Highly nucleophilic Vitamin B12-assisted nickel-catalysed reductive coupling of aryl halides and non-activated alkyl tosylates

Article abstract of DOI:10.1039/c7cc01932g

Reductive cross-coupling of aryl halides with ubiquitous alkyl tosylates was developed using a combination of nickel and vitamin B₁₂ (VB₁₂: cyanocobalamin) catalysts. The tosylate was activated by reduced VB₁₂ to form alkyl cobalt(iii), which served as a good alkylating agent for aryl-nickel species, leading to C(sp³)-C(sp²) bond formation.

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Highly nucleophilic vitamin B12-assisted nickel-catalysed reductive
coupling of aryl halides and non-activated alkyl tosylates†
Received 00th January 2017,
Accepted 00th January 2017
Kimihiro Komeyama,* Ryo Ohata, Shinnosuke Kiguchi and Itaru Osaka
Reductive cross-coupling of aryl halides with ubiquitous alkyl tosylates was developed using a combination of nickel and
vitamin B12 (VB12: cycnocobalamin) catalysts. The tosylate was activated by reduced VB12 to form alkyl cobalt(III) which
served as a good alkylating agent for aryl-nickel species, leading to the C(sp3)–C(sp2) bond formation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Transition metal-catalysed traditional cross-coupling between
aryl metals (Ar-M) and alkyl electrophiles (Alkyl-X) has been
recognised as a mainstay approach for C(sp3)–C(sp2) bond
formation for organic synthesis (Scheme 1a).1 In the past few
decades, several methods for the bond formation have been
developed where inhibition of
a competitive β-hydride
elimination2 and stabilisation of the generated alkyl metal
species3 are essential for effective cross-coupling. In contrast, a
radical-type cross-coupling by transition metal catalysts has
been recently developed.4 In particular, Ni-catalysed reactions
have been extensively explored in Kumada-Tamao-Corriu,4e
Negishi,4f
Suzuki-Miyaura,4g,h
Stille,4i
Hiyama4j
and
Sonogashira4j couplings, leading to numerous C(sp3)–C(sp2)
bonds (Scheme 1b). In these couplings, most transformations
contain single electron transfer (SET) as the key process for the
activation of the alkyl electrophile with a generated aryl-nickel
species
A to form an alkyl-radical. The SET process can employ
the reaction of not only simple alkyl halides but also N-
hydroxyphthalimide (NHP) esters as alkylating agents to form a
high-valent organonickel species B.5 Recently, the Ni-catalysed
coupling was merged with a photocatalytic reaction in which
alkyl boronates,6 silicates7 or carboxylic acids8 were used as
alternative alkylating agents (Scheme 1c). However, parts of
this approach require organometallic reagents prepared from
abundant alkyl halides; they occasionally require expensive
photocatalysts and awkward activation steps to transform
from abundant organic functions such as hydroxyl and carboxyl
groups to redox-active forms. Hence, an alternative approach
that utilizes more ubiquitous alkylating agents is in high
demand.
Scheme 1 Synthetic approaches towards C (sp3)–C (sp2) bonds.
electrophilicity, as shown in Cu- and Ni-catalysed reactions.2g,3
However, alkyl tosylates are inactive in the SET process
because of the high-lying antibonding orbital of the C–O bond.9
In fact, the low reactivity of alkyl tosylates has been reported
in the Ni-catalysed radical-type cross-couplings4h,i without a
halogen/sulfonate exchange.4b, 10 In contrast to the radical-
type-couplings described above, the reductive cross-coupling
between aryl and alkyl halide is an ideal approach for the
C(sp3)–C(sp2) bond formation11 because it does not require
preparation of organometallic species (Scheme 1d). However,
Alkyl tosylates are attractive alkylating agents for the
C(sp3)–C(sp2) bond formation because of their availability from
the corresponding abundant alcohols and their high
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Table
cyclohexyl tosylate (1a).a
1
Screening of Ni/VB12-catalysed cross-coupling of 4-anisyl iodide (2a) with Table 2 Substrate scope of the Ni/VB12-catalysed coupling.a
entry
change from standard conditions
yield of 3aa (%)b
yield of 4 (%)b
3b 87% (70%b), X = I
3c 77%, X = I
3d 74%, X = I
1
none
68
0
trace
0
2
3c
without NiBr2 and 2,2’-bpy
without VB12
0
59
4
CoCl(dmgH)(py) instead of VB12
Co(Pc) instead of VB12
CoBr2(PPh3)2 instead of VB12
CoBr2(2,2’-bpy) instead of VB12
without KI
50
0
15
3e 51%, X = Cl
3f 84%, X = Br
3g 94%, X = Br
5
64
6
0
30
7
0
50
8
52
27
44
43
39
7
11
3h 91%, X = Br
3i 52%, X = Br
9
NaI instead of KI
trace
trace
5
10
11
12
13
14
15
16
Et4NI instead of KI
Et4NBr instead of KI
Zn instead of Mn
trace
7
Terpyridinec instead of 2,2’-bpy
6,6’-Me 2bpy instead of 2,2’-bpy
4,4’-(MeO)2bpy instead of 2,2’-bpy
4,4’-(tBu)2bpy instead of 2,2’-bpy
trace
64
47
72
3j 61%, X = I
3k 72%, X = I
3l 80%, X = I
trace
trace
a
b
Reaction conditions: 1a (0.38 mmol) and 2a (0.25 mmol).
GC yield.
cTertpyridine: 4'-(4-tolyl)-2,2':6',2''-terpyridine.
3n 61%, X = I
alkyl sulfonates have been utilized in a limited number of
studies.12 Recently, Weix13 demonstrated a new strategy for
using alkyl-alcohol derivatives as alkylating reagents in the Ni-
catalysed reductive C (sp3)–C (sp2) coupling (Scheme 1e). A
reduced cobalt phthalocyanine anion {CoI(Pc)–} served as a
nucleophile for activation of benzyl mesylates and phosphates,
giving rise to a benzyl radical. Although the strategy allowed a
diarylmethanes synthesis from benzyl alcohol derivatives, the
alkylating agents were limited to benzyl alcohol derivatives.
Non-activated alkyl tosylates were not available in the coupling
(see below). Conversely, the nucleophilicity of such cobalt
3m 75%, X = I
3o 82%, X = I
3p 75%, X = Br
a
b
Reaction conditions: 1 (0.38 mmol) and 2 (0.25 mmol). Isolated yields.
Without KI.
complete the reaction (ca. 100 h). The combination of nickel
and cobalt complexes was extremely important for the
coupling. Thus, most of alkyl tosylate 1a was consumed
without a NiBr2(2,2’-bpy) catalyst, but the aryl iodide 2a
remained unchanged after the reaction (entry 2). The reaction
in the absence of VB12 produced 4,4’-dimethoxybiphenyl (4)
(59% yield) as the sole product without the consumption of 1a
complexes is enhanced by the axial ligand connected to the
14
tetracoordinated square-planar cobalt (I).
The axial
coordination elevates the energy of the electron-occupied dz2
orbital, resulting in increased nucleophilicity. During the course
of our studies of Ni- and Co-catalysed transformations,15 we
found that vitamin B12 (VB12, cyanocobalamin) was a highly
effective catalyst for the activation of primary and secondary
alkyl tosylates.16 Herein, we report a preliminary observation
for a Ni/VB12-catalysed cross-coupling of aryl halides with non-
activated alkyl tosylates (Scheme 1f).
(entry
CoCl(dmgH)2(py)17 was also effective in the coupling, giving rise
to 3a (50% yield) as well as (15% yield) (entry 4). In contrast,
3).
Other nucleophilic
cobaloxime(III)
like
4
Co(Pc), CoBr2 (PPh3)2 and CoBr2 (bpy) were not effective,
exclusively gave 4, in 30–60% yields (entries 5–7). These results
strongly indicate a requirement for highly nucleophilic cobalt
catalysts for coupling with the non-activated alkyl tosylates.
Furthermore, a reaction with cyclohexyl mesylate, instead of
1a, afforded trace amount of 3a. Addition of KI increased the
Cross-coupling of cyclohexyl tosylate (1a) with 4-anisyl
iodide (2a) was carried out using a mixture of NiBr2 (10 mol%),
2,2’-bipyridine (2,2’-bpy, 10 mol%) and VB12 (10 mol%) with
Mn reductant (2.0 equiv.) in the presence of KI (1.0 equiv.) as
an additive (Table 1). Under standard conditions, 1-cyclohexyl-
4-methoxybenzene (3a) was obtained in 68% yield (entry 1).
The reaction proceeded at 25 °C, but it required more time to
reaction efficiency, preventing the formation of 4 12c
however,
;
it was not indispensable (entry 8). A control experiment for the
reaction of 1a with KI (see ESI†) and the result in entry 3 (Table
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Me-cobalamin (III)-induced methylation of nickel complexes.20
1) clearly revealed that 1a was not converted into cyclohexyl
iodide during the reaction. Other salt additives, NaI, Et4NI and
Et4NBr, provided 3a in 27%–44% yields (entries 9–11). The
role of the salt is not clear; it may accelerate an electron
transfer from Mn reductant to catalysts18 and/or it may
stabilise the nickel intermediate.19 Zinc reductant was inferior
to manganese, wherein a large amount of dehalogenation
product of 2a was formed (entry 12). In the coupling, the
choice of ligand was crucial. Terpyridine and bulky bipyridine
ligands resulted in a decreasing of the reaction rate and
Scheme 3 Plausible reaction mechanism. DMB = 5,6-dimethylbenzimidazolyl.
The nucleophilic substitution of alkyl halides with reduced
VB12 to form alkyl-cobalamin(III) was recognised as a key
process in the VB12-induced organic transformation.16 In
addition, the methylcobalamin(III) served as a “methyl iodide
equivalent” for the methylation of a nickel complex under
forming of 4 (entries 13 and 14). Electron-rich bipyridines were
also effective, although with slightly lower yields (entries 15
and 16).
Further, we investigated the substrate scope of the Ni/VB12-
catalysed coupling by employing various aryl halides and alkyl
tosylates as summarised in Table 2. For cross-coupling, primary
alkyl tosylates were more active than secondary ones, probably
due to the reactivity towards the nucleophilic substitution of
cobalt, where no biaryl by-product was detected. The effect of
KI was re-investigated in the reaction with primary alkyl
tosylate; the alkylated arene 3b (70% yield) was obtained in
the absence of KI. Aryl halides possessing electron-donating
and -withdrawing substituents were well-tolerated, giving rise
reducing conditions via
a reaction with the nickel and
generated methyl radicals (Scheme 2). In line with the
literature, 20 we tested the possibility of the radical-type
methylation of nickel intermediates with methylcobalamin(III)
under (Eq. 1). Consequently, the reaction gave 2-
methylnaphthalene (5) in 30% yield and naphthalene in 20%
yield. This result strongly supports the involvement of radical-
type alkylation of nickel with the alkyl-cobalamin in the
coupling. Moreover, a radical-clock experiment using 5-hexenyl
tosylate (1q) and 4-(EtO2C)C6H4I resulted in the selective
formation of cross-coupling products 3q’ along with a radical
cyclisation product 3q” as a minor constituent (Eq. 2). This
result implies that the alkylation of aryl-nickel species with the
generated alkyl radicals is faster than the radical cyclisation as
described in the previously reported Ni-catalysed couplings.21
to the corresponding coupling products 3b–3f in good yields. Cl
and Br functions were partially efficacious for the reaction of
electron-deficient aryl halides (for 3e and 3f). Naphthyl and
heteroaryl halides also underwent this transformation to
produce the alkylated arenes 3g–3j in good to high yields. For
Although reason of the olefin-isomerisation is not clear,22
a
the alkyl tosylate, various substituents such as phenyl (for 3j),
branched alkyl chain (for 3k), ether (for 3l), phthalimide (for
3m), ester (for 3n) and ketone (for 3o) were also capable of
coupling. Cyclopentyl tosylate (for 3p) also showed good
reactivity in the cross coupling as cyclohexyl tosylate 1a did in
Table 1.
similar isomerisation was observed in the reaction of 9-decenyl
tosylate (1r), giving rise to 3r and 3r’ with a closely equimolar
ratio of isomers (Eq. 3).
Based on these results, a plausible catalytic cycle for the
Ni/VB12-catalysed cross-coupling between aryl halides and alkyl
tosylates is illustrated in Scheme 3. The coupling comprises
two cycles catalysed by nickel and cobalt that can be initiated
by the generation of a [Ni0] complex and [CoI] from the
reduction of the initial Ni(II) and vitamin B12 with Mn
reductant. The oxidative addition of aryl halides
the sequent reduction with Mn preferentially produces
monovalent aryl nickel species . In contrast, the generated
highly nucleophilic [CoI]
undergoes a facile-substitution
reaction with alkyl tosylates to give alkyl-cobalamin(III) . The
alkylation of with via the alkyl-radical transfer would
produce the high-valent aryl(alkyl)nickel(III) intermediate as
well as . The rapid reductive elimination of could take place
to produce the alkylated arenes followed by the regeneration
2
to [Ni0] and
C
E
1
F
C
F
D
E
D
3
of [Ni0] with Mn. At present, we cannot rule out an alternative
mechanism that can be initiated from the reaction of zero-
valent nickel species with alkyl radicals followed by oxidative
addition of aryl halides.23
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In conclusion, we have demonstrated a cross-coupling
approach for C(sp3)–C(sp2) bond formation from the reaction
of aryl halides and ubiquitous alkyl-alcohol derivatives using a
combination of nickel and highly nucleophilic cobalt catalysts.
This serves as a new and complementary bond-forming
protocol that is likely to find broad application because
alcohols are abundant, stable and inexpensive carbon sources.
Preliminary mechanistic studies suggest that the reduced VB12
activates alkyl tosylate via substitution to give alkyl-
cobalamin(III), leading to radical-type alkylation to produce the
high-valent aryl(alkyl)nickel intermediate. Further mechanistic
studies and further substrate scope including synthetic
applications of this transformation are ongoing in our
laboratory.
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This work was supported by a Grant-Aid for Scientific
Research (KAKENHI) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
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Highly nucleophilic vitamin B12-assisted nickel-catalysed reductive coupling of aryl halides and non-
activated alkyl tosylates
Kimihiro Komeyama,* Ryo Ohata, Shinnosuke Kiguchi and Itaru Osaka
Reductive cross-coupling of aryl halides with ubiquitous alkyl tosylates was developed using a combination of nickel and vitamin
B12 catalysts. The tosylate was activated by reduced vitamin B12 to form alkyl cobalt(III) which served as a good alkylating agent
for aryl-nickel species, leading to the C(sp3)–C(sp2) bond formation.
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