Nickel-catalyzed cross-coupling of unactivated alkyl halides using bis(pinacolato)diboron as reductant

Article abstract of DOI:10.1039/c3sc51098k

The use of bis(pinacolato)diboron as the terminal reductant allows the efficient Ni-catalyzed coupling of unactivated secondary and primary alkyl halides, generating the C(sp³)-C(sp³) coupling products in good yields. The mild cataly

Full text of DOI:10.1039/c3sc51098k

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Nickel-catalyzed cross-coupling of unactivated alkyl
halides using bis(pinacolato)diboron as reductant†
Cite this: Chem. Sci., 2013, 4, 4022
*
Hailiang Xu, Chenglong Zhao, Qun Qian, Wei Deng and Hegui Gong
The use of bis(pinacolato)diboron as the terminal reductant allows the efficient Ni-catalyzed coupling of
unactivated secondary and primary alkyl halides, generating the C(sp3)–C(sp3) coupling products in
good yields. The mild catalytic conditions display excellent functional group tolerance, and good
chemoselectivities which require only 1.5 equiv. of primary bromides for the coupling with secondary
bromides. Preliminary mechanistic studies suggest that an in situ organoborane/Suzuki process is not
likely. It was identified that the base and ligand have more profound impact on selecting this reductive
coupling pathway. The good chemoselectivity appears to be evoked by the formation of Ni–Bpin
catalytic intermediates, which demands matched sizes and reactivities of the alkyl halide coupling
partners for optimal coupling efficiency.
Received 24th April 2013
Accepted 23rd July 2013
DOI: 10.1039/c3sc51098k
www.rsc.org/chemicalscience
Herein, we report the efficient cross-coupling of two unac-
tivated alkyl halides, employing bis(pinacolato)diboron as the
Introduction
The catalytic formation of C(sp3)–C(sp3) bonds is generally
realized via transition-metal-catalyzed cross-coupling of alkyl
electrophiles and organometallic nucleophiles.1–10 The nickel-
catalyzed methods in particular appear to be highly effective for
the coupling on sp3 carbon electrophiles, including sterically
hindered secondary alkyl halides.6–8 Although these conven-
tional protocols are ideal in the sense of chemoselectivity, extra
steps of conversion of the electrophilic precursors into alkyl-
metallic nucleophiles are generally required. In some cases, the
formation of alkyl nucleophiles could be difficult, e.g., for those
bearing b-leaving groups.9,10
reductant, with which good coupling yields can be achieved
using only 1.5 equiv. of primary bromides for the coupling with
secondary bromides. To the best of our knowledge, this work
should represent the rst efficient coupling of unactivated alkyl
halides using boron as the terminal reductant.14 Our initial
studies indicated that the in situ Suzuki mechanism is not
operative, which bypasses the formation of alkyl boronate esters
as evidenced in the recent Ni-, Pd-, and Cu-catalyzed borylation
of alkyl halides (Scheme 2).15
On the other hand, direct reductive coupling of two alkyl
electrophiles can afford an alternative yet more facile method for
the construction of alkyl–alkyl compounds,11–13 considering alkyl
halides are generally more accessible and easy-to-handle than
alkyl nucleophiles. However the major challenge of this strategy
resides in the poor selectivities between the two coupling alkyl
electrophiles. In our previous study, although the use of zinc
powder as the terminal reductant gave the coupling products in
moderate yields, one of the coupling halides need to be 3 equiv.13
Signicant amounts of highly competitive homocoupling side
reactions are observed, e.g., >2 equiv. of ((3-bromopropoxy)-
methyl)benzene underwent homocoupling in the reaction shown
in Scheme 1, due in part to a statistically controlled mechanism.
The Ni/Zn-catalytic conditions thus cannot effectively bias the
two structurally similar alkyl coupling partners.
Results and discussions
Homocoupling of secondary and primary bromides
We rst studied the homocoupling of unactivated alkyl halides
1a and 2a (Table 1), and identied that NiI2, NMP (N-methyl-
pyrrolidone) and LiOMe were superior to other Ni sources,
solvents and bases.16 Examination of the ligands indicated that
7a was optimal for 1a at 45 ꢀC (Table 1, entry 3), and 8a was
optimal for 2a using reduced catalyst and ligand loading
(Table 1, entry 4), producing 3 and 4 in 74% and 99% yields,
respectively.16 The primary alkyl tosylate-, iodo-, and chloro
ꢀ
analogs 2b–d delivered 4 in 94% (45 C), 70%, and 70% (with
Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444,
China. E-mail: Hegui_gong@shu.edu.cn; Tel: +86 21 6613 2410
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3sc51098k
Scheme
1
Coupling of ((3-bromopropoxy)methyl)benzene and 4-bromo-1-
tosylpiperidine.
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Scheme 3 Cross-coupling of 10a and n-heptylbromide.
Scheme 2 Alkyl borylation vs. alkyl–alkyl coupling.
Table 1 Optimization for the dimerization of 1 and 2a
results. The use of bis(neopentyl glycolato)diboron and
bis(hexylene glycolato)diboron gave 11a in 50% and 68%
yields, respectively. Under the optimized conditions, the use of
n-heptyl bromide as the limiting regent for the coupling with
1.5 equiv. of 10a only delivered 11a in 46% yield, implying that
the intrinsic selectivity arising from the substrates and cata-
lysts takes effect.
Under the optimized reaction conditions, the scope and
limitations of alkyl bromides were explored, affording 12–28
(Table 2). Both cyclic and open-chain secondary alkyl
bromides were generally competent providing the coupling
products in moderate to good yields. Notably, substrates
containing b-leaving groups also afforded the coupling
products 21–24 in reasonably good results (Table 2, entries
10–13). In general, the side reactions for the primary halides
primarily arose from homocoupling, whereas those for the
secondary bromides were from hydrodehalogenation and
homocoupling, along with recovered starting materials (vide
infra). The reactions tolerated a range of functional groups,
including ester, acteal, ketone, amide containing NH proton
(Table 2, entry 11), cyanide, and silyl ether. However, the
sterically more congested primary bromides, and secondary
bromides lacking in polar functional groups appeared to
be less efficient as evident in 15, 19–20 and 25 (Table 2, entries
4, 8–9, 14).17
Yieldb (%)
Entry
X (1 or 2)
Ligand
ꢀC
3 (R ¼ Me)
4 (R ¼ H)
1
2
3
4
5
6
7
Br (1a or 2a)
Br (1a or 2a)
Br (1a or 2a)
Br (1a or 2a)
OTs (1b or 2b)
I (1c or 2c)
5a
6a
7a
8a
8a
8a
8a
30
30
45
30
45
30
80
35
22c
74
80
NAd
86
50
99e
94
NAd
NAd
NAd
70
Cl (1d or 2d)
70f
a
1 or 2 (100 mol%, 0.16 M in NMP), NiI2 (10 mol%), ligand (10 mol%),
(Bpin)2 (150 mol%), LiOMe (200 mol%), NMP (1 mL), 16 h. Isolated
b
yields; for 3, an inseparable mixture of diastereomers was collected.
c
d
e
HPLC yield (see the ESI†). Not available. 5% NiI2 and 5% ligand
f
were used. Similar conditions to 2a except 1 equiv. of Bu4NBr was
added.
(2) Cross-coupling involving alkyl iodides, chlorides and
tosylates. Interestingly, in a sharp contrast to bromocyclo-
hexane (Table 2, entry 8), the coupling of 2a with iodocyclo-
hexane under the standard conditions generated 19 in 60%
yield (Table 3, entry 1). A 1.5 to 1 molar ratio of iodocyclo-
hexane to 2a further boosted the yield to 77% (Table 3, entry 2).
The generality of using iodo surrogates for unfunctionalized
secondary bromides can be evidenced in the efficient synthesis
of 29, 20 and 25 (Table 3, entries 3–5). The effectiveness of
5-bromopentyl 4-methoxybenzoate (Table 3, entry 3) under
these modied conditions suggests an inductive effect on
primary bromides is not crucial. Application of the modied
methods to the sterically bulky primary iodide, e.g., 1-iodo-2-
Bu4NBr) yields, respectively (Table 1, entries 5–7). Possible iodo/
tosylate exchange may account for the reactivity of 2b as
Ni(COD)2 was ineffective.16
Cross-coupling of secondary and primary halides
(1) Cross-coupling of secondary and primary bromides. We methylpropane for the coupling with secondary bromide 10a
next examined whether cross-coupling between a 2ꢀ and a 1ꢀ was not successful (Table 3, entry 6). Next, we examined the
alkyl halide is feasible. To our delight, under the optimized coupling efficiency of secondary bromide 10a with n-heptyl
reaction conditions for 2a (Table 1, entry 4), the desired chloride, tosylate, and iodide (Table 3, entries 7–9). It was
coupling product 11a was obtained in 50% yield using only 1.5 revealed that only the primary tosylate gave a moderate
equiv. of n-heptyl bromide for the coupling with 10a. Raising coupling yield. The chloride (in the presence of Bu4NBr) and
the temperature to 40 ꢀC, doubling the concentration of 10a in iodide analogs were ineffective. In contrast, the coupling of
NMP, and using 2 equiv. of B2(Pin)2 and 2.5 equiv. of LiOMe iodo analog 10b with n-butyl iodide generated 11b in a 43%
boosted the yield to 74% (Scheme 3). The use of 2 equiv. of yield, implying that a matched reactivity between the two
n-heptyl bromide slightly increased the yield to 77%. Tuning coupling partners is an important factor for better cross-
the ligand structures as in 8b–d and 9 did not yield better coupling efficiency (Table 3, entry 10).
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Table 2 Coupling of secondary with primary alkyl bromidesa
Entry
Product
Yieldb
1
2
3
4
12, R ¼ Ph(CH2)2
79
75
80
40c
13, R ¼ BnO(CH2)2
14, R ¼ (1,3-dioxolan-2-yl)methyl
15, R ¼ iPr
5
6
16, R ¼ H
85
83
17, R ¼ CN
7
8
18
19
70
15
9
20
21
45d
63
10
11
12
22, R ¼ CbzNH
74
74
23, R ¼ 4-MeO-C6H4C(O)O
13
14
24
25
61
Trace
15
16
26, n ¼ 1
27, n ¼ 2
70
60
17
28
67
a
Standard reaction conditions: secondary bromide (100 mol%, 0.32 M in NMP), primary bromide (150 mol%), NiI2 (10 mol%), 8a (10 mol%),
b
c
(Bpin)2 (200 mol%), LiOMe (250 mol%), NMP (0.5 mL), 40 ꢀC, 16 h. Isolated yields. The yield was estimated by NMR analysis of an
inseparable mixture containing the product of hydrodehalogenation of 10a. d Exo : endo > 20 : 1.
coupling of 1-iodo-2-methylpropane and 2a (Table 4, entry 8),
reactions of 1-iodo-2,2-dimethylpropane with primary
bromides afforded 33 and 34 in high yields, suggesting that a
steric effect is a pivotal factor for the origin of selectivity
(Table 4, entries 9–10). The much improved coupling effi-
ciency for 1-iodo-2,2-dimethylpropane as compared to the
bromo-analog is supportive of a matched reactivity between
the two coupling partners being important (Table 4, entries
7 and 9).
The coupling of two secondary halides, such as 10a and
cyclohexylbromide was not satisfactory (Table 4, entries 11–13);
only 20% of the desired product 35 was observed. The secondary
iodide and bromide were primarily converted into hydro-
dehalogenation byproducts.16
Cross-coupling of secondary with secondary, and primary with
primary halides
The cross-coupling of 2a and n-heptyl bromide or (3-bromo-
propoxy)benzene which possess similar steric demands gave
the coupling products 30 and 31 in moderate yields (Table 4,
entries 1–3). The ratio of 1 : 1.5 or 1.5 : 1 of the coupling
partners did not seem to be important (Table 4, entries 1–3).
The tosylate analog 2b generated comparable coupling
results (Table 4, entries 4–5). The coupling yields for 2a with
1-bromo-2-methylpropane and the more hindered 1-bromo-
2,2-dimethylpropane were both low, with the former being
better (Table 4, entries 6–7). This is possibly due to low
reactivity of hindered primary bromides. It was interesting,
however, to note that in contrast to a moderate yield for the
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Table 3 Coupling involving alkyl iodides, tosylates and chloridesa
Entry
R1X
R2Y
R1X/R2Y
Product
Yieldb (%)
1
2
1.5 : 1
1 : 1.5
60
77
19
3
4
1 : 1.5
1 : 1.5
29
20
66
65c
5
6
2a
1 : 1.5
1 : 1.5
25
15
50
10a
Trace
7
8
9
10a
10a
10a
10b:
n-C7H15Cl
n-C7H15OTs
1 : 1.5
1 : 1.5
1 : 1.5
11a
11a
11a
Trace
48
Trace
n-C7H15
l
10
n-C4H9l
1 : 1.5
11b
43
a
b
Reaction conditions as in Table 2. Isolated yield. c Exo : endo > 20 : 1.
10a was transferred into homocoupling and hydro-
dehalogenation byproducts (Fig. 1). At 16 h, the yield for 13 was
75% (with respect to 1 equiv. of 10a). While ꢁ40% of the
primary bromide (with respect to 1.5 equiv. of primary bromide)
was converted into the homocoupling product, ꢁ15% of which
is recovered; ꢁ10% of 10a was recovered along with <10% of
the homocoupling and ꢁ5% of the hydrodehalogenation
Side reactions in the cross-coupling process
In order to understand the details of the reactions, we tracked
the reaction progress of 10a with 1.5 equiv. of ((3-bromopro-
poxy)methyl)benzene (BnO(CH2)3Br) (Table 2, entry 2). During
the course of the reaction, in addition to formation of the
product 13, the primary bromide gradually dimerized, whereas
Table 4 Cross-coupling of primary with primary and secondary with secondary alkyl halidesa
Entry
R1X
R2Y
R1X/R2Y
Product
Yieldb (%)
1
2
3
2a
n-C7H15Br
1 : 1.5
1.5 : 1
1 : 1.5
30
55
52
52
2a
2b
31
30
4
5
6
7
n-C7H15Br
1 : 1.5
1 : 1.2
1 : 1.5
1 : 1.5
50
48
34
19
32, R ¼ H
2a
2a
33, R ¼ Me
8
1 : 1.5
32
45
9
10
1 : 1.5
1 : 1.5
33, n ¼ 3
34, n ¼ 5
74
80
11
10a
1 : 1.5
35
35
20
12
13
10a
10b
1 : 1.5
1 : 1.5
10
5
a
b
Reaction conditions as in Table 2. Isolated yield.
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conditions.15a In situ Suzuki coupling is therefore a possible
explanation for the selective coupling in this method. The
coupling of alkyl bromides 2a, 10a and 3-phenylpropyl bromide
with alkyl-Bpin 36 and 37 in the presence of (Bpin)2 did not
provide the Suzuki coupling products. Rather, the alkyl-Bpin
derivatives were primarily recovered along with the products of
homocoupling of the primary alkyl bromides or hydro-
dehalogenation of 10a (Scheme 4).16 These observations suggest
that alkyl-Bpin does not participate in the reductive coupling
process, and therefore an in situ alkyl-Bpin/Suzuki sequence is
less plausible. Thus, the coupling of 10a with 38 reasonably
afforded 39 in good yield.
Fig. 1 Reaction profile of 10a with ((3-bromopropoxy)methyl)benzene.
(2) Radical process. Moreover, the coupling of 10a with
(bromomethyl)cyclopropane furnished ring opening product 40
in 55% yield (eqn (1)), suggesting that alkyl radical intermedi-
ates were generated during the course of coupling.19,20 The
involvement of alkyl radicals has been suggested in the oxida-
tive addition of Ralkyl1–NiI or Bpin–NiI intermediates to Ralkyl2–X
in the recent mechanistic considerations on Ni-catalyzed
Miyaura borylation, and alkyl–alkyl Negishi and Suzuki
coupling reactions.15a,21,22
byproducts. Interestingly, >0.3 equiv. of (Bpin)2 can be recov-
ered. The use of 1.7 equiv. of (Bpin)2, however, slightly dimin-
ished the yield to 70%. The reaction seems to slow down aer 8
h and almost stops aer 16 h, leaving ꢁ10% of both halides
being recovered even aer 36 h.18
Interestingly, under the same standard reaction conditions
in the absence of 10a, BnO(CH2)3Br rapidly dimerized within 1
hour (ꢁ90%), whereas 10a in the absence of BnO(CH2)3Br was
gradually converted into the hydrodehalogenation product
(>70%) within 16 hours (Fig. 2).16 This observation indicates
that the homocoupling rate for the primary bromide is signi-
cantly slowed down when the secondary bromide is present,
and the coupling of two secondary halides is not favored,
possibly due to steric hindrance.
The collective data of product distribution for different
reactions that support side reactions of primary halides
generally arises from homocoupling (Tables S13 and S14†),16
whereas the side reactions of secondary halides comprise
homocoupling and hydrodehalogenation. More importantly,
substantial amount of unreacted (Bpin)2 (>0.3 equiv.) and
secondary bromides can be recovered in many examples in
Tables 2–4.16
(1)
(3) Proposed catalytic cycle. We proposed a catalytic cycle
as in Scheme 5. Borylation of the NiI–X complex (A) offers a
Bpin–NiI species B, which undergoes a one electron transfer to
R1–X, leading to R1 radical and a NiII intermediate C, followed
by rapid combination to afford Bpin–NiIII(R1)–Br (complex D)
(Scheme 5).15a Subsequent elimination of Bpin–X (X ¼ Br or
OMe, etc.) gives an R1–NiI species E, which oxidatively adds to
R2–Br, involving rapid combination of the R2 radical and a NiII
complex F to produce an R1–NiIII–R2 intermediate G. Reductive
elimination of G gives the product and regenerates NiI–X
complex A. In contrast to Fu's proposal in the Ni-catalyzed
borylation of alkyl halides, the elimination of R1–Bpin from
complex D may become energetically disfavored under our
reaction conditions.15a
Mechanistic considerations
(1) Non-in situ Suzuki process. Fu has demonstrated that
borylation of secondary alkyl bromides is kinetically more
favored than primary alkyl bromides under NiBr2/5a-catalyzed
Fig. 2 Reaction profiles of 10a and ((3-bromopropoxy)methyl)benzene that
were independently run under the standard cross-coupling reaction conditions.
Scheme 4 Coupling of alkyl bromides with alkyl-Bpin.
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Conclusions
In summary, we present a mild, easy-to-handle Ni-catalyzed
reductive coupling of two alkyl halides displays high chemo-
selectivity between primary and secondary alkyl halides, which
allows excellent functional group tolerance, and provides alkyl–
alkyl coupling products in good to excellent yields. The coupling
efficiency can be higher considering that a substantial amount
of (Bpin)2 (>0.3 equiv.) and secondary bromides may be recov-
ered.16 Given that the known Ni-catalyzed Suzuki method for the
construction of C(sp3)–C(sp3) bonds requires excess alkylbor-
anes (>1.5 equiv.),8 and Ni/Cu-catalyzed formation of alkyl-Bpin
generally requires excess pinB–Bpin (1.2–1.5 equiv.),15 the
current method that avoids the extra step of preparation of
alkylboranes may be practically useful in terms of atom
economy. Our preliminary studies suggest that an in situ alkyl-
boronate ester/Suzuki process is less likely. Instead, we propose
a mechanism involving a double oxidative addition of alkyl
halides to NiI. With suitable choices of base and ligands, the
formation of Ni–Bpin complexes may be the key to differenti-
ating the coupling alkyl partners.
Scheme 5 Proposed reaction pathways.
(4) Alkyl borylation vs. reductive coupling. Investigation of
the key factors favoring Fu's borylation and our reductive
coupling products reveals that the bases and ligands are more
signicant in altering the product formation. Using (3-bro-
mopropyl)benzene as the model substrate and iPr-Pybox 5a
as the ligand, the trace amount of borylation of (3-bromo-
propyl)benzene using LiOMe in our procedure can be boosted
to 26% using KOEt, and 35% using KOMe. This clearly
demonstrates that the lithium cation plays an important role
in reductive homocoupling (Scheme 6).16 In addition, even
with KOMe being the base, the dimerization product of
(3-bromopropyl)benzene was obtained in 60% yield using 8a
as the ligand.
Therefore, the use of 8a and LiOMe without premixing with
(Bpin)2 in NMP may facilitate formation of complex E from
complex D. We speculate that reductive elimination of Br–Bpin
from complex D is less likely. If it occurs, subsequent conver-
sion of Br–Bpin into the more stable MeOBpin may be crucial.
Alternatively, complex E may directly arise from nucleophilic
attack of methoxide on the boron of complex D.
(5) Origin of the cross-coupling selectivity. The present
Ni/(Bpin)2 reductive cross-coupling method is effective for
reactions between secondary and primary halides, and
between hindered primary iodide and a less hindered primary
bromide, wherein the more reactive alkyl halides are in
excess. It however is not efficient for the coupling between two
secondary halides varying polar substituents, and between
hindered primary and secondary halides, as well as between a
tertiary and a primary bromide.23 Hence, only matched sizes
and reactivities of the alkyl halides deliver the optimal cross-
coupling selectivities.
Acknowledgements
The reviewers are acknowledged for helpful comments. Finan-
cial support was provided by the Chinese NSF (nos 2097209 and
21172140), the general research grant (no. 10YZ04) and the
Program for Professor of Special Appointment (Eastern Scholar)
at Shanghai Institutions of Higher Learning Shanghai Educa-
tion Committee. Dr Hongmei Deng (Shanghai Univ.) is thanked
for helping with use of the NMR facility.
Notes and references
1 For selected reviews on coupling of alkyl halides, see: (a)
A. Rudolph and M. Lautens, Angew. Chem., Int. Ed., 2009,
48, 2656; (b) A. C. Frisch and M. Beller, Angew. Chem., Int.
Ed., 2005, 44, 674; (c) X. Hu, Chem. Sci., 2011, 2, 1867; (d)
J. Terao and N. Kambe, Acc. Chem. Res., 2008, 41, 1545; (e)
N. Kambe, T. Iwasaki and J. Terao, Chem. Soc. Rev., 2011,
40, 4937.
2 Pd-catalyzed alkyl–alkyl coupling, Suzuki: (a) J. H. Kirchhoff,
C. Dai and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 1945; (b)
M. R. Netherton and G. C. Fu, Angew. Chem., Int. Ed., 2002,
¨
41, 3910; (c) M. R. Netherton, C. Dai, K. Neuschutz and
G. C. Fu, J. Am. Chem. Soc., 2001, 123, 10099; (d)
T. Ishiyama, S. Abe, N. Miyaura and A. Suzuki, Chem. Lett.,
1992, 21, 691; Pd-Suzuki: (e) C. Valente, S. Baglione,
D. Candito, C. J. O'Brien and M. G. Organ, Chem.
Commun., 2008, 735; Negishi: (f) J. Zhou and G. C. Fu,
J. Am. Chem. Soc., 2003, 125, 12527.
3 Co-catalyzed Kumada reaction: G. Cahiez, C. Chaboche,
C. Duplais, A. Giulliani and A. Moyeux, Adv. Synth. Catal.,
2008, 350, 1484.
4 For recent examples of Cu-catalzyed C(sp3)–C(sp3) coupling,
Kumada: (a) J. Terao, H. Todo, S. A. Begum, H. Kuniyasu and
N. Kambe, Angew. Chem., Int. Ed., 2007, 46, 2086; (b) R. Shen,
Scheme 6 Comparison of the effect of bases.
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I. Takanori, J. Terao and N. Kambe, Chem. Commun., 2012,
48, 9313; (c) P. Ren, L. A. Stern and X. L. Hu, Angew. Chem.,
C.-S. Yan, Y. Peng, X.-B. Xu and Y.-W. Wang, Chem.–Eur. J.,
2012, 18, 6039.
Int. Ed., 2012, 51, 9110; (d) C.-T. Yang, Z.-Q. Zhang, 12 For catalytic C(sp3)–C(sp3) coupling, see: (a) M. R. Prinsell,
J. Liang, J.-H. Liu, X.-Y. Lu, H.-H. Chen and L. Liu, J. Am.
Chem. Soc., 2012, 134, 11124; Suzuki: (e) C.-T. Yang,
Z.-Q. Zhang, Y.-C. Liu and L. Liu, Angew. Chem., Int. Ed.,
2011, 50, 3904; Negishi: (f) C. F. Malosh and J. M. Ready, J.
Am. Chem. Soc., 2004, 126, 10240.
5 Fe-catalyzed alkyl–alkyl Suzuki coupling: T. Hatakeyama,
T. Hashimoto, K. K. A. D. S. Kathriarachchi, T. Zenmyo,
H. Seike and M. Nakamura, Angew. Chem., Int. Ed., 2012,
51, 8834.
D. A. Everson and D. J. Weix, Chem. Commun., 2010, 46,
5743; (b) S. M. Goldup, D. A. Leigh, R. T. McBurney,
P. R. McGonigal and A. Plant, Chem. Sci., 2010, 1, 383; (c)
X. Qian, A. Auffrant, A. Felouat and C. Gosmini, Angew.
Chem., Int. Ed., 2011, 50, 10402; (d) Y. Dai, F. Wu, Z. Zang,
H. You and H. Gong, Chem.–Eur. J., 2012, 18, 808; (e)
M. Iyoda, H. Sakaitani, M. Otsuka and M. Oda, Chem. Lett.,
1985, 14, 127; (f) J. Ma and T.-H. Chan, Tetrahedron Lett.,
´
~
1998, 39, 2499; (g) A. Millan, A. G. Campana, B. Bazdi,
´
6 For examples of Ni-catalyzed alkyl–alkyl Negishi reactions,
see: (a) S. W. Smith and G. C. Fu, Angew. Chem., Int. Ed.,
2008, 47, 9334; (b) F. O. Arp and G. C. Fu, J. Am. Chem.
Soc., 2005, 127, 10482; (c) S. Son and G. C. Fu, J. Am.
Chem. Soc., 2008, 130, 2756; (d) C. Fischer and G. C. Fu,
J. Am. Chem. Soc., 2005, 127, 4594; (e) J. Zhou and
G. C. Fu, J. Am. Chem. Soc., 2003, 125, 14726; (f) H. Gong,
D. Miguel, L. A. de Cienfuegos, A. M. Echavarren and
J. M. Cuerva, Chem.–Eur. J., 2011, 17, 3985; (h)
A. F. Barrero, M. M. Herrador, J. F. Q. del Moral,
P. Arteaga, M. Akssira, F. El Hanbali, J. F. Arteaga,
H. R. Dieguez and E. M. Sanchez, J. Org. Chem., 2007, 72,
2251; (i) V. S. Sridevi, W. K. Leong and Y. Zhu,
Organometallics, 2006, 25, 283; (j) A. F. Barrero,
M. M. Herrador, J. F. Q. del Moral, P. Arteaga, J. F. Arteaga,
´
´
´
R. Sinisi and M. R. Gagne, J. Am. Chem. Soc., 2007, 129,
´
´
1908; (g) A. E. Jensen and P. Knochel, J. Org. Chem.,
H. R. Dieguez and E. M. Sanchez, J. Org. Chem., 2007, 72,
2988. For Cu-mediated cross-coupling of activated alkyl
halides, see: (k) F. O. Ginah, T. A. Donovan, Jr,
S. D. Suchan, D. R. Pfennig and G. W. Ebert, J. Org. Chem.,
1990, 55, 584.
¨
2002, 67, 79; (h) A. Devasagayaraj, T. Studemann and
P. Knochel, Angew. Chem., Int. Ed. Engl., 1996, 34,
2723.
7 For Ni-catalyzed alkyl–alkyl Kumada reactions, see: (a)
P. M. Perez Garcia, T. Di Franco, A. Orsino, P. Ren and 13 X. Yu, T. Yang, S. Wang, H. Xu and H. Gong, Org. Lett., 2011,
X. L. Hu, Org. Lett., 2012, 14, 4286; (b) Z. Csok, 13, 2138.
O. Vechorkin, S. B. Harkins, R. Scopelliti and X. L. Hu, J. 14 Dimerization of allylic electrophiles as the byproducts under
Am. Chem. Soc., 2008, 130, 8156; (c) O. Vechorkin and
X. L. Hu, Angew. Chem., Int. Ed., 2009, 48, 2937; (d) P. Ren,
Pd/B2(pin)2 conditions is known: N. Miyaura, Tetrahedron
Lett., 1996, 37, 6889.
O. Vechorkin, K. von Allmen, R. Scopelliti and X. L. Hu, J. 15 (a) A. S. Dudnik and G. C. Fu, J. Am. Chem. Soc., 2012, 134,
Am. Chem. Soc., 2011, 133, 7084; (e) J. Terao, H. Watanabe,
A. Ikumi, H. Kuniyasu and N. Kambe, J. Am. Chem. Soc.,
2002, 124, 4222.
8 For Ni-catalyzed alkyl–alkyl Suzuki reactions: (a)
A. N. Owston and G. C. Fu, J. Am. Chem. Soc., 2010, 132,
11908; (b) B. Saito and G. C. Fu, J. Am. Chem. Soc., 2008,
130, 6694; (c) B. Saito and G. C. Fu, J. Am. Chem. Soc., 2007,
10693; (b) C.-T. Yang, Z.-Q. Zhang, H. Tajuddin, C.-C. Wu,
J. Liang, J.-H. Liu, Y. Fu, M. Czyzewska, P. G. Steel,
T. B. Marder and L. Liu, Angew. Chem., Int. Ed., 2012, 51,
528; (c) H. Ito and K. Kubota, Org. Lett., 2012, 14, 890; (d)
A. Joshi-Pangu, X. Ma, M. Diane, S. Iqbal, R. J. Kribs,
R. Huang, C.-Y. Wang and M. R. Biscoe, J. Org. Chem.,
2012, 77, 6629.
129, 9602; (d) Z. Lu and G. C. Fu, Angew. Chem., Int. Ed., 16 See the ESI† for details.
2010, 49, 6676; (e) A. Wilsily, F. Tramutola, N. A. Owston 17 In the preparation of organozinc reagents, a polar group less
and G. C. Fu, J. Am. Chem. Soc., 2012, 134, 5794; (f)
S. L. Zultanski and G. C. Fu, J. Am. Chem. Soc., 2011, 133,
15362.
9 For a review on alkyl-metallics, see: R. Jana, T. P. Pathak and
M. S. Sigman, Chem. Rev., 2011, 111, 1417.
10 A. K. Steib, T. Thaler, K. Komeyama, P. Mayer and
P. Knochel, Angew. Chem., Int. Ed., 2011, 50, 3303.
11 For selected examples of C(sp3)–C(sp2) coupling, without in
than 3 carbons away from that of C–X bond may accept a
single electron followed by electron transfer into the s*(C–
X) bond: P. Knochel and R. D. Singer, Chem. Rev., 1993, 93,
2117.
18 The reason why the reaction ceases aer 16 hours is not
clear, but the intentional addition of 11a to the reaction
resulted in lower product formation, suggesting the
reactions display product inhibition.
´
situ organometallic reagents: (a) F. Wu, W. Lu, Q. Qian, 19 (a) F. Gonzalez-Bobes and G. C. Fu, J. Am. Chem. Soc., 2006,
Q. Ren and H. Gong, Org. Lett., 2012, 14, 3044; (b) H. Yin,
C. Zhao, H. You, Q. Lin and H. Gong, Chem. Commun.,
2012, 48, 7034; (c) D. A. Everson, R. Shrestha and
128, 5360; and references cited therein; (b) H. Gong,
´
R. S. Andrews, J. L. Zuccarello, S. J. Lee and M. R. Gagne,
Org. Lett., 2009, 11, 879.
D. J. Weix, J. Am. Chem. Soc., 2010, 132, 920; and with in 20 A non-radical process involving the ring opening of a
situ organometallic formation: (d) A. Krasovskiy,
C. Duplais and B. H. Lipshutz, J. Am. Chem. Soc., 2009,
131, 15592; (e) W. M. Czaplik, M. Mayer and A. J. von
Wangelin, Angew. Chem., Int. Ed., 2009, 48, 607; (f)
(cyclopropylmethyl)nickel complex is less likely, since a
product bearing cyclopropylmethyl group may be observed,
see: (a) T. Iwasaki, H. Takagawa, S. P. Singh, H. Kuniyasu
and N. Kambe, J. Am. Chem. Soc., 2013, 135, 9604; (b)
4028 | Chem. Sci., 2013, 4, 4022–4029
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J. M. Brown, J. A. Conneely and K. Mertis, J. Chem. Soc., 23 Coupling of tBu–Br with 2a generated 20% of isomeric
Perkin Trans. 2, 1974, 905; (c) M. S. Silver, P. R. Shafer,
J. E. Nordlander, C. Ruchardt and J. D. Roberts, J. Am.
Chem. Soc., 1960, 82, 2646.
product. For references involving t-Bu–Ni intermediates,
see: (a) S. L. Zultanski and G. C. Fu, J. Am. Chem. Soc.,
¨
2013, 135, 624–627; (b) C. Lohre, T. Droge, C. Wang and
21 For a proposed Negishi mechanism involving alkyl radical
species, see: (a) G. D. Jones, J. L. Martin, C. McFarland,
O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon,
T. Konovalova, P. J. Desrochers, P. Pulay and D. A. Vicic, J.
Am. Chem. Soc., 2006, 128, 13175; (b) X. Lin, J. Sun, Y. Xi
and D. Lin, Organometallics, 2011, 30, 3284; (c)
F. Glorius, Chem.–Eur. J., 2011, 17, 6052; (c) A. Joshi-
Pangu, C.-Y. Wang and M. R. Biscoe, J. Am. Chem. Soc.,
2011, 133, 8478; (d) J. Breitenfeld, O. Vechorkin,
C. Corminboeuf, R. Scopelliti and X. Hu, Organometallics,
2010, 29, 3686.
~
´
V. B. Phapale, E. Bunuel, M. Garcıa-Iglesias and
´
D. J. Cardenas, Angew. Chem., Int. Ed., 2007, 46, 8790.
22 Z. Li, Y.-Y. Jiang and Y. Fu, Chem.–Eur. J., 2012, 18, 4345.
This journal is ª The Royal Society of Chemistry 2013
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