Nickel/Cobalt-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates

Article abstract of DOI:10.1021/acscatal.9b03352

The C(sp³)-C(sp³) cross-coupling of alkyl halides with alkyl tosylates has been developed by employing a combination of nickel and nucleophilic cobalt catalysts in the presence of a manganese reductant. This method provides a straightforward route to a diverse set of not only secondary-primary but also primary-primary C(sp³)-C(sp³) linkages under mild conditions without using alkyl-metallic reagents. Mechanistic studies suggest the formation of alkyl radicals from both alkyl halides and alkyl tosylates. Additionally, cross-coupling could be applied to the short-step synthesis of a histone deacetylase inhibitor, Vorinostat.

Full text of DOI:10.1021/acscatal.9b03352

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Article
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Nickel/Cobalt-Catalyzed C(sp)-C(sp) Cross-
Coupling of Alkyl Halides with Alkyl Tosylates
Kimihiro Komeyama, Takuya Michiyuki, and Itaru Osaka
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03352 • Publication Date (Web): 04 Sep 2019
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ACS Catalysis
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Nickel/Cobalt-Catalyzed C(sp3)-C(sp3) Cross-Coupling of
Alkyl Halides with Alkyl Tosylates
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Kimihiro Komeyama,* Takuya Michiyuki, and Itaru Osaka
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, 1-4-1 Kagamiyama, Higashi-
Hiroshima City, Hiroshima 739-8527, Japan
KEYWORDS: C(sp3)-C(sp3) Cross-Coupling, Nickel Catalyst, Cobalt Catalyst, Alkyl Tosylate, Alkyl Halide
ABSTRACT: The C(sp3)-C(sp3) cross-coupling of alkyl halides with alkyl tosylates has been developed by employing a combination
of nickel and nucleophilic cobalt catalysts in the presence of manganese reductant. This method provides a straightforward route to
a diverse set of not only secondary-primary but also primary-primary C(sp3)-C(sp3) linkages under mild conditions without using
alkyl-metallic reagents. Mechanistic studies suggest the formation of alkyl radicals from both alkyl halides and alkyl tosylates.
Additionally, the cross-coupling could be applied into a short-step synthesis of a histone deacetylase inhibitor, Vorinostat.
C(sp3)-C(sp3) linkages are ubiquitous in a range of
Scheme 1. Transition metal-catalyzed C(sp3)-C(sp3) cross-
naturally occurring products and pharmaceuticals.1 The C(sp3)-
coupling
moiety possesses a three-dimensional spread, the introduction
of which increases not only the compound lipophilicity but also
its hydrophilicity. Thereby, a statistical correlation between
clinical success and the complexity of drug candidates has been
demonstrated in association with the number of C(sp3)-moieties
in a molecule.2 The development of a direct and selective
C(sp3)-C(sp3) cross-coupling approach could, therefore, lead to
efficient synthetic pathways to C(sp3)-rich drug candidates.
To accomplish such C(sp3)-C(sp3) cross-couplings, how to
distinguish between two different carbon-sources is of
particular importance. Thereby, alkyl-metallic reagents such as
alkyl-magnesium, -zinc, or -boranes are commonly employed
as nucleophilic carbon-sources to alkyl halide electrophiles in
traditional cross-couplings3 and even in recently developing Ni-
catalyzed radical-type cross-couplings4 (Scheme 1a). However,
these approaches using reactive alkyl-metallic reagents limit the
molecular diversity of the resulting C(sp3)-C(sp3) linkages and
might lead to the halogen-metal exchange.5 Although the
Barbier-type cross-coupling, which involves the in-situ
generation of alkyl-metallic reagents from alkyl halides and
6
magnesium metal, has been developed, it does not offer a
reliable solution to the problem. Hence, the development of a
C(sp3)-C(sp3) cross-coupling in the absence of alkyl-metallic
reagents remains highly desirable.
In this context, the reductive cross-coupling between two
different alkyl halides has attracted increasing attention as an
alternative for the traditional cross-coupling. More specifically,
Gong and coworkers pioneered a nickel-catalyzed reductive
cross-coupling (Scheme 1b), wherein the halides could be
activated by the single-electron-transfer (SET) mechanism of a
low-valent nickel to provide an alkyl-nickel intermediate.7a
Recently, this protocol has been improved using diboron as a
hindered and less-hindered primary alkyl halides to avoid the
terminal reductant.7b However, the chemoselectivity of the
reductive cross-coupling relies heavily on the reactivity of the
alkyl halides. Thus, this coupling is limited to transformations
between secondary and primary alkyl halides as well as between
competitive homo-coupling,8 because this method involves the
same SET event for the first and second activation-steps of alkyl
halides. Very recently, the reductive cross-coupling protocol
has been extended to the transformation between alkyl halides
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and benzyl oxalates9a (or benzaldehyde hydrazones9b), but
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Table 1. Optimization of the reaction conditions
formable C(sp3)-C(sp3) linkages have been still limited. In
contrast, MacMillan and co-workers have developed a Ni/Ir-
catalyzed C(sp3)-C(sp3) cross-coupling between alkyl halides
and alkyl carboxylic acids under photo-irradiation conditions
(Scheme 1c).10 This process is of particular interest except for
using expensive iridium catalyst because the abundant,
inexpensive, and bench-stable alkyl carboxylic acids can be
used as alternatives to alkyl-metallic reagents, providing a
powerful synthetic method for a wide range of C(sp3)-C(sp3)
linkages.
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Aliphatic alcohols can also be considered abundant C(sp3)-
sources11 and versatile starting materials for C-H bond
functionalizations guided by the hydroxyl group.12
Furthermore, alkyl alcohols can be easily converted into stable
and electrophilic alkyl sulfonic esters by simple and
sophisticated procedures.13 In particular, alkyl tosylates could
be utilized as superior surrogates of alkyl halides in traditional
Pd-,14 Ni-,15 or Cu-catalyzed16 cross-couplings using alkyl-
metallic reagents. However, the tosylate cannot be used in the
nickel-catalyzed radical-type cross-coupling (Scheme 1a–c)17
since it is inactive in the SET process due to its high-lying σ*(C-
O) orbital.18
entry change from standard conditions
yield (%)a
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none
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with KI (1.0 equiv
NiCl2(6,6’-Mebpy) instead of NiCl2(bpy)
NiCl2(4,4’-MeO2Cbpy) instead of NiCl2(bpy)
NiCl2(4,4’-MeObpy) instead of NiCl2(bpy)
NiCl2(4,4’-Phbpy) instead of NiCl2(bpy)
NiCl2(4,4’-Mesbpy) instead of NiCl2(bpy)
NiCl2(4,4’-tBubpy) instead of NiCl2(bpy)
without NiCl2(bpy)
trace
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83 (77)
0
To render alkyl tosylates available in the radical-type
cross-coupling, we recently developed a hybrid-catalytic
system consisting of nickel and nucleophilic cobalt catalysts.19
As illustrated in Scheme 1d, the highly nucleophilic planar-
cobalt species, derived from the reduction of vitamin B12,
undergoes an SN2-type oxidative addition of alkyl tosylates to
give an alkyl-[Co] intermediate A.20 The subsequent reaction of
A with aryl halides or alkyl tosylates in the presence of a nickel-
catalyst then leads to C(sp2)-C(sp3)19b,c or homo-C(sp3)-C(sp3)
cross-coupling products,19a respectively. These findings for
alkyl tosylate utilization led us to hypothesize that our catalytic
system could be employed for the formation of cross-C(sp3)-
C(sp3) linkages between alkyl halides with alkyl tosylates
(Scheme 1d). Thus, the intermediate A would perform a
transalkylation with a low-valent nickel to give an alkyl-[Ni]
intermediate B.21 In contrast, alkyl halides could oxidatively
add into the alkyl-[Ni] via the SET-type oxidative addition
(SET-OA)22 rather than the cobalt23 to provide dialkyl-[Ni]
species C, thereby producing a cross-coupling product through
the reductive elimination. The nickel/cobalt-catalyst system
would, therefore, be expected to efficiently distinguish between
two carbon-sources to accomplish a selective C(sp3)-C(sp3)
cross-coupling reaction. We herein report a C(sp3)-C(sp3) cross-
coupling between alkyl halides and alkyl tosylates using a
combination of nickel and nucleophilic cobalt catalysts,
wherein this method demonstrated high catalytic performance
and broad substrate scope, offering a new synthetic approach
for a diverse set of not only secondary-primary but also
primary-primary C(sp3)-C(sp3) linkages from readily available
C(sp3)-sources under mild reaction conditions.
10 without VB12
0
a
GC yield determined by using dimethyl terephthalate as an
internal standard. The value in parenthesis indicates the isolated
yield.
optimal results.24 Although the use of a KI additive positively
affected the Ni/Co-catalyzed C(sp2)-C(sp3) cross-coupling,19a,b
its addition had no significant effect on the present coupling
(entry 2). In the cross-coupling, other nucleophilic cobalt
catalysts were not effective (See, Table S2 in SI). The further
screening revealed the pivotal role of the nickel-ligands. Thus,
substituents at the 6,6ʹ-positions of the bipyridine ligand
completely suppressed the coupling. Electron-withdrawing and
-donating groups at the 4,4ʹ-positions gave low yields (entries 4
and 5). While as the bulkiness of the 4,4ʹ-substituents increased,
the yield of 3a trended to increase (entries 6–8). Although the
substituent effect is not clear, bulkier substituents may increase
the solubility of the nickel-complex in the reaction media22b
and/or stabilize the transition state for the activation of alkyl
halides by the Ni-catalyst.25 Furthermore, the substituent may
provoke monomerization of the Ni-complex, which would
possess a high reduction ability22a,25 in terms of performing a
To test the feasibility of this process for the C(sp3)-C(sp3)
cross-coupling, we selected 3-phthalimidyl-1-propyl tosylate
(1a) as a coupling partner for cyclohexyl bromide (2a). After
careful evaluation of the reaction conditions, we found that a
combination of NiCl2(bpy) (10 mol %, bpy = 2,2ʹ-bipyridine)
and VB12 (10 mol %, VB12 = vitamin B12) in the presence of Mn
powder (2.0 equiv) gave cross-coupling product 3a in 70%
yield (entry 1, Table 1). The coupling highly depended on the
solvent used, with DMF (N,N-dimethylformamide) giving
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transalkylation between nickel and alkyl-[CoIII], as illustrated in
Table 2. Scope of alkyl halides 2 a
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Scheme 2. Thus, the transalkylation would be triggered by a
SET event of nickel center for the alkyl-cobalamin Aʹ to form
alkyl-[CoII] Bʹ. Spontaneous cleavage of the labile Co-C bond
on Bʹ would then yield a super-reduced vitamin B12s (VB12s) and
an alkyl radical. The nickel would subsequently trap the radical
to give alkyl-[Ni]OTs Cʹ 21 In fact, in the absence of the nickel-
catalyst, little consumption of 1a was observed, and a catalytic
amount (10% yield) of a proto-detosylated product of 1a was
obtained as a single product (entry 9). Moreover, no cross-
coupling product was observed in the absence of VB12 (entry
10). These results would suggest that the reductive cleavage of
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3b 60%, 48 h
3c 59%, 21 h b
3d 55%, 16 h
Scheme 2. Transalkylation between nickel and alkyl-cobalt
3f 68% (98:2),
3g 23% (1:99),
3e 48%, 22 h b
24 h c,d
59 h c,e
alkyl-cobalamin Aʹ would be induced by low-valent nickel not
manganese reductant, and also clearly indicating the importance
of the combination of nickel and nucleophilic cobalt in the
cross-coupling.
3h 48% (1:99), 24 h c,d 3i 65%, 37 h
3j 23%, 16 h
With the optimized conditions in hand (entry 8, Table 1),
we subsequently explored the scope of alkyl halides for the
cross-coupling reaction using 1a. As presented in Table 2, the
catalytic system displayed widespread functional-group
tolerance. Aza- and oxa-cyclohexyl bromides were compatible,
providing the corresponding cross-coupling products 3b–3e in
good yields. Substituted cycloalkyl bromides (for 3f–3h),
cyclobutyl bromide (for 3i), and 3-oxetanyl bromide (for 3j)
were also tolerated. Notably, a diastereoconvergent formation
of 3h from the cis-rich 4-tert-butylcyclohexyl bromide
indicated the generation of a cyclohexyl radical, as previously
described for the transition metal-catalyzed radical-type cross-
coupling.4f,26 Acyclic secondary alkyl bromides also took part
in the coupling process, giving rise to the desired products 3k
and 3l. Furthermore, the present cross-coupling allowed
primary alkyl tosylate 1a to join with not only secondary but
also primary alkyl halides. Thus, the treatment of alkyl
chlorides under the modified conditions in the presence of 10
mol % pyrazine (See, Table S3 in SI)27 gave C(1º)-C(1º)
linkages, thereby yielding 3m–3x. Notably, alkyl chlorides
attached with amide functions at the appropriate positions
positively affected the cross-coupling, giving rise to coupling
products 3t and 3u in excellent yields.28 In addition, the
substituent effect depended on the tether-length, with
chlorinated alkyl amides bearing longer chains (n = 2 and 3)
giving the desired coupling products (3v and 3w) in moderate
yields. Importantly, the transformation allowed alkyl tosylate to
regioselectively coupled with primary alkyl chlorides in the
presence of secondary alkyl chloride, yielding the chloride-
containing cross-coupling product 3x in 55% yield.
3m (n=2), 56%, 28 h f,g
3n (n=5), 60%, 18 hf,g
3k 23%, 13 h
3l, 28%, 18 h
3o, 60%, 28 h f,g
3p, 54%, 40 h f,g
3q, 38%,45 h f,g
3r, 54%, 36 h f,g,h
3s, 66%, 24 h g
3t, 93%, 22 h f,g
3u (n=1), 93%, 27 h f,g
3v (n=2), 39%, 22 h f,g
3w (n=3), 44%, 28 h f,g
b
3x, 55%, 24 h f,g
a
c
Isolated yield. Boc: tert-butoxycarbonyl. The value in
parenthesis indicates the diastereomeric ratio (cis:trans) of the
d
product. A cis/trans-mixture (90:10) of alkyl bromides was
e
f
used. trans-Alkyl bromide was used. Alkyl chlorides were
used. Substrate ratio (1a:RCl) = 1.5:1. g Pyrazine (10 mol %) was
added. h TBS: tert-butyldimethylsilyl.
The substrate scope for alkyl tosylates was then examined
as outlined in Table 3. It was found that alkenyl and alkynyl
groups (for 4d and 4e) as well as simple alkyl substituents (for
4a–4c) were tolerated. Furthermore, silyl ethers (for 4f and 4g),
the ketone moiety (for 4h), and the ester functionality (for 4i)
were also compatible, giving rise to the corresponding C(sp3)-
C(sp3) linkages in good yields. The presence of chloro and
pinacolboryl groups on the aryl ring did not interfere with the
coupling, selectively forming C(sp3)-C(sp3) linkages to give 4j
and 4k. The critical step of the cross-coupling reaction would
be considerable to be the substitution of the alkyl tosylates with
the nucleophilic cobalt species to provide alkyl-[CoIII] A as
shown in Scheme 1d. Indeed, cyclohexyl and cycloheptyl
tosylates failed to produce the cross-coupling products under
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identical conditions. In contrast, a slightly bulker primary alkyl
tosylate bearing an alkyl substituent at the 2-position was
compatible, as were 5-membered cyclic tosylates, giving the
desired cross-coupling products 4l–4n in good yields.
Furthermore, the Ni/Co-catalyzed cross-coupling reaction
Page 4 of 8
provided a short synthetic pathway to access a histone
deacetylase inhibitor, Vorinostat, precursor 4o in 82% yield.
Facile removal of the 2,4-dimethoxybenzyl group of 4o (See,
page S-23–24 in SI) and subsequent amidation of the ester
functionality29 could give Vorinostat itself.30
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3
4
Compared with entry 8 (Table 1), the reaction of 1a-
Br with 2a mainly afforded homo-coupling product 5 in 61%
yield, along with the cross-coupling product 3a in 28% yield
(Scheme 3a). The low chemoselectivity of this process suggests
that the substrate combination of alkyl tosylates and alkyl
halides is essential to distinguish between two different carbon
sources. In the present cross-coupling, methyl-cobalamin acted
as both the alkylating agent as well as the catalyst, yielding
cross-coupling products 6 and 3a in 15 and 54% yields,
respectively (Schemes 3b and 3c). This supports the generation
of alkyl-[CoIII] species during the transformation. Furthermore,
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Table 3. Scope of alkyl tosylate 1 a
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Scheme 3. Mechanistic investigations.
4a 65%, 18 h b,c
4b 54%, 15 h b,c
(a) Reductive cross-coupling between different alkyl halides
4c 65%, 48 h
4e 36%, 48 h
4d 60%, 48 h
(b) Me-cobalamin acting as an alkylation agent
4f 41%, 48 h b,c
(c) Me-cobalamin acting as an catalyst
4g 55%, 48 h
4h 84%, 24 h b,c
(d) Radical-clock experiment using cyclopropylmethyl tosylate
Ar = 4-ClC6H4: 4j 98%, 24 h
4i 43%, 13 h b,c
Ar = 4-BpinC6H4: 4k 77%, 24 h
X = CH2: 4m 54%, 24 h
X = NBoc: 4n 71%, 24 h
(e) Radical-clock experiment using cyclopropylmethyl chloride
4l 56%, 48 h
4o 82%, 30 h
a
b
Isolated yield. Alkyl bromides were used. Substrate ratio
radical-clock experiments using cyclopropylmethyl tosylate or
chloride provided ring-opening products 7 and 8 in 26 and 34%
(1:RBr) = 1:1.5. c Without pyrazine.
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Experimental procedures, characterization and spectra date,
additional experimental results (PDF)
yields, respectively (Schemes 3d and 3e), with no other
products bearing the cyclopropylmethyl moiety. In addition to
the diastereoconvergent transformation of 4-substituted
cyclohexyl bromide into trans-3h (Table 2), these experiments
also indicate that the present cross-coupling employs two alkyl
radicals generated from not only alkyl halides via the SET-OA
but also alkyl tosylates via homolytic cleavage of Co-C bond on
the generated alkyl cobalt intermediate as illustrate in Scheme
2.
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AUTHOR INFORMATION
Corresponding Author
* Kimihiro Komeyama. E-mail: kkome@hiroshima-u.ac.jp
ORCID
Kimihiro Komeyama: 0000-0001-7111-2112
Itaru Osaka: 0000-0002-9879-2098
Although a detailed mechanism of the Ni/Co-catalyzed
C(sp3)-C(sp3) cross-coupling process has yet to be developed,
based on our experimental results and literature reports into similar
systems, we tentatively proposed a mechanistic outline, as
presented in Scheme 4. More specifically, the nucleophilic cobalt
species D, generated from the reduction of VB12 by Mn, initially
engages with alkyl tosylate 1 in an SN2 displacement to provide
alkyl-[CoIII] intermediate E, which undergoes a transalkylation
with zero-valent nickel F to form alkyl-[NiII] F.21b Mn then reduces
G to give alkyl-[NiI] intermediate H, and the oxidative addition of
alkyl halide 2 to intermediate H produces dialkyl-[NiIII] I.10 Rapid
reductive elimination of I then yields cross-coupling product 3 or
4, in addition to [NiI]-X J. Finally, the catalytic cycle is closed by
the reduction of J to F. However, we cannot rule out another
pathway; the transmetallation of alkyl-[CoIII] E with alkyl-[NiI],
delivered from the reaction of zero-valent nickel with an alkyl
halide and sequent reduction with manganese, would also give the
similar dialkyl-[NiIII] intermediate I.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI (Grant Number:
JP18K05106).
REFERENCES
(1) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances
in Homogeneous Nickel Catalysis. Nature 2014, 509, 299–309.
(2) (a) Lovering, F.; Bikker, J.; Humblet, C. Escape From Flatland:
Increasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52, 6752–6756. (b) Lovering, F. Escape From
Flatland 2: Complexity and Promiscuity. Med. Chem. Commun. 2013,
4, 515–519.
(3) With Pd catalysts: (a) Netherton, M. R.; Dai, C. Y.; Neuschütz,
K.; Fu, G. C. Room-Temperature Alkyl-Alkyl Suzuki Cross-Coupling
of Alkyl Bromides That Possess Beta Hydrogens. J. Am. Chem. Soc.
2001, 123, 10099–10100. (b) Hadei, N.; Kantchev, E. A. B.; O'Brien,
C. J.; Organ, M. G. Room-Temperature Negishi Cross-Coupling of
Unactivated Alkyl Bromides with Alkyl Organozinc Reagents
Utilizing a Pd/N-Heterocyclic Carbene Catalyst. J. Org. Chem. 2005,
70, 8503–8507. With Ag catalyst: (c) Someya, H.; Yorimitsu, H.;
Oshima, K. Silver-Catalyzed Cross-Coupling Reactions of Alkyl
Bromides with Alkyl or Aryl Grignard Reagents. Tetrahedron Lett.
2009, 50, 3270–3272. With Ni catalysts: (d) Devasagayaraj, A.;
Stüdemann, T.; Knochel, P. A New Nickel‐Catalyzed Cross‐Coupling
Reaction Between sp3 Carbon Centers. Angew. Chem. Int. Ed. 1995,
34, 2723–2725. (e) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. Ni-
or Cu-Catalyzed Cross-Coupling Reaction of Alkyl Fluorides with
Grignard Reagents. J. Am. Chem. Soc. 2003, 125, 5646–5647. With Cu
catalysts: (f) Cahiez, G.; Chaboche, C.; Jézéquel, M. Cu-Catalyzed
Scheme 4. Plausible reaction mechanism
Alkylation of Grignard Reagents:
a New Efficient Procedure.
Tetrahedron 2000, 56, 2733–2737. (g) Terao, J.; Todo, H.; Begum, S.
A.; Kuniyasu, H.; Kambe, N. Copper-Catalyzed Cross-Coupling
Reaction of Grignard Reagents with Primary-Alkyl Halides:
Remarkable Effect of 1-Phenylpropyne. Angew. Chem. Int. Ed. 2007,
46, 2086–2089. With Fe catalyst: (h) Dongol, K. G.; Koh, H.; Sau, M.;
Chai, C. L. L. Iron-Catalysed sp3–sp3 Cross-Coupling Reactions of
Unactivated Alkyl Halides with Alkyl Grignard Reagents. Adv. Synth.
Catal. 2007, 349, 1015–1018. (i) Hatakeyama, T.; Hashimoto, T.;
Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M.
Iron-Catalyzed Alkyl-Alkyl Suzuki-Miyaura Coupling. Angew. Chem.
Int. Ed. 2012, 51, 8834–8837. (j) Guisán Ceinos, M.; Tato, F.; Buñuel,
E.; Calle, P.; Cárdenas, D. J. Fe-Catalysed Kumada-Type Alkyl–Alkyl
Cross-Coupling. Evidence for the Intermediacy of Fe(I) Complexes.
Chem. Sci. 2013, 4, 1098–1104. (k) Iwasaki, T.; Shimizu, R.; Imanishi,
R.; Kuniyasu, H.; Kambe, N. Cross-Coupling Reaction of Alkyl
Halides with Alkyl Grignard Reagents Catalyzed by Cp-Iron
Complexes in the Presence of 1,3-Butadiene. Chem. Lett. 2018, 47,
763–766. With Co catalyst: (l) Cahiez, G.; Chaboche, C.; Duplais, C.;
Giulliani, A.; Moyeux, A. Cobalt‐Catalyzed Cross‐Coupling Reaction
Between Functionalized Primary and Secondary Alkyl Halides and
Aliphatic Grignard Reagents. Adv. Synth. Catal. 2008, 350, 1484–
1488. (m) Zhou, W.; Napoline, J. W.; Thomas, C. M. A Catalytic
Application of Co/Zr Heterobimetallic Complexes: Kumada Coupling
of Unactivated Alkyl Halides with Alkyl Grignard Reagents. Eur. J.
In conclusion, we reported the successful C(sp3)-C(sp3)
cross-coupling between alkyl tosylates and alkyl halides
catalyzed by the combination of nickel and nucleophilic cobalt
complexes. The cross-coupling was found to proceed under
mild conditions and was able to tolerate a diverse set of
functional groups, thereby providing a direct approach for not
only secondary-primary but also primary-primary C(sp3)-C(sp3)
linkages from abundant carbon-sources. Mechanistic studies
revealed the participation of alkyl-[CoIII] species and the
generation of alkyl radicals from both alkyl halides and alkyl
tosylates. Further investigations into the synthetic utility of this
protocol for various organic transformations are ongoing in our
laboratory.
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Inorg. Chem. 2011, 2011, 2029–2033. (n) Iwasaki, T.; Takagawa, H.;
W. C. Metallaphotoredox-Catalysed sp3-sp3 Cross-Coupling of
Carboxylic Acids with Alkyl Halides. Nature 2016, 536, 322–325.
(11) Luk, H. T.; Mondelli, C.; Ferré, D. C.; Stewart, J. A.; Pérez-
Ramírez, J. Status and Prospects in Higher Alcohols Synthesis From
Syngas. Chem. Soc. Rev. 2017, 46, 1358–1426.
Singh, S. P.; Kuniyasu, H.; Kambe, N. Co-Catalyzed Cross-Coupling
of Alkyl Halides with Tertiary Alkyl Grignard Reagents Using a 1,3-
Butadiene Additive. J. Am. Chem. Soc. 2013, 135, 9604–9607. (o)
Iwasaki, T.; Takagawa, H.; Okamoto, K.; Singh, S. P.; Kuniyasu, H.;
Kambe, N. The Cobalt-Catalyzed Cross-Coupling Reaction of Alkyl
Halides with Alkyl Grignard Reagents: a New Route to Constructing
Quaternary Carbon Centers-. Synthesis 2014, 46, 1583–1592. (p)
Iwasaki, T.; Yamashita, K.; Kuniyasu, H.; Kambe, N. Co-Catalyzed
Cross-Coupling Reaction of Alkyl Fluorides with Alkyl Grignard
Reagents. Org. Lett. 2017, 19, 3691–3694.
1
2
3
4
5
6
7
8
(12) (a) Wang, X.; Lu, Y.; Dai, H. X.; Yu, J.-Q. Pd(II)-Catalyzed
Hydroxyl-Directed C−H Activation/C−O Cyclization: Expedient
Construction of Dihydrobenzofurans. J. Am. Chem. Soc. 2010, 132,
12203–12205. (b) Hu, A.; Guo, J.-J.; Pan, H.; Tang, H.; Gao, Z.; Zuo,
Z. Δ-Selective Functionalization of Alkanols Enabled by Visible-
Light-Induced Ligand-to-Metal Charge Transfer. J. Am. Chem. Soc.
2018, 140, 1612–1616. (c) Guo, J.-J.; Hu, A.; Zuo, Z. Photocatalytic
Alkoxy Radical-Mediated Transformations. Tetrahedron Lett. 2018,
59, 2103–2111. (d) Zhu, Y.; Huang, K.; Pan, J.; Qiu, X.; Luo, X.; Qin,
Q.; Wei, J.; Wen, X.; Zhang, L.; Jiao, N. Silver-Catalyzed Remote
Csp3-H Functionalization of Aliphatic Alcohols. Nat. Commun. 2018,
9, 2625. (e) Xia, G.; Weng, J.; Liu, L.; Verma, P.; Li, Z.; Yu, J.-Q.
Reversing Conventional Site-Selectivity in C(sp3)-H Bond Activation.
Nat. Chem. 2019, 11, 571–577.
(13) (a) Kotsuki, H.; Kadota, I.; Ochi, M. A New Expeditious
Synthesis of (+)-Exo-Brevicomin via Efficient C-C Bond Formation of
Triflates. Tetrahedron Lett. 1989, 30, 3999–4000. (b) Martinelli, M. J.;
Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.;
Vaidyanathan, R. Dibutyltin Oxide Catalyzed Selective Sulfonylation
of Α-Chelatable Primary Alcohols. Org. Lett. 1999, 1, 447–450. (c)
Bouzide, A.; Sauvé, G. Silver(I) Oxide Mediated Highly Selective
Monotosylation of Symmetrical Diols. Application to the Synthesis of
Polysubstituted Cyclic Ethers. Org. Lett. 2002, 4, 2329–2332. (d)
Michael J Martinelli; Rajappa Vaidyanathan; Joseph M Pawlak;
Naresh K Nayyar; Ulhas P Dhokte; Christopher W Doecke; Lisa M H
Zollars; Eric D Moher; Vien Van Khau, A.; Košmrlj, B. Catalytic
Regioselective Sulfonylation of α-Chelatable Alcohols:ꢀ Scope and
Mechanistic Insight. J. Am. Chem. Soc. 2002, 124, 3578–3585. (e) Lee,
D.; Williamson, C. L.; Chan, L.; Taylor, M. S. Regioselective, Borinic
Acid-Catalyzed Monoacylation, Sulfonylation and Alkylation of Diols
and Carbohydrates: Expansion of Substrate Scope and Mechanistic
Studies. J. Am. Chem. Soc. 2012, 134, 8260–8267.
9
(4) (a) Saito, B.; Fu, G. C. Alkyl-Alkyl Suzuki Cross-Couplings of
Unactivated Secondary Alkyl Halides at Room Temperature. J. Am.
Chem. Soc. 2007, 129, 9602–9603. (b) Gong, H.; Gagné, M. R.
Diastereoselective Ni-Catalyzed Negishi Cross-Coupling Approach to
Saturated, Fully Oxygenated C-Alkyl and C-Aryl Glycosides. J. Am.
Chem. Soc. 2008, 130, 12177–12183. (c) Vechorkin, O.; Hu, X. Nickel-
Catalyzed Cross-Coupling of Non-Activated and Functionalized Alkyl
Halides with Alkyl Grignard Reagents. Angew. Chem. Int. Ed. 2009,
48, 2937–2940. (d) Owston, N. A.; Fu, G. C. Asymmetric Alkyl−Alkyl
Cross-Couplings of Unactivated Secondary Alkyl Electrophiles:
Stereoconvergent Suzuki Reactions of Racemic Acylated Halohydrins.
J. Am. Chem. Soc. 2010, 132, 11908–11909. (e) Choi, J.; Fu, G. C.
Catalytic Asymmetric Synthesis of Secondary Nitriles via
Stereoconvergent Negishi Arylations and Alkenylations of Racemic Α-
Bromonitriles. J. Am. Chem. Soc. 2012, 134, 9102–9105. (f) Perez
Garcia, P. M.; Di Franco, T.; Orsino, A.; Ren, P.; Hu, X. Nickel-
Catalyzed Diastereoselective Alkyl-Alkyl Kumada Coupling
Reactions. Org. Lett. 2012, 14, 4286–4289. (g) Jiang, X.; Sakthivel, S.;
Kulbitski, K.; Nisnevich, G.; Gandelman, M. Efficient Synthesis of
Secondary Alkyl Fluorides via Suzuki Cross-Coupling Reaction of 1-
Halo-1-Fluoroalkanes. J. Am. Chem. Soc. 2014, 136, 9548–9551. (h)
Perez Garcia, P. M.; Di Franco, T.; Epenoy, A.; Scopelliti, R.; Hu, X.
From Dimethylamine to Pyrrolidine: the Development of an Improved
Nickel Pincer Complex for Cross-Coupling of Nonactivated Secondary
Alkyl Halides. ACS Catal. 2016, 6, 258–261. (i) Qin, T.; Cornella, J.;
Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.;
Eastgate, M. D.; Baran, P. S. A General Alkyl-Alkyl Cross-Coupling
Enabled by Redox-Active Esters and Alkylzinc Reagents. Science
2016, 352, 801–805. (j) Lévêque, C.; Corcé, V.; Chenneberg, L.;
Ollivier, C.; Fensterbank, L. Photoredox/Nickel Dual Catalysis for the
C(Sp3)–C(Sp3) Cross‐Coupling of Alkylsilicates with Alkyl Halides.
Eur. J. Org. Chem. 2017, 2017, 2118–2121.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Netherton, M. R.; Fu, G. C. Suzuki Cross‐Couplings of Alkyl
Tosylates That Possess β Hydrogen Atoms: Synthetic and Mechanistic
Studies. Angew. Chem. Int. Ed. 2002, 41, 3910–3912.
(15) Eno, M. S.; Lu, A.; Morken, J. P. Nickel-Catalyzed Asymmetric
Kumada Cross-Coupling of Symmetric Cyclic Sulfates. J. Am. Chem.
Soc. 2016, 138, 7824–7827.
(5) Klement, I.; Knochel, P.; Chau, K.; Cahiez, G. Preparation of
Alkylzinc Bromides Using a New Mn/Cu Catalyzed Bromine-Zinc
Exchange Reaction. Tetrahedron Lett. 1994, 35, 1177–1180.
(6) Liu, J.-H.; Yang, C.-T.; Lu, X.-Y.; Zhang, Z.-Q.; Xu, L.; Cui,
M.; Lu, X.; Xiao, B.; Fu, Y.; Liu, L. Copper-Catalyzed Reductive
Cross-Coupling of Nonactivated Alkyl Tosylates and Mesylates with
Alkyl and Aryl Bromides. Chem. Eur. J. 2014, 20, 15334–15338.
(7) (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-
Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides.
Org. Lett. 2011, 13, 2138–2141. (b) Xu, H.; Zhao, C.; Qian, Q.; Deng,
W.; Gong, H. Nickel-Catalyzed Cross-Coupling of Unactivated Alkyl
Halides Using Bis(Pinacolato)Diboron as Reductant. Chem. Sci. 2013,
4, 4022.
(8) (a) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal,
P. R.; Plant, A. Ligand-Assisted Nickel-Catalysed sp3–sp3
Homocoupling of Unactivated Alkyl Bromides and Its Application to
the Active Template Synthesis of Rotaxanes. Chem. Sci. 2010, 1, 383.
(b) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Nickel-Catalyzed,
Sodium Iodide-Promoted Reductive Dimerization of Alkyl Halides,
Alkyl Pseudohalides, and Allylic Acetates. Chem. Commun. 2010, 46,
5743–5745.
(16) (a) Fouquet, G.; Schlosser, M. Improved Carbon‐Carbon
Linking by Controlled Copper Catalysis. Angew. Chem. Int. Ed. 1974,
13, 82–83. (b) Ramírez-Contreras, R.; Morandi, B. Chemo- and
Regioselective Functionalization of Polyols Through Catalytic C(sp3)-
C(sp3) Kumada-Type Coupling of Cyclic Sulfate Esters. Org. Lett.
2016, 18, 3718–3721. (c) Iwasaki, T.; Imanishi, R.; Shimizu, R.;
Kuniyasu, H.; Terao, J.; Kambe, N. Copper-Catalyzed Alkyl-Alkyl
Cross-Coupling Reactions Using Hydrocarbon Additives: Efficiency
of Catalyst and Roles of Additives. J. Org. Chem. 2014, 79, 8522–
8532. (d) Yang, C.-T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-H.; Lu, X.-Y.;
Chen, H.-H.; Liu, L. Copper-Catalyzed Cross-Coupling of
Nonactivated Secondary Alkyl Halides and Tosylates with Secondary
Alkyl Grignard Reagents. J. Am. Chem. Soc. 2012, 134, 11124–11127.
(17) (a) Powell, D. A.; Fu, G. C. Nickel-Catalyzed Cross-Couplings
of Organosilicon Reagents with Unactivated Secondary Alkyl
Bromides. J. Am. Chem. Soc. 2004, 126, 7788–7789. (b) Powell, D. A.;
Maki, T.; Fu, G. C. Stille Cross-Couplings of Unactivated Secondary
Alkyl Halides Using Monoorganotin Reagents. J. Am. Chem. Soc.
2005, 127, 510–511. (c) González-Bobes, F.; Fu, G. C. Amino
Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of
Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with
Arylboronic Acids. J. Am. Chem. Soc. 2006, 128, 5360–5361. (d) Lu,
X.; Wang, Y.; Ben Zhang; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Bin
Xiao; Fu, Y. Nickel-Catalyzed Defluorinative Reductive Cross-
Coupling of Gem-Difluoroalkenes with Unactivated Secondary and
Tertiary Alkyl Halides. J. Am. Chem. Soc. 2017, 139, 12632–12637.
(e) Chen, H.; Jia, X.; Yu, Y.; Qian, Q.; Gong, H. Nickel-Catalyzed
Reductive Allylation of Tertiary Alkyl Halides with Allylic
(9) (a) Yan, X.-B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z.
Reductive Coupling of Benzyl Oxalates with Highly Functionalized
Alkyl Bromides by Nickel Catalysis. Chem. Sci. 2018, 9, 4529–4534.
(b) Zhu, D.; Lv, L.; Qiu, Z.; Li, C.-J. Nickel-Catalyzed Cross-Coupling
of Umpolung Carbonyls and Alkyl Halides. J. Org. Chem. 2019, 84,
6312–6322.
(10) Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D.
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Page 7 of 8
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Carbonates. Angew. Chem. Int. Ed. 2017, 129, 13283–13286. (f) Wang,
Diastereoinduction. Chem. Commun. 2012, 48, 9376. (d) Zultanski, S.
L.; Fu, G. C. Nickel-Catalyzed Carbon-Carbon Bond-Forming
Reactions of Unactivated Tertiary Alkyl Halides: Suzuki Arylations. J.
Am. Chem. Soc. 2013, 135, 624–627.
X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.; Wang, X.;
Gong, H. Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl
Iodides with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2018, 140,
14490–14497.
1
2
3
4
5
6
7
8
(27) Although the actual role of the pyrazine additive is not clear at
present, a similar additive effect was demonstrated in Ni-catalyzed
couplings. (a) An, L.; Xiao, Y.-L.; Min, Q.-Q.; Zhang, X. Facile Access
to Fluoromethylated Arenes by Nickel‐Catalyzed Cross‐Coupling
Between Arylboronic Acids and Fluoromethyl Bromide. Angew.
Chem. Int. Ed. 2015, 54, 9079–9083. (b) Xu, C.; Guo, W.-H.; He, X.;
Guo, Y.-L.; Zhang, X.-Y.; Zhang, X. Difluoromethylation of
(Hetero)Aryl Chlorides with Chlorodifluoromethane Catalyzed by
Nickel. Nat. Commun. 2018, 9, 1170. (c) Sheng, J.; Ni, H. Q.; Zhang,
H. R.; Zhang, K. F.; Wang, Y. N.; Wang, X.-S. Nickel‐Catalyzed
Reductive Cross‐Coupling of Aryl Halides with Monofluoroalkyl
Halides for Late‐Stage Monofluoroalkylation. Angew. Chem. Int. Ed.
2018, 317, 1881–7639.
(28) The similar substituent effect was reported in reference 4d.
(29) (a) Salmi-Smail, C.; Fabre, A.; Dequiedt, F.; Restouin, A.;
Castellano, R.; Garbit, S.; Roche, P.; Morelli, X.; Brunel, J. M.;
Collette, Y. Modified Cap Group Suberoylanilide Hydroxamic Acid
Histone Deacetylase Inhibitor Derivatives Reveal Improved Selective
Antileukemic Activity. J. Med. Chem. 2010, 53, 3038–3047. (b)
Gediya, L. K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.;
Njar, V. C. O. A New Simple and High-Yield Synthesis of
Suberoylanilide Hydroxamic Acid and Its Inhibitory Effect Alone or in
Combination with Retinoids on Proliferation of Human Prostate
Cancer Cells. J. Med. Chem. 2005, 48, 5047–5051.
(18) (a) Ganson, J. R.; Schulenberg, S.; Closson, W. D. Competitive
C-O and S-O Cleavage Mechanisms in Reaction of Alkyl
Alkanesulfonates with Arene Anion Radicals. Tetrahedron Lett. 1970,
11, 4397–4400. (b) Lipshutz, B. H.; Wilhelm, R. S.; Nugent, S. T.;
Little, R. D.; Baizer, M. M. Electrochemical Peak Potentials of Typical
Substrates Used for Coupling Reactions with Organocuprates: Effects
of Solvent. J. Org. Chem. 1983, 48, 3306–3308. (c) Ashby, E. C.;
Argyropoulos, J. N. Single Electron Transfer in the Reaction of
Enolates with Alkyl Halides. J. Org. Chem. 1985, 50, 3274–3283.
(19) (a) Komeyama, K.; Tsunemitsu, R.; Michiyuki, T.; Yoshida, H.;
Osaka, I. Ni/Co-Catalyzed Homo-Coupling of Alkyl Tosylates.
Molecules 2019, 24, 1458. (b) Komeyama, K.; Yamahata, Y.; Osaka,
I. Nickel and Nucleophilic Cobalt-Catalyzed Trideuteriomethylation of
Aryl Halides Using Trideuteriomethyl P-Toluenesulfonate. Org. Lett.
2018, 20, 4375–4378. (c) Komeyama, K.; Ohata, R.; Kiguchi, S.;
Osaka, I. Highly Nucleophilic Vitamin B12-Assisted Nickel-Catalysed
Reductive Coupling of Aryl Halides and Non-Activated Alkyl
Tosylates. Chem. Commun. 2017, 53, 6401–6404.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) (a) Schrauzer, G. N.; Deutsch, E.; Windgassen, R. J. The
Nucleophilicity of Vitamin B12s. J. Am. Chem. Soc. 1968, 90, 2441–
2442. (b) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K. Preparation
of Alkylchromium Reagents by Reduction of Alkyl Halides with
Chromium(II) Chloride Under Cobalt Catalysis. J. Org. Chem. 1989,
54, 4732–4734.
(30) (a) Stowell, J. C.; Huot, R. I.; Van Voast, L. The Synthesis of
N-Hydroxy-N′-Phenyloctanediamide and Its Inhibitory Effect on
Proliferation of AXC Rat Prostate Cancer Cells. J. Med. Chem. 1995,
38, 1411–1413. (b) Grant, S.; Easley, C.; Kirkpatrick, P. Vorinostat.
Nat Rev Drug Discov 2007, 6, 21–22.
(21) (a) Ram, M. S.; Riordan, C. G. Methyl Transfer From a Cobalt
Complex to Ni(Tmc)+ Yielding Ni(Tmc)Me+:
a
Model for
Methylcobalamin Alkylation of CO Dehydrogenase. J. Am. Chem. Soc.
1995, 117, 2365–2366. (b) Eckert, N. A.; Dougherty, W. G.; Yap,
G. P. A.; Riordan, C. G. Methyl Transfer From Methylcobaloxime to
(Triphos)Ni(PPh3): Relevance to the Mechanism of Acetyl Coenzyme
a Synthase. J. Am. Chem. Soc. 2007, 129, 9286–9287.
(22) (a) Anderson, T. J.; Jones, G. D.; Vicic, D. A. Evidence for a
NiI Active Species in the Catalytic Cross-Coupling of Alkyl
Electrophiles. J. Am. Chem. Soc. 2004, 126, 8100–8101. (b) Jones, G.
D.; McFarland, C.; Anderson, T. J.; Vicic, D. A. Analysis of Key Steps
in the Catalytic Cross-Coupling of Alkyl Electrophiles Under Negishi-
Like Conditions. Chem. Commun. 2005, 4211–4213. (c) Breitenfeld,
J.; Ruiz, J.; Wodrich, M. D.; Hu, X. Bimetallic Oxidative Addition
Involving Radical Intermediates in Nickel-Catalyzed Alkyl–Alkyl
Kumada Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004–
12012. (d) Breitenfeld, J.; Wodrich, M. D.; Hu, X. Bimetallic Oxidative
Addition in Nickel-Catalyzed Alkyl–Aryl Kumada Coupling
Reactions. Organometallics 2014, 33, 5708–5715. (e) Choi, J.; Martín-
Gago, P.; Fu, G. C. Stereoconvergent Arylations and Alkenylations of
Unactivated Alkyl Electrophiles: Catalytic Enantioselective Synthesis
of Secondary Sulfonamides and Sulfones. J. Am. Chem. Soc. 2014, 136,
12161–12165.
(23) Murakami, Y.; Hisaeda, Y.; Kajihara, A.; Ohno, T.
Hydrophobic Vitamin B12. II. Coordination Geometry and Redox
Behavior of Heptamethyl Cobyrinate in Nonaqueous Media. Bull.
Chem. Soc. Jpn. 1984, 57, 405–411.
(24)
DMA
(N,N-dimethylacetamide):
trace,
DMSO
(dimethylsulfoxide): 4%, DMPU (N,N'-dimethylpropyleneurea): 8%,
MeCN: 0%, DMF/DMSO (10:1): 16% yield.
(25) Lin, X.; Phillips, D. L. Density Functional Theory Studies of
Negishi Alkyl–Alkyl Cross-Coupling Reactions Catalyzed by a
Methylterpyridyl-Ni(I) Complex. J. Org. Chem. 2008, 73, 3680–3688.
(26) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. Iron-
Catalyzed Cross-Coupling of Primary and Secondary Alkyl Halides
with Aryl Grignard Reagents. J. Am. Chem. Soc. 2004, 126, 3686–
3687. (b) Ito, S.; Fujiwara, Y.-I.; Nakamura, E.; Nakamura, M. Iron-
Catalyzed Cross-Coupling of Alkyl Sulfonates with Arylzinc Reagents.
Org. Lett. 2009, 11, 4306–4309. (c) Kawamura, S.; Kawabata, T.;
Ishizuka, K.; Nakamura, M. Iron-Catalysed Cross-Coupling of
Halohydrins with Aryl Aluminium Reagents: a Protecting-Group-Free
Strategy
Attaining
Remarkable
Rate
Enhancement
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