Nickel-Catalyzed Mizoroki–Heck-Type Reactions of Unactivated Alkyl Bromides

Article abstract of DOI:10.1002/anie.201810757

The development of a general, nickel-catalyzed alkyl-Mizoroki–Heck reaction of unactivated alkyl bromides is described. The mild reaction proceeds efficiently using a wide range of primary and secondary alkyl bromides, and examples of intermolecular cross

Full text of DOI:10.1002/anie.201810757

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Nickel-Catalyzed Mizoroki-Heck-Type Reactions of Unactivated
Alkyl Bromides
Authors: Megan Kwiatkowski and Erik John Alexanian
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810757
Angew. Chem. 10.1002/ange.201810757
Link to VoR: http://dx.doi.org/10.1002/anie.201810757
http://dx.doi.org/10.1002/ange.201810757

10.1002/anie.201810757
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Mizoroki-Heck-Type Reactions of Unactivated
Alkyl Bromides
Megan R. Kwiatkowski and Erik J. Alexanian*
Abstract: The development of a general, nickel-catalyzed alkyl-
Mizoroki-Heck reaction of unactivated alkyl bromides is described.
The mild reaction proceeds efficiently using a wide range of primary
and secondary alkyl bromides, and examples of intermolecular cross-
couplings are provided. Reaction alkene regioselectivity is
significantly enhanced over prior carbocyclizations using palladium
catalysis. Mechanistic investigations are consistent with a direct
carbocyclization in contrast to the auto-tandem atom-transfer
cyclization and halide elimination previously observed with palladium
catalysis.
Recent studies have established the utility of nickel catalysts
in the activation of alkyl halides for a variety of useful C–C bond
formations.[4] The development of a nickel-catalyzed Mizoroki-
Heck-type reaction of unactivated alkyl halides remains a major
challenge, in part owing to the significantly higher energetic
barrier to β-hydride elimination as compared to palladium
systems.[5] Previous work towards this goal was limited to the use
of more reactive alkyl iodides, and generated both alkene
regioisomers and reductive cyclization byproducts.[2e] Herein, we
report a general nickel-catalyzed Mizoroki-Heck-type reaction of
unactivated alkyl bromides. This catalytic transformation
proceeds under mild conditions with excellent alkene
regioselectivity using an inexpensive first-row metal. We also
demonstrate that intermolecular cross-couplings are possible
using this simple catalytic system.
The Mizoroki-Heck reaction is an invaluable transformation for the
construction of C–C bonds under mild conditions.[1] While the use
of aryl or vinyl electrophiles in these coupling reactions has been
widely demonstrated, recent efforts have successfully extended
the scope to include unactivated alkyl electrophiles.[2] Owing to
the general difficulty in activating alkyl electrophiles using
transition metal catalysts, this has typically required either: 1) the
use of alkyl iodides[2e,g,k] or 2) the use of strongly reducing
conditions (e.g., alkylmetal reductants).[2a–d] Recent efforts in our
group have led to the development of a general palladium-
catalyzed carbocyclization of unactivated primary and secondary
alkyl bromides under mild conditions.[3] While this work
significantly increased the scope of catalytic carbocyclizations of
unactivated alkyl electrophiles, control over the production of
alkene regioisomers was poor, limiting the overall synthetic utility
(Figure 1). Moreover, the development of a system using an
inexpensive, first-row metal catalyst in lieu of palladium would be
highly desirable.
Our studies commenced with the carbocyclization of
unactivated alkyl bromide 1 (Table 1). A catalytic system
comprised of 10 mol % NiBr2·glyme and 10 mol % bisphosphine
ligand
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xantphos) provided the cyclized products 2 and 3 in excellent
yield and alkene regioselectivity (entry 1). For comparison, the
palladium-based catalytic system we previously reported[3] proved
inferior with respect to both reaction efficiency and especially
alkene regioselectivity (entry 2). Substituting Ni(cod)2 as
precatalyst gave 2 and 3 with comparable yield and selectivity
relative to the standard conditions (entry 3). Notably, the use of
air stable NiBr2·glyme enables reaction setup without a glovebox
with only a slight decrease in yield and selectivity (entry 4).
Decreasing the catalyst loading to 5 mol % had a minor effect on
chemical yield but significantly decreased alkene regioselectivity
(entry 5). Substituting 1,10-phenanthroline or PPh3 as ligand
decreased reaction efficiency (entries 6–7), as did switching to
Cs2CO3 as base (entry 8). No reaction occurred in the absence of
Mn or the nickel precatalyst (entries 9–10).
Previous work: palladium-catalyzed carbocyclizations of alkyl bromides via auto-tandem catalysis
5 mol % [Pd(allyl)Cl]2
20 mol % dtbpf
Br
TsN
TsN
+
TsN
2 equiv Et3N
PhCF3, 100 °C
Me
Me
74% combined yield, 4.7:1 rr
This work: nickel-catalyzed alkyl-Mizoroki-Heck-type carbocyclizations
Table 1. Catalyst system development for the nickel-catalyzed alkyl-Mizoroki-
Heck-type carbocyclizations.[a,b]
Inexpensive first-row catalyst
Excellent alkene regioselectivity
10 mol % NiBr2•glyme
Br
10 mol % xantphos
TsN
TsN
Broad substrate scope with
increased reaction efficiency
3 equiv Mn
3 equiv Et3N
MeCN, 80 °C
Me
Me
Me
Me
97% yield, 23:1 rr
10 mol % NiBr2•glyme
10 mol % xantphos
Br
Intermolecular cross-coupling
possible
TsN
+
TsN
TsN
3 equiv Mn
3 equiv Et3N
MeCN, 80 °C
O
Me
Me
Ph2P
PPh2
Figure 1. Metal-catalyzed carbocyclizations of unactivated alkyl bromides with
alkenes.
xantphos
1
2
3
combined
yield (%)
entry
variation from standard conditions above
none
ratio 2:3
1
2
97
23:1
5 mol % [Pd(allyl)Cl]2, 20 mol % dtbpf, 2
equiv Et3N, PhCF3, 100 °C
74
1:4.7
3
4
10 mol % Ni(cod)2 instead of NiBr2•glyme
no glovebox
88
86
>25:1
21:1
[*]
M. R. Kwiatkowski, Prof. E. J. Alexanian
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
5 mol % instead of 10 mol %
NiBr2•glyme/xantphos
5
6
85
<5
8.4:1
-
10 mol % 1,10-phenanthroline instead of
xantphos
E-mail: eja@email.unc.edu
7
8
20 mol % PPh3 instead of xantphos
3 equiv Cs2CO3 instead of Et3N
no Mn
25
0
1.8:1
-
-
-
Supporting information for this article is given via a link at the end
of the document.
9
0
10
no NiBr2•glyme
0
This article is protected by copyright. All rights reserved.

10.1002/anie.201810757
Angewandte Chemie International Edition
COMMUNICATION
Br
TsN
TsN
[a] Reactions were performed with [1]0 = 0.25 M. [b] Yield and alkene
regioisomeric ratio determined by 1H NMR spectroscopy of crude reaction
mixture using an internal standard. Product 2 formed as a mixture of alkene E
and Z isomers, see Supporting Information for details.
H
88
14:1.7:1 rr
10
H
21
20
Br
Me
H
With optimized conditions in hand, we applied our catalytic
system to the carbocyclizations of a range of substrates (Table 2).
Reactions of primary alkyl bromides were successful with di- and
trisubstituted alkenes (entries 1–6), styrenes (entry 7), and
terminal alkenes (entry 8) to afford a variety of five-membered
carbo- and heterocyclic products.[6] Reactions proceeded with
good to excellent levels of alkene regioselectivity, a distinct
advantage over palladium-based systems. Efficient construction
of bicyclic frameworks was also possible, as demonstrated by the
reactions of cycloalkenyl substrates 18 and 20 (entries 9–10).
Moreover, spirocycle 19 was inaccessible with palladium catalysis,
further highlighting the utility of the present system.[7] Secondary
alkyl bromides were also viable substrates, as bis-tetrahydrofuran
product 23 was formed from 22 with high diastereoselectivity
(entry 11). Importantly, the reaction is not limited to five-
membered ring synthesis; primary bromide 24 undergoes a 6-exo
cyclization to afford piperidine derivative 25 in good yield and with
excellent olefin regioselectivity (entry 12).[8]
73[d]
(>95:5 dr)
O
11
O
O
O
H
23
22
Br
TsN
TsN
64
>25:1 rr
12[c]
25
24
[a] Reactions were performed with [substrate]0 = 0.25 M in MeCN at 80 °C with
10 mol % NiBr2•glyme, 10 mol % xantphos, 3 equiv Mn, and 3 equiv Et3N as
base. [b] Isolated yield, rr = regioisomeric ratio, see Supporting Information for
details regarding minor alkene regioisomers. [c] Reactions were performed with
[substrate]0 = 0.25 M in DMSO. [d] Yield determined by 1H NMR spectroscopy
of crude reaction mixture using an internal standard. [e] Yield of major alkene
regioisomer, see Supporting Information for details.
We continued by exploring the use of the nickel-based system
in intermolecular cross-coupling. Despite the development of a
number of intermolecular alkyl-Mizoroki-Heck-type cross-
couplings using palladium catalysis,[9] there are no general nickel-
catalyzed variants available.[10,11] We examined the cross-
coupling of several alkyl bromides and alkene coupling partners
(Table 3). Aryl-substituted acyclic bromide 26 delivered alkyl-
Mizoroki-Heck-type products 27 and 28 in moderate yields in
reactions with acrylonitrile and methyl acrylate, respectively
(entries 1–2). The cross-coupling of the N-methylpyrrole
derivative 29 proceeded with similar reaction efficiency (entry 3).
Reactions involving the simple aliphatic substrate 2-bromooctane
also produced cross-coupling products in moderate yield (entries
4–5). Cyclic bromides are also viable coupling partners, as
demonstrated by the coupling of cycloheptyl bromide (entry 6).[12]
While the acrylate couplings in Table 3 solely delivered E-alkene
products, the moderate Z-selectivity of couplings with acrylonitrile
is consistent with our prior studies involving palladium-catalyzed
couplings of alkyl iodides.[9a]
Table 2. Scope of nickel-catalyzed Mizoroki-Heck-type carbocyclizations of
diverse unactivated alkyl bromides.[a]
entry
1
substrate
product
yield (%)[b]
Br
94
23:1 rr
(1.4:1 E:Z)
TsN
TsN
Me
Me
Br
2
5
1
4
EtO2C
EtO2C
EtO2C
EtO2C
86
(1.1:1 E:Z)
2
Me
Me
Ts
N
Br
TsN
3[c]
84
Me
7
6
Br
TsN
TsN
84
>25:1 rr
4
Table 3. Nickel-catalyzed Mizoroki-Heck-type cross-couplings of alkyl bromides
9
8
with acrylonitrile and methyl acrylate.[a]
4-(MeO)C6H4
4-(MeO)C6H4
Br
yield
(%)[b]
entry
1
substrate
product
5[c]
46[e]
MeO
MeO
64
(5.7:1
Z:E)
11
10
Br
nBuO
nBuO
CN
Br
26
27
82[d]
15:1 rr
O
O
6
MeO
MeO
Br
CO2Me
2[c,d]
36[e]
12
13
Br
26
29
28
30
TsN
86
(1.6:1 E:Z)
TsN
7
8
Ph
Ph
Br
15
14
57
(5.7:1
Z:E)
Br
N
3[c]
N
Me
MeO2C
Me
MeO2C
CN
70
>25:1 rr
Ph
Ph
Br
17
50
(7.3:1
Z:E)
16
4
CN
CO2Me
Br
TsN
31
31
32
33
TsN
Br
80
3.1:1 rr
9[c]
5[c,d]
31[e]
18
19
This article is protected by copyright. All rights reserved.

10.1002/anie.201810757
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Plausible catalytic cycle for the nickel-catalyzed alkyl-Mizoroki-
Heck-type carbocyclization.
Br
47
(5.6:1
Z:E)
CN
6
35
34
In conclusion, we have developed a general approach to the
Mizoroki-Heck-type reaction of unactivated alkyl bromides using
an inexpensive nickel catalyst under mild conditions. The
reactions proceed in good yield and alkene regioselectivity across
a range of substrates, and initial results involving cross-coupling
have been demonstrated. We anticipate that the improved
efficiency and selectivity of this process versus other protocols will
prove valuable in implementing alkyl-Mizoroki-Heck-type
reactions towards target-oriented synthesis.
[a] Reactions performed with [substrate]0 = 0.5 M in DMF at 70 °C with 10 mol %
Ni(cod)2, 10 mol % xantphos, 3 equiv alkene, 3 equiv Mn, and 3 equiv Et3N as
base. [b] Isolated yield. [c] Na2CO3 used as base instead of Et3N. [d] Reactions
were performed with [substrate]0 = 0.5 M in MeCN. [e] Yield determined by 1
NMR spectroscopy of crude reaction mixture using an internal standard.
H
We performed several experiments to shed light on the
reaction mechanism, specifically to compare the nickel-catalyzed
reaction to prior work involving palladium catalysis (eqs 1 and 2).
The reaction of alkyl bromide 1 under standard conditions in the
presence of 10 mol % of the single-electron transfer inhibitor 1,4-
dinitrobenzene led to complete recovery of starting material,
consistent with the presence of radical intermediates (eq 1).
Furthermore, a reaction stopped at partial conversion did not yield
any product of an atom-transfer radical cyclization, in contrast to
the previously reported palladium-catalyzed carbocyclization
which involved auto-tandem catalysis (eq 2).[3] This experiment
also suggests that alkene isomerization occurs over the course of
the reaction; the regioisomeric ratio of the product at partial
conversion (2.3:1 rr) is much lower than that observed at
completion (23:1 rr).[13]
Acknowledgements
Financial support was provided by Award R01 GM 107204 from
the National Institute of General Medical Sciences.
Keywords: radical reactions • cross-coupling • nickel • synthetic
methods • alkyl halides
[1]
[2]
The Mizoroki-Heck Reaction (Ed.: M. Oestrich), Wiley, Chichester, 2009.
For representative examples, see: a) J. Terao, H. Watabe, M. Miyamoto,
N. Kambe, Bull. Chem. Soc. Jpn. 2003, 76, 2209; b) J. Terao, N. Kambe,
Bull. Chem. Soc. Jpn. 2006, 79, 663; c) W. Affo, H. Ohmiya, T. Fujioka,
Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, Y. Imamura, T. Mizuta,
K. Miyoshi, J. Am. Chem. Soc. 2006, 128, 8068; d) K. Wakabayashi, H.
Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2001, 123, 5374; e) A. Millán,
L. Álvarez de Cienfuegos, D. Miguel, A. G. Campaña, J. M. Cuerva, Org.
Lett. 2012, 14, 5984; f) J. Xie, J. Li, V. Weingand, M. Rudolph, A. S. K.
Hashimi, Chem. - Eur. J. 2016, 22, 12646; g) M. E. Weiss, L. M. Kreis,
A. Lauber, E. M. Carreira, Angew. Chem. Int. Ed. 2011, 50, 11125; h) S.
Busato, O. Tinembart, Z. Zhang, R. Scheffold, Tetrahedron 1990, 46,
3155; i) H. Bhandal, G. Pattenden, J. J. Russell, Tetrahedron Lett. 1986,
27, 2299; j) L. Firmansjah, G. C. Fu, J. Am. Chem. Soc. 2007, 129,
11340; k) K. S. Bloome, R. L. McMahen, E. J. Alexanian, J. Am. Chem.
Soc. 2011, 133, 20146.
Reaction in the Presence of SET Inhibitor 1,4-dinitrobenzene:
10 mol % NiBr2•glyme
10 mol % xantphos
Br
10 mol % 1,4-dinitrobenzene
>99%
unreacted 1
(1)
TsN
3 equiv Mn
3 equiv Et3N
Me
MeCN, 80 °C, 16 h
1
Reaction Stopped at Partial Conversion:
10 mol % NiBr2•glyme
10 mol % xantphos
Br
73%
+
TsN
(2)
TsN
unreacted 1
3 equiv Mn
3 equiv Et3N
Me
Me
MeCN, 80 °C, 15 min
2
1
26% (2.3:1 rr)
A plausible mechanism consistent with our observations is
shown in Scheme 1. We hypothesize that activation of the alkyl
bromide substrate by Ni(0) delivers a carbon-centered radical
which undergoes C–C bond-forming alkene addition. Following
cyclization, trapping of the newly generated carbon-centered
radical by the nickel catalyst generates an alkylnickel(II)
intermediate. b-Hydride elimination of this species then delivers
the alkyl-Mizoroki-Heck-type carbocyclization product. As
previously mentioned, alkene isomerization proceeds over the
course of the reaction, likely via the LnNiII(H)(Br) intermediate
initially produced prior to a relatively slow catalytic turnover.
[3]
[4]
A. R. O. Venning, M. R. Kwiatkowski, J. E. Roque Peña, B. C. Lainhart,
A. A. Guruparan, E. J. Alexanian, J. Am. Chem. Soc. 2017, 139, 11595.
a) T. Iwasaki, N. Kambe, Top. Curr. Chem. 2016, 374, 1; b) X. Wang, Y.
Dai, H. Gong, Top. Curr. Chem. 2016, 374, 61; c) S. Z. Tasker, E. A.
Standley, T. F. Jamison, Nature 2014, 509, 299.
[5]
[6]
B.-L. Lin, L. Liu, Y. Fu, S.-W. Luo, Q. Chen, Q.-X. Guo, Organometallics
2004, 23, 2114.
A reaction involving the alkyl chloride of substrate 6 under slightly
modified conditions proceeded in 33% yield as determined by 1H NMR
spectroscopy of the crude reaction mixture using an internal standard.
See Supporting Information for details.
Br
base
Me
H
Br
TsN
TsN
[7]
[8]
See Supporting Information for a detailed comparison of the current
protocol and our previous palladium protocol.
Me
LnNi0
2
1
Common minor byproducts in the carbocyclizations include
dehydrohalogenation and reductive cyclization products. As an example,
pyrrolidine 7 is produced along with 6% of a dehydrohalogenation
byproduct and 3% of a reductive cyclization byproduct as calculated by
1H NMR spectroscopy of the crude reaction mixture using an internal
standard.
base
LnNiIBr
Me
TsN
TsN
Me
LnNiIIBr
[9]
a) C. M. McMahon, E. J. Alexanian, Angew. Chem. Int. Ed. 2014, 53,
5974; b) Y. Zou, J. Zhou, Chem. Commun. 2014, 50, 3725; c) D.
Kurandina, M. Rivas, M. Radzhabov, V. Gevorgyan, Org. Lett. 2018, 20,
357; d) G.-Z. Wang, R. Shang, W.-M. Cheng, Y. Fu, J. Am. Chem. Soc.
2017, 139, 18307.
TsN
LnNiIBr
Me
This article is protected by copyright. All rights reserved.

10.1002/anie.201810757
Angewandte Chemie International Edition
COMMUNICATION
[10] For a study disclosing several examples of nickel-catalyzed styrylation of
unactivated alkyl bromides, see: S. A. Lebedev, V. S. Lopatina, E. S.
Petrov, I. P. Beletskaya, J. Organomet. Chem. 1988, 344, 253. In this
study, the use of activated alkene coupling partners (e.g., acrylates) led
only to reductive addition products.
[11] For examples of nickel-catalyzed Mizoroki-Heck-type cross-couplings of
activated sp3-hybridized electrophiles, see: a) S. Tang, C. Liu, A. Lei,
Chem. Commun. 2013, 49, 2442; b) C. Liu, S. Tang, D. Liu, J. Yuan, L.
Zheng, L. Meng, A. Lei, Angew. Chem. Int. Ed. 2012, 51, 3638; c) R.
Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc. 2011, 133,
19020; d) E. A. Standley, T. F. Jamison, J. Am. Chem. Soc. 2013, 135,
1585; e) M. R. Harris, M. O. Konev, E. R. Jarvo, J. Am. Chem. Soc. 2014,
136, 7825.
[12] Using the current conditions, reactions involving primary alkyl bromides
proceed with lower yields.
[13] See Supporting Information for additional details regarding changes in
alkene regioisomeric ratios over time.
This article is protected by copyright. All rights reserved.

10.1002/anie.201810757
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Megan R. Kwiatkowski, Erik J.
Alexanian*
10 mol % NiBr2•glyme
10 mol % xantphos
Br
TsN
TsN
3 equiv Mn
3 equiv Et3N
MeCN, 80 °C
Me
Me
Page No. – Page No.
94% isolated yield
23:1 rr
Nickel-Catalyzed Mizoroki-Heck-Type
Reactions of Unactivated Alkyl
Bromides
nickel-catalyzed carbocyclizations with high alkene regioselectivity
The development of a general, nickel-catalyzed alkyl-Mizoroki-Heck reaction of
unactivated alkyl bromides is described. The mild reaction proceeds efficiently using
a wide range of primary and secondary alkyl bromides, and examples of
intermolecular cross-couplings are provided. Reaction alkene regioselectivity is
significantly enhanced over prior carbocyclizations using palladium catalysis.
Mechanistic investigations are consistent with a direct carbocyclization in contrast to
the auto-tandem atom-transfer cyclization and halide elimination previously observed
with palladium catalysis.
This article is protected by copyright. All rights reserved.