Improved procedure for single-electron-transfer-induced grignard cross-coupling reaction

Article abstract of DOI:10.1246/cl.140155

Aryl Grignard reagents were found to undergo coupling with aryl or alkenyl bromides in the presence of LiCl in a mixed solvent consisting of toluene and THF (2/1). Previously employed removal of THF with evacuation from Grignard solutions is no longer needed to obtain biaryls and styrene derivatives.

Full text of DOI:10.1246/cl.140155

CL-140155
Received: February 25, 2014 | Accepted: March 19, 2014 | Web Released: March 26, 2014
Improved Procedure for Single-electron-transfer-induced Grignard Cross-coupling Reaction
1
1
1
1
2,3
Eiji Shirakawa,* Keisho Okura, Nanase Uchiyama, Takuya Murakami, and Tamio Hayashi
1
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
Institute of Materials Research and Engineering, 3 Research Link, 117602, Singapore
Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
2
3
(
E-mail: shirakawa@kuchem.kyoto-u.ac.jp)
Aryl Grignard reagents were found to undergo coupling with
aryl or alkenyl bromides in the presence of LiCl in a mixed
solvent consisting of toluene and THF (2/1). Previously
employed removal of THF with evacuation from Grignard
solutions is no longer needed to obtain biaryls and styrene
derivatives.
Table 1. Effect of solvents and LiCl in the coupling of
phenylmagnesium bromide with 3,5-xylyl bromide
a
Transition-metal-catalyzed cross-coupling reactions of aryl-
metals with aryl and alkenyl halides are widely used for the
synthesis of biaryls and styrene derivatives. On the other hand,
Amount of Conv. Yield
Entry Toluene/THF
3aa/(4a + 5a)b
b
b
1
LiCl/equiv
/%
/%
c
1
2
3
4
5
6
7
8
9
40/1
40/1
2/1
2/1
2/1
2/1
3/1
1/1
0/1
0
19
40
84
94
97
16
87
66
29
17
40
80
92
92
14
86
62
20
98/2
>99/1
97/3
96/4
96/4
94/6
97/3
94/6
84/16
we have recently developed the cross-coupling reaction of aryl
Grignard reagents with aryl and alkenyl halides induced by
single electron transfer (SET), where transition-metal catalysis is
c
1.5
1.5
4
6
0
4
4
4
2­5
not required. However, the original procedure for this cross-
coupling reaction includes removal of the solvent from a THF
solution of an aryl Grignard reagent and its scope of aryl halides
2
is limited essentially to iodides. Here, we report an improved
procedure for the Grignard cross-coupling using LiCl as an
6
activator and toluene and THF as a solvent system, where the
aThe reaction was carried out at 110 °C for 48 h in a mixture
above drawbacks from the practical and synthetic views are
(
4.0 mL, 0.05 M of 2a) of toluene and THF under a nitrogen
atmosphere using phenylmagnesium bromide (1a: a THF solution,
.30 mmol) and 3,5-xylyl bromide (2a: 0.20 mmol) in the presence
overcome.
2
For the coupling of aryl iodides in the previous study, we
0
b
c
used aryl Grignard reagents, which are prepared in THF and
evacuated to remove most of the solvent, and toluene as a
solvent in combination with a small amount (6 equiv) of THF.
Aryl bromides were found to be unreactive under this system.
Thus, a low conversion (19%) of 3,5-xylyl bromide (2a) was
observed upon treatment with phenylmagnesium bromide (1a:
or absence of LiCl. Determined by GC. 1a was used after
evacuation to remove most of the solvent.
for practical convenience, omitting the evacuation of THF from
the Grignard solution. This method is applicable to various aryl
bromides and aryl Grignard reagents (Table 2). In addition to
3,5-xylyl bromide (2a), methyl- and methoxy-substituted phenyl
bromides 2b­2e as well as 2-naphthyl bromide (2f) underwent
the coupling reaction in high yields (Entries 1­6). The coupling
reaction with aryl bromides 2g, 2f, and 2d is also applicable to
phenylmagnesium bromides 1b­1f having a methoxy, fluoro, or
methyl group (Entries 7­15). Ortho-substitution is tolerated in
this coupling reaction (Entries 3, 14, and 15).
For the coupling of aryl iodides, use of LiCl was found to
be unsuitable. Thus, treatment of 2-iodonaphthalene (2¤f) and
PhMgBr (1a: 1.5 equiv) with LiCl (4 equiv) in toluene­THF
(2:1, 0.05 M of 2¤f), as in Table 2 but at a lower temperature
(80 °C), afforded cross-coupling product 3af, reduction product
4f, and homocoupling product 5f in 38%, 27%, and 35% yields,
respectively (Entry 1 of Table 3). I­Mg exchange is likely to
take place to afford a naphthyl Grignard reagent, which is
converted to 4f and 5f through hydrolysis upon work-up and
coupling with 2f, respectively. The selectivity for cross-coupling
over I­Mg exchange was improved by the omission of LiCl;
however, the reaction was not completed in 24 h (Entry 2).
Doubling the concentration brought about the full conversion of
2¤f (Entry 3) and change of the toluene­THF ratio from 2:1 to
1.5 equiv) in toluene in the presence of additionally added THF
(
(
6 equiv) at 110 °C for 48 h, affording 3,5-dimethylbiphenyl
3aa) in 17% yield only (Entry 1 of Table 1). Addition of
1.5 equiv of LiCl increased the conversion (40%), though most
of LiCl was not dissolved (Entry 2). Change of the toluene/THF
ratio from 40:1 to 2:1 increased the solubility of LiCl and
improved the conversion of 2a to 84% (Entry 3). Using THF in
this amount, the removal of THF in vacuo is no longer required.
An increased amount of LiCl further accelerated the reaction,
where its amount was sufficient with 4 equiv (Entries 4 and 5).
The reaction rate in the absence of LiCl in toluene/THF (2:1)
was similar to that in toluene/THF (40:1) (Entry 6, cf. Entry 1),
showing that the acceleration is ascribed to LiCl, which is
7
dissolved in a sufficient amount in toluene­THF (2:1). Both the
decrease and increase of the ratio of THF retarded the reaction
(Entries 7­9), where a low selectivity for 3aa over reduction
product 4a and homocoupling product 5a was observed in the
reaction in THF alone.
Compared with our previous procedure, the present method
using LiCl (4 equiv) and toluene­THF (2:1) as an additive and a
solvent is advantageous not only from the acceleration effect but
922 | Chem. Lett. 2014, 43, 922–924 | doi:10.1246/cl.140155
© 2014 The Chemical Society of Japan

Table 2. Coupling of arylmagnesium bromides with aryl
bromides
Table 4. Coupling of arylmagnesium bromides with aryl
iodides
a
a
1
2
Yield/%b Product
Entry
Ar in 1
Ar in 2¤
1
2
Yield/%b Product
Entry Ar in 1
Ar in 2
1
2
3
Ph (1a)
Ph (1a)
2-naphthyl (2¤f)
4-MeOC6H4 (2¤d)
2-EtC6H4 (2¤h)
94
97
86
94
90
3af
3ad
3fh
3cf
3gf
1
2
3
4
5
6
7
8
9
0
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
3,5-Me2C6H4 (2a)
4-MeC6H4 (2b)
2-MeC6H4 (2c)
4-MeOC6H4 (2d)
3-MeOC6H4 (2e)
2-naphthyl (2f)
93
84
89
87
84
91
90
91
83
83
93
79
90
94
99
3aa
3ab
3ac
3ad
3ae
3af
3bg
3bf
3cf
3dg
3df
3ed
3ef
c
2-MeC6H4 (1f)
4-MeOC6H4 (1b) 2-naphthyl (2¤f)
4-ClC6H4 (1g) 2-naphthyl (2¤f)
4
5
d
aThe reaction was carried out at 80 °C for 24 h in toluene­THF
(3:1, 2.0 mL, 0.1 M of 2¤) under a nitrogen atmosphere using an
arylmagnesium bromide (1: a THF solution, 0.30 mmol) and an
4-MeOC6H4 (1b) Ph (2g)
4-MeOC6H4 (1b) 2-naphthyl (2f)
b
c
3-MeOC6H4 (1c)
4-FC6H4 (1d)
4-FC6H4 (1d)
4-MeC6H4 (1e)
4-MeC6H4 (1e)
2-MeC6H4 (1f)
2-MeC6H4 (1f)
2-naphthyl (2f)
Ph (2g)
aryl iodide (2¤: 0.20 mmol). Isolated yield based on 2¤. Reaction
d
1
time: 48 h. At 110 °C.
1
1
2-naphthyl (2f)
4-MeOC6H4 (2d)
2-naphthyl (2f)
4-MeOC6H4 (2d)
2-naphthyl (2f)
12
13
14
15
3fd
3ff
aThe reaction was carried out at 110 °C for 48 h in toluene­THF
2:1, 4.0 mL, 0.05 M of 2) under a nitrogen atmosphere using an
(
arylmagnesium bromide (1: a THF solution, 0.30 mmol), an aryl
bromide (2: 0.20 mmol), and LiCl (0.80 mmol). bIsolated yield
based on 2.
Table 3. Coupling of phenylmagnesium bromide with 2-
a
iodonaphthalene
Toluene/THF, Conv./%b
Yield/%b
4f
LiCl
Entry
/
equiv
Concentration
2¤f
3af
5f
Scheme 1.
1
2
3
4
5
4
0
0
0
0
2/1, 0.05M
2/1, 0.05M
2/1, 0.1 M
3/1, 0.1 M
20/1, 0.1 M
>99
76
>99
>99
>99
38
70
90
97
96
27
2
1
1
1
35
3
5
2
3
the reaction time was reduced from 24­48 to 12 h. The
stereochemistries of alkenyl bromides are conserved. In the
case with styryl derivatives, even the chloride participated in the
coupling, though in a long reaction period. Use of LiCl is not
suitable for the coupling of alkenyl iodides because of I­Mg
exchange as in the case with aryl iodides. The reaction
conditions employed for aryl iodides (Table 4) are convenient
for the coupling of alkenyl iodides.
aThe reaction was carried out at 80 °C for 24 h in toluene­THF (2
or 4 mL) under a nitrogen atmosphere using phenylmagnesium
bromide (1a: a THF solution, 0.30 mmol) and 2-iodonaphthalene
b
(
2¤f: 0.20 mmol). Determined by GC.
In conclusion, we have developed an improved procedure
for the single-electron-transfer-induced cross-coupling reaction
of aryl Grignard reagents with aryl and alkenyl halides. The
previously required evacuation process is omitted; use of LiCl
accelerates the cross-coupling, where a wide variety of aryl
Grignard reagents undergo coupling not only with aryl and
3
(
6
:1 improved the selectivity, affording 3af in 97% yield
Entry 4). The reaction under the conditions (toluene with
equiv of THF) employed in the previous report2 was also
completed in 24 h, showing that increasing the amount of THF
does not affect the reaction rate very much (Entry 5, cf. Entries 1
and 6 in Table 1). Under the conditions of Entry 4, where the
removal of THF in vacuo is not required, various combinations
of arylmagnesium bromides and aryl iodides underwent the
coupling reaction (Table 4).
8
,9
alkenyl iodides but with bromides.
This work has been supported financially in part by Grant-
in-Aids for Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis” (No.
23105521 to E.S.) from MEXT and by Grant-in-Aid for
Scientific Research (B) (No. 25288046 to E.S.) from JSPS. N.U.
thanks the JSPS for a Research Fellowship for Young Scientists.
The LiCl in toluene­THF (2:1) protocol is also applicable to
the coupling of alkenyl bromides with arylmagnesium bromides
(Scheme 1). Compared with the previous protocol (in the
3
absence of LiCl in toluene with 6 equiv of THF at 110 °C),
Chem. Lett. 2014, 43, 922–924 | doi:10.1246/cl.140155
© 2014 The Chemical Society of Japan | 923

References and Notes
2014, 53, 521. An independent study on the single-electron-
transfer-induced aryl­aryl coupling using diarylzinc and aryl
halides is also available: b) H. Minami, X. Wang, C. Wang,
M. Uchiyama, Eur. J. Org. Chem. 2013, 7891.
We used LiCl as an activator in the coupling of arylzinc
reagents with aryl and alkenyl halides. See ref 5.
1
The nickel-catalyzed Grignard cross-coupling reaction was
reported independently by groups of Kumada­Tamao and
2
2
Corriu as the first transition-metal-catalyzed C(sp )­C(sp )
cross-coupling reaction using arylmetals. a) K. Tamao, K.
Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94, 4374.
b) R. J. P. Corriu, J. P. Masse, J. Chem. Soc., Chem.
Commun. 1972, 144a. For reviews on the transition-metal-
catalyzed cross-coupling reactions, see: c) J. Hassan, M.
Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev.
6
7
LiBr, LiOTf, and NaCl were found to be much less effective
as an additive than LiCl, giving 3aa in 31% (33%), 28%
(30%), and 16% (17%) yields (conv.), respectively, under
the conditions of Entry 4. A Grignard reagent (RMgX) and
+
¹
2
002, 102, 1359. d) Metal-Catalyzed Cross-Coupling
LiCl are considered to form magnesiate Li [RMgX] , which
has an enhanced reactivity. For examples of the enhance-
ment, see: a) A. Krasovskiy, P. Knochel, Angew. Chem., Int.
Ed. 2004, 43, 3333. b) F. Kopp, A. Krasovskiy, P. Knochel,
Chem. Commun. 2004, 2288. c) A. Krasovskiy, B. F. Straub,
P. Knochel, Angew. Chem., Int. Ed. 2006, 45, 159. d) A.
Krasovskiy, A. Tishkov, V. del Amo, H. Mayr, P. Knochel,
Angew. Chem., Int. Ed. 2006, 45, 5010. e) N. Hirone, H.
Sanjiki, R. Tanaka, T. Hata, H. Urabe, Angew. Chem., Int.
Ed. 2010, 49, 7762. For investigation on the structure of
RMgX•LiCl, see: f) F. Blasberg, M. Bolte, M. Wagner,
H.-W. Lerner, Organometallics 2012, 31, 1001.
Reactions, 2nd ed., ed. by A. de Meijere, F. Diederich,
Wiley-VCH, Weinheim, 2004, Vol. 1­2. doi:10.1002/
9
783527619535.
2
For the coupling of aryl iodides, see: E. Shirakawa, Y.
Hayashi, K.-i. Itoh, R. Watabe, N. Uchiyama, W. Konagaya,
S. Masui, T. Hayashi, Angew. Chem., Int. Ed. 2012, 51, 218.
Aryl bromides are much less reactive than iodides under the
conditions reported in this paper, where a stoichiometric
amount (1 equiv to the aryl bromide) of NaOt-Bu is used as
an activator.
3
4
5
For the coupling of alkenyl halides, see: E. Shirakawa, R.
Watabe, T. Murakami, T. Hayashi, Chem. Commun. 2013,
8
9
Although we do not mention the reaction mechanism at all,
the same mechanism as that under the previous conditions
is considered to be operative. See refs 2­4. See also ref 5a
for the mechanistic discussion on the zinc cross-coupling
reaction.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
4
9, 5219.
For the mechanistic studies on the coupling of aryl halides,
see: N. Uchiyama, E. Shirakawa, T. Hayashi, Chem.
Commun. 2013, 49, 364.
We have also developed the single-electron-transfer-induced
coupling of arylzinc reagents with aryl and alkenyl halides.
a) E. Shirakawa, F. Tamakuni, E. Kusano, N. Uchiyama, W.
Konagaya, R. Watabe, T. Hayashi, Angew. Chem., Int. Ed.
924 | Chem. Lett. 2014, 43, 922–924 | doi:10.1246/cl.140155
© 2014 The Chemical Society of Japan