Iron-catalyzed Suzuki-Miyaura coupling reaction of unactivated alkyl halides with lithium alkynylborates

Article abstract of DOI:10.1246/cl.141167

A Suzuki-Miyaura coupling reaction between unactivated alkyl halides and lithium alkynylborates was performed using an iron-bisphosphine catalyst. The reaction shows high chemoselectivity and is applicable to a broad scope of substrates bearing electrophilic functional groups. A radical probe experiment using cyclopropylmethyl bromide was conducted to investigate the nature of the intermediate in the reaction, showing that an alkyl radical species is generated from the alkyl halide substrate.

Full text of DOI:10.1246/cl.141167

CL-141167
Received: December 17, 2014 | Accepted: December 23, 2014 | Web Released: December 27, 2014
Iron-catalyzed Suzuki-Miyaura Coupling Reaction of Unactivated Alkyl Halides
with Lithium Alkynylborates
Naohisa Nakagawa,1,2 Takuji Hatakeyama,1,3,³ and Masaharu Nakamura*1,2
1International Research Center for Elements Science (IRCELS), Institute for Chemical Research (ICR),
Kyoto University, Uji, Kyoto 611-0011
2Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Nishikyo-ku, Kyoto 615-8510
3Elements Strategy Initiative for Catalysts and Batteries (ESICB), Kyoto University, Nishikyo-ku, Kyoto 615-8520
(E-mail: masaharu@scl.kyoto-u.ac.jp)
(A) Previous work: Iron-catalyzed Sonogashira-type coupling of alkyl halides
A Suzuki-Miyaura coupling reaction between unactivated
alkyl halides and lithium alkynylborates was performed using an
R
MgBr
tBu
tBu
"slow addition"
cat.
[FeCl2(SciOPP)]
iron-bisphosphine catalyst. The reaction shows high chemo-
selectivity and is applicable to a broad scope of substrates bearing
electrophilic functional groups. A radical probe experiment using
cyclopropylmethyl bromide was conducted to investigate the
nature of the intermediate in the reaction, showing that an alkyl
radical species is generated from the alkyl halide substrate.
tBu
tBu
tBu
tBu
P
P
R
X
THF, reflux
R = bulky alkyl or silyl
up to 92%
X = I, Br
tBu
tBu
SciOPP
(B) This work: Iron-catalyzed Suzuki–Miyaura coupling of alkyl halides
cat.
[FeCl2(SciOPP)]
R
B(OMe)3Li
X
R
+
The Suzuki-Miyaura coupling reaction has been widely
used for the synthesis of functional organic molecules, such
as pharmaceuticals, agrochemicals, and electronic materials.1
In particular, the Suzuki-Miyaura coupling of alkynyl borate
reagents has become recognized as a powerful tool for installing
a C-C triple bond moiety without altering other reactive
functional groups on the substrates.2 Since Soderquist and
Fürstner independently reported the palladium-catalyzed alky-
nylation between alkynyl borate reagents and aryl or alkenyl
halides,2b,2c the reaction has been successfully applied as a key
step in the synthesis of natural products.3 However, while aryl
and alkenyl halides have been widely employed in this
alkynylation reaction, the use of unactivated alkyl halides
has remained challenging due to their reluctance to oxidative
addition and the competing nonproductive β-hydrogen elimi-
nation from the alkyl-metal intermediate. Consequently, there
has been no report on the use of alkynylborates in Csp-Csp3
bond-forming reactions with unactivated alkyl halides, despite
extensive studies using various combinations of alkynyl
donors and transition-metal catalysts such as palladium,4a,4b,5a
nickel,4c,4d,5b cobalt,5c-5f and iron.5g,5h
We have previously reported a Sonogashira-type coupling
between alkyl halides and alkynyl Grignard reagents with the
iron-bisphosphine catalyst [FeCl2(SciOPP)]5g,6 (Scheme 1A).
Although this reaction demonstrated the potential of the iron
catalyst in the alkynylation of alkyl halides, significant synthetic
limitations have remained, i.e., low functional group compati-
bility, the inapplicability of the reaction to secondary alkyl
chlorides, and the need for overly elaborate protocols such as the
slow addition of Grignard reagents at refluxing temperature.
Herein we present the first example of Suzuki-Miyaura coupling
between alkynylborates and unactivated alkyl halides in the
presence of an iron catalyst,7,8 which overcomes these limita-
tions to provide a facile route to alkyl-substituted functionalized
alkynes in good to excellent yields (Scheme 1B).
X = I, Br, Cl
R = silyl, alkyl, aryl
high chemoselectivity
Scheme 1. Iron-bisphosphine-catalyzed Csp-Csp3 bond-forming re-
action of unactivated alkyl halides.
Table 1. Effect of reaction parameters on iron-catalyzed alkynylation
Optimal condition
Cl
[FeCl2(SciOPP)]
(5 mol %)
4
5
iPr3Si
1
THF/hexane
80 °C, 5 h
3
iPr3Si
B(OMe)3Li
2 (1.50 equiv)
Yield/%b
Recovery
of 1/%b
Entrya Variations from the optimal conditions
3
4
5
1
2
3
4
5
6
7
8
none
80 16
3
<1
>99
74
>99
94
without [FeCl2(SciOPP)]
0
10
0
0
4
0
0
5
0
c
5 mol % of FeCl2
5 mol % of [FeCl2(dppbz)2]
5 mol % of FeCl2 and DPPEc
<1 <1 <1
d
5 mol % of FeCl2 with NMP (2 mL)
8
0
5
1
1
1
63
97
94
B(OiPr)3 instead of B(OMe)3 in 2
9-MeO-9-BBN instead of B(OMe)3 in 2 0 <1 <1
aReactions were carried out at the 0.50 mmol scale. bYields were
determined by quantitative GC analyses using dodecane as an internal
standard. FeCl2(thf)1.5 was used. Anhydrous FeCl2 was used.
c
d
silyl)ethynyltrimethoxoborate (2),9 readily prepared from the
terminal alkyne, BuLi, and trimethyl borate, and found that by
using 5 mol % of [FeCl2(SciOPP)] the target coupling product 3
was obtained in 80% yield, along with cycloheptene (4) and
cycloheptane (5) (Table 1, Entry 1). Further investigation into
the reaction conditions was conducted by altering individual
reaction parameters from those considered to be optimal.10 In the
absence of the iron catalyst, 1 was recovered quantitatively and
no other products were observed (Table 1, Entry 2). Without
the SciOPP ligand, the coupling reaction gave 3 in only 10%
We began our investigation by evaluating the coupling
reaction of chlorocycloheptane (1) and lithium (triisopropyl-
486 | Chem. Lett. 2015, 44, 486–488 | doi:10.1246/cl.141167
© 2015 The Chemical Society of Japan

iPr3Si
B(OMe)3Li
Table 2. Scope of substrates in iron-catalyzed Suzuki-Miyaura
coupling with lithium alkynylboratesa
[FeCl2(SciOPP)]
(5 mol %)
2
(1.5 equiv)
+
iPr3Si
[FeCl2(SciOPP)]
(5 mol %)
THF, 60 °C, 18 h
7
41%
Br
X
R'
R
R'
R
B(OMe)3Li
(1.5 equiv)
+
6
THF/hexane
or toluene
X = I, Br. Cl
3
40–80 °C, 5–28 h
in THF/hexane
Scheme 2. Radical probe experiment.
iPr3Si
iPr3Si
Et3Si
P
R
R
Cl
2
3a, 76% (X = Cl)
80 °C, 5 h
3b, 81% (X = Cl)
80 °C, 12 h
3c, 83% (X = Br)
60 °C, 12 h
P
P
X
R
B(OMe)3Li
Fe
Alkyl
FeIII
Cl
P
P
X
Alkyl
R
O
O
iPr3Si
Hex
= SciOPP
B
P
P
3e, 25% (X = I)
60 °C, 6 h
FeII
3d, 73% (X = Cl)
80 °C, 28 h
3f, 46% (X = I)
40 °C, 8 h
excess of
R
P
B(OMe)3Li
R
A
Br
P
P
X
tBuMe2SiO
iPr3Si
Fen
R
–m
FeII
n+m
B(OMe)3 + LiX
B(OMe)3Li
R
Alkyl
3g, 53% (X = I)
40 °C, 8 h
3h, 83% (X = Br)
60 °C, 18 h
n = 0–2, m = 1–4
R
R
D
C
in toluene
Figure 1. A plausible catalytic cycle for the current reaction.
CN
NBoc
iPr3Si
3j, 98% (X = Br)b
80 °C, 22 h [<20% in THF]
3i, 53% (X = Br)
80 °C, 24 h [0% in THF]
Figure 1). We thus replaced the THF solvent with toluene, and
found that the coupling reaction worked well even with the
sterically unhindered alkynylborate and obtained the cyclo-
propylethynylated compound 3i in 53% yield. Toluene solvent
was effective also for the alkyl halides possessing a reactive
functional group, such as nitrile, imide, and ketone (3j-3l). We
reasoned that the low polarity of the toluene solvent prevented
the side reactions on these functional groups with alkynyl iron
species.12
To investigate the reaction mechanism, we conducted the
reaction of (bromomethyl)cyclopropane (6) with 2 (Scheme 2).
The linear 1,5-enyne 7 formed in 41% yield selectively,
suggesting that the reaction proceeds via formation of an alkyl
radical species. Based on the experimental observations de-
scribed above, and accumulated knowledge of iron-catalyzed
cross-coupling reactions,5g,7,8 we present a possible catalytic
cycle, shown in Figure 1. We assume that the dialkynyl-iron-
SciOPP intermediate A is responsible for the selective cross
coupling through the putative iron intermediates B and C, whilst
the ferrate complexes D that can form in the presence of an
excess of the Grignard reagent13 do not possess sufficient
reactivity towards the alkyl halides. Presumably, the steric bulk
of SciOPP prevents the formation of the undesired ferrate
formation.
O
Ph
O
N
iPr3Si
Et3Si
O
3k, 67% (X = I)b
60 °C, 18 h
3l, 44% (X = Br)b
70 °C, 24 h
aReactions were carried out at the 0.50 mmol scale. Yields of isolated
products are reported. b10 mol % of [FeCl2(SciOPP)] and 2 equivalents
of 2 were used.
yield, and showed diminished selectivity (Table 1, Entry 3).
DPPBz,7e-7g DPPE,11 and NMP,5h,7a which are well-recognized
modifiers for iron-catalyzed cross-coupling reactions, were
totally ineffective (Table 1, Entries 4-6). Other alkynylborates
derived from B(OiPr)32e and 9-MeO-9-BBN2b,2c did not take part
in the cross-coupling reaction (Table 1, Entries 7 and 8).
We next investigated the scope of the current protocol and
found that it was applicable to various combinations of alkyl
halides and alkynylborates (Table 2). (Triethylsilyl)ethynyl-
borate also showed good reactivity toward bromocyclohexane,
affording the target alkyne 3c in 83% yield. A cyclic acetal was
tolerant to the reaction conditions to give 3d in 73% yield.
(Phenyl)ethynylborate reacted to give 3e albeit in a low yield.
Reactions of primary alkyl-substituted alkynylborates were also
found to be sluggish, yet they reacted with primary or secondary
alkyl iodides to afford the coupling products 3f and 3g in
moderate yields. The reaction of 1-bromo-4-(2-bromoethyl)ben-
zene with 2 occurred selectively at the Csp3 -Br position to afford
3h in 83% yield, leaving the Csp2 -Br bond completely intact.
In the case of sterically small alkyne substituents, such as the
(cyclopropyl)ethynyl group, the target product 3i was not
obtained, even with refluxing in THF. We assumed that even
the borate reagent, which possesses a small substituent on the
alkyne carbon, could form inert iron intermediates such as
ferrate complexes in a polar solvent like THF (Table 2 and
In summary, we have developed the iron-catalyzed Suzuki-
Miyaura coupling of unactivated alkyl halides with alkynylbo-
rate reagents. The reaction has synthetic advantages over more
traditional methods, such as its simple operation, its applicability
to a broad scope of alkyl halides including chlorides, and its
high functional group compatibility. At present, details of the
reaction mechanism are unclear, and evaluation of the postulated
catalytic cycle is imperative. Further efforts on the elucidation of
the mechanism are currently underway.
This research was funded in part by a grant from the Japan
Society for the Promotion of Science (JSPS) through the
“Funding Program for Next Generation World-Leading Re-
searchers (NEXT Program),” initiated by the Council for
Chem. Lett. 2015, 44, 486–488 | doi:10.1246/cl.141167
© 2015 The Chemical Society of Japan | 487

phenylene-bisphosphine, which is commercially available from
Wako Pure Chemical Industries, Ltd.
Science and Technology Policy (CSTP), and also supported by
the Japan Science and Technology Agency (JST), and the Core
Research for Evolutional Science and Technology (CREST
1102545) Program. This research is also supported in part by the
MEXT program “Elements Strategy Initiative to Form Core
Research Center.” We thank Prof. Dr. Katsuhiro Isozaki (Kyoto
University) for the FT-MS analyses.
7
Selected examples of the iron-catalyzed cross-coupling reaction
of alkyl halides with aryl Grignard reagents: a) A. Fürstner, R.
Martin, H. Krause, G. Seidel, R. Goddard, C. W. Lehmann, J. Am.
Chem. Soc. 2008, 130, 8773. b) T. Hatakeyama, Y. Fujiwara, Y.
Okada, T. Itoh, T. Hashimoto, S. Kawamura, K. Ogata, H. Takaya,
M. Nakamura, Chem. Lett. 2011, 40, 1030. c) C.-L. Sun, H.
Krause, A. Fürstner, Adv. Synth. Catal. 2014, 356, 1281. With
arylzinc reagents: d) M. Nakamura, S. Ito, K. Matsuo, E.
Nakamura, Synlett 2005, 1794. e) R. B. Bedford, M. Huwe,
M. C. Wilkinson, Chem. Commun. 2009, 600. f) T. Hatakeyama,
Y. Kondo, Y. Fujiwara, H. Takaya, S. Ito, E. Nakamura, M.
Nakamura, Chem. Commun. 2009, 1216. g) C. J. Adams, R. B.
Bedford, E. Carter, N. J. Gower, M. F. Haddow, J. N. Harvey, M.
Huwe, M. Á. Cartes, S. M. Mansell, C. Mendoza, D. M. Murphy,
E. C. Neeve, J. Nunn, J. Am. Chem. Soc. 2012, 134, 10333.
We previously reported the iron-catalyzed Suzuki-Miyaura
coupling of alkyl halides. With aryl borate reagents: a) T.
Hatakeyama, T. Hashimoto, Y. Kondo, Y. Fujiwara, H. Seike, H.
Takaya, Y. Tamada, T. Ono, M. Nakamura, J. Am. Chem. Soc.
2010, 132, 10674. With alkenyl borate reagents: b) T. Hashimoto,
T. Hatakeyama, M. Nakamura, J. Org. Chem. 2012, 77, 1168.
With alkyl borate reagents: c) T. Hatakeyama, T. Hashimoto,
K. K. A. D. S. Kathriarachchi, T. Zenmyo, H. Seike, M.
Nakamura, Angew. Chem., Int. Ed. 2012, 51, 8834.
Supporting Information is available electronically on J-STAGE.
References and Notes
³
Present address: School of Science and Technology, Department
of Chemistry, Kwansei Gakuin University, 2-1 Gakuen, Sanda,
Hyogo 669-1337
1
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9
The 11B NMR spectrum for the mixture of lithium triisopropyl
ethynylide and a small excess of trimethyl borate showed four
peaks in the range of 19 to ¹4 ppm. These peaks are attributed
to trimethyl borate (18.7 ppm as a minor peak), 2 (3.4 ppm as a
dominant peak), lithium tetramethoxoborate (1.7 ppm as a minor
peak), and lithium dimethoxodialkynylborate (¹3.7 ppm as a
minor peak) relative to BF3¢Et2O as an external standard. We
assume that these boron compounds can form through
disproportionation reaction. See also Refs. 2g and 3a.
a
10 Ligand, additive, and boron reagent structure abbreviations:
3
4
5
O
MeO
B
Ph2P
PPh2
N
Me
Ph2P
PPh2
dppbz (DPPBz)
DPPE
NMP
9-MeO-9-BBN
11 Bedford and his co-workers recently demonstrated that simple
bisphosphines, such as dppe, also work as an effective ligand on
the iron-catalyzed Suzuki-Miyaura coupling of alkyl halides with
aryl borate reagents: R. B. Bedford, P. B. Brenner, E. Carter, T. W.
Carvell, P. M. Cogswell, T. Gallagher, J. N. Harvey, D. M.
Murphy, E. C. Neeve, J. Nunn, D. R. Pye, Chem.®Eur. J. 2014,
20, 7935.
12 Lithium alkynyl trimethylborates react with aldehydes but not
with nitrile, ester, and ketone. See: I. N. Francesco, A. Renier, A.
Wagner, F. Colobert, Tetrahedron Lett. 2010, 51, 1386.
13 Alkynylferrate complexes were previously reported. a) R. Nast, F.
Urban, Z. Anorg. Allg. Chem. 1956, 287, 17. b) L. A. Berben, J. R.
Long, Inorg. Chem. 2005, 44, 8459. c) G. M. Yee, K. Kowolik, S.
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11680. An organoiron(II)-SciOPP complex is proven as a reactive
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with mesityl Grignard reagent. d) H. Takaya, S. Nakajima, N.
Nakagawa, K. Isozaki, T. Iwamoto, R. Imayoshi, N. J. Gower, L.
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6
SciOPP is the abbreviation for spin-controlled intended ortho-
488 | Chem. Lett. 2015, 44, 486–488 | doi:10.1246/cl.141167
© 2015 The Chemical Society of Japan