970, 26, 4041.
4
5
A. Inoue, K. Kitagawa, H. Shinokubo and K. Oshima, 12 (a) See ref. 11f; (b) Z. Mo, Y. Li, H. K. Lee and L. Deng,
Tetrahedron, 2000, 56, 9601.
Organometallics, 2011, 30, 4687; (c) G. Cahiez and
(a) T. Ishikawa, A. Ogawa and T. Hirao, Organometallics,
A. Moyeux, Chem. Rev., 2010, 110, 1435.
1998, 17, 5713; (b) C. C. Vernon, J. Am. Chem. Soc., 1931, 13 P. I. Aparna and B. R. Bhat, J. Mol. Catal. A: Chem., 2012, 358,
53, 3831.
73.
6
(a) J. Krizewsky and E. E. Turner, J. Chem. Soc., Trans., 1919, 14 (a) See ref. 11f; (b) Y. Zhu, T. Xiong, W. Han and Y. Shi, Org.
15, 559; (b) J. I. Lee, J. Korean Chem. Soc., 2005, 49, 117; (c)
Lett., 2014, 16, 6144.
D. S. Surry, X. Su, D. J. Fox, V. Franckevicius, 15 Extensive screening showed that the optimized reaction
1
S. J. F. Macdonald and D. R. Spring, Angew. Chem., Int. Ed.,
005, 44, 1870.
(a) For CrCl : G. M. Bennett and E. E. Turner, J. Chem. Soc.,
Trans., 1914, 105, 1057; (b) For AgBr: J. H. Gardner and 16 LiClO served as an oxidant.
P. Borgstrom, J. Am. Chem. Soc., 1929, 51, 3375; (c) For 17 The optimal reaction conditions screened were 0.3 mmol
conditions were 0.3 mmol Grignard reagent, 10 mol%
2
Pd(OAc)2 and 1.0 equiv. of LiClO in toluene under N2
4
ꢀ
7
8
3
atmosphere at 100 C. (See Table 1 in ESI†).
4
some other metals see: ref. 2b.
For reactions on transition-metal-free
homocoupling using organic oxidants as mediators. See:
a) M. S. Maji and A. Studer, Synthesis, 2009, 2467; (b) 18 The optimized reaction conditions were 0.3 mmol Grignard
M. S. Maji, T. Pfeifer and A. Studer, Chem.–Eur. J., 2010, 16,
reagent and 15 mol% CuI in 2.0 mL toluene under air
872; (c) T. Nishiyama, T. Seshita, H. Shodai, K. Aoki,
H. Kameyama and K. Komura, Chem. Lett., 1996, 25, 549; 19 The optimal reaction conditions were 0.3 mmol Grignard
d) J.-W. Cheng and F.-T. Luo, Tetrahedron Lett., 1988, 29,
reagent, 10 mol% nano-Fe O and 1.2 equiv. of AgNO3
293; (e) A. Krasovskiy, A. Tishkov, V. Amo, H. Mayr and
P. Knochel, Angew. Chem., Int. Ed., 2006, 45, 5010; (f)
Grignard reagent, 10 mol% Ni(OAc)2 and 1.0 equiv. of
Ag O which was used as an oxidant in 1.5 mL CH Cl
2
oxidative
2
2
ꢀ
under N atmosphere at 25 C. (See Table 2 in ESI†).
2
(
ꢀ
atmosphere at 100 C. (See Table 3 in ESI†).
5
(
1
3
4
utilized as an oxidant in 2.0 mL toluene under N2
ꢀ
atmosphere at 100 C. (See Table 4 in ESI†).
T. Amaya, R. Suzuki and T. Hirao, Chem.–Eur. J., 2014, 20, 20 J. Mao, Q. Hua, G. Xie, Z. Yao and D. Shi, Eur. J. Org. Chem.,
53; (g) M. S. Maji, T. Pfeifer and A. Studer, Angew. Chem.,
2009, 2262.
6
Int. Ed., 2008, 47, 9547.
9
(a) T. Hatakeyama and M. Nakamura, J. Am. Chem. Soc., 2007,
129, 9844; (b) A. K. Steib, O. M. Kuzmina, S. Fernandez,
87002 | RSC Adv., 2016, 6, 86998–87002
This journal is © The Royal Society of Chemistry 2016