Divergent Nickel-Catalysed Ring-Opening-Functionalisation of Cyclobutanone Oximes with Organozincs

Article abstract of DOI:10.1055/s-0039-1690690

The development of a nickel-catalysed strategy for the remote alkylation, arylation, vinylation and alkynylation of nitriles is presented. The methodology uses electron-poor O-Ar cyclic oximes and organozincs as coupling partners. This redox process proceeds through the generation of an iminyl radical and its following ring-opening reaction.

Full text of DOI:10.1055/s-0039-1690690

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Georg Thieme Verlag Stuttgart · New York
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L. Angelini et al.
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Divergent Nickel-Catalysed Ring-Opening–Functionalisation of
Cyclobutanone Oximes with Organozincs
Lucrezia Angelinia
Laia Malet Sanzb
Daniele Leonori*a
OAr
R =
alkyl
N
+
R
[Zn]
[Ni]
NC
R
0
0
0
0-0
0
0
2-7
6
9
2-4
5
0
4
17 examples
Ar
up to 91% yield
a
School of Chemistry, University of Manchester, Oxford Road,
Manchester, M13 9PL, UK
daniele.leonori@manchester.ac.uk
Eli Lilly and Company Limited, Erl Wood Manor, Windelesham,
Surrey, GU20 6PH, UK
b
Published as part of the Cluster 9th Pacific Symposium on Radical
Chemistry
3
Received: 23.08.2019
Accepted after revision: 10.09.2019
Published online: 24.09.2019
As the ability to introduce C-based groups at distal sp –C
7
atoms remains a fundamental synthetic challenge, we re-
DOI: 10.1055/s-0039-1690690; Art ID: st-2019-v0444-c
cently questioned if the redox requirements for iminyl radi-
cal generation and nickel cross-coupling mode could be
changed to enable the use of nucleophilic coupling part-
ners. Such an umpolung approach would deliver related
Abstract The development of a nickel-catalysed strategy for the re-
mote alkylation, arylation, vinylation and alkynylation of nitriles is pre-
sented. The methodology uses electron-poor O-Ar cyclic oximes and or-
ganozincs as coupling partners. This redox process proceeds through
the generation of an iminyl radical and its following ring-opening reac-
tion.
A) Common reactivities of iminyl radicals
N
N
N
Key words radical ring-opening, nickel catalysis, nitrogen radicals, C–
C bond formation, alkylation, arylation, vinylation, alkynylation
H
R1
( )n R1
R
R
R1
NC
R1
( )n
exo-trig
1,5-HAT
ring-opening
Iminyl radicals are a powerful class of reactive interme-
diates with a broad reactivity profile spanning intramolecu-
lar exo-trig cyclisation, 1,5-hydrogen atom transfer (HAT)
B) Ni-catalysed cyclisation–functionalisation cascades of amidyl radicals
R1
Ar
Ar B(OH)2
R
(III)
N
[
Ni]
R
1
and -fragmentation (Scheme 1A). Among these transfor-
R
O
OAr
R
N
N
O
via:
R1
[Ni]
mations, the ring-opening of cyclic iminyl radicals pio-
R1
R1
O
2
alkyl
neered by Zard has recently received considerable atten-
alkyl [Zn]
R
O
common Ni(III) intermediate
N
tion as key step in many photoredox and transition-metal-
3
mediated processes. This reactivity pattern carries inter-
Ar = 2,4-(NO2)2-C6H3
esting synthetic potential as it enables easy access to car-
bon radicals at distal positions from nitrile functionalities
and can be used to achieve remote sp –C functionalisation.
C) Ni-catalysed iminyl radical ring-opening functionalisation cascades
previous work
alkyl [Zn]
this work
alkyl Br
3
NC
alkyl
NO2
As part of an effort to explore the reactivity of nitrogen
4
radicals, we have recently developed a class of redox-active
Me
Me
HO2C
Ar Br
Ar [Zn]
O2N
NC
Ar
oximes and used them in oxidative photoinduced radical
cascades based on iminyl radical generation, radical ring-
opening and S 2 reaction with SOMOphiles like Selectfluor,
O
O
N
hν
Ni]
N
[Ni]
[
H
R
[Zn]
5
N-chlorosuccinimide and sulfonyl azide. More recently, we
NC
NC
have merged this reactivity with nickel catalysis and ex-
tended the range of coupling partners to electrophiles such
as aryl and alkyl halides and terminal alkynes (Scheme 1C,
left). This dual catalytic approach has enabled remote ary-
lations, alkylations and vinylations of nitriles.
(III)
[Ni] R
via: NC
[Zn]
common Ni(III) intermediate
6
Scheme 1 Reactivity of iminyl radicals
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2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
L. Angelini et al.
Cluster
products to our previous oxidative approach but it will use
a different class of building blocks which might offer com-
plementarity in terms of substrate scope.
ingly, the desired alkylated nitrile 2 was immediately ob-
tained in 65% yield by using one equivalent of the organo-
metallic species, 20 mol% of Ni catalyst in a 1:1 mixture of
THF–DMF as the solvent at room temperature (entry 1). De-
creasing the amount of catalyst to 10 and 5 mol% still en-
abled reactivity but had a detrimental effect on the reaction
efficiency (entries 2 and 3). The counterion of the Ni cata-
lyst was not important (entry 4), while the absence of the
dtbpy ligand completely suppressed the reactivity (entry 5).
We also evaluated the possibility of using a larger amount
of dipentyl zinc but this led to a decrease in reaction yield
suggesting that a 1:1 ratio between iminyl precursor and
organozinc is the optimum (entry 6). The solvent plays an
important role in this reaction. Indeed, when the DMF co-
solvent was replaced with the similarly polar aprotic sol-
vent dimethylacetamide (DMA), a severe reduction in prod-
uct formation was observed (entry 7). In line with the in-
tramolecular nature of the transformation, a higher dilution
affected negatively the reaction outcome (entry 8), al-
though the optimal concentration reaches a plateau and no
extra beneficial effect is observed at increased concentra-
tion (entry 9).
From this perspective, we have recently developed a
nickel-catalysed protocol for the generation of amidyl radi-
cals from electron-poor O-Ar-hydroxyl amides in the pres-
ence of nucleophiles like aryl boronic acids and dialkyl or-
8
ganozincs (Scheme 1B). This redox activation mode en-
abled the development of radical cascades based on amidyl
exo-trig cyclisation followed by arylation/alkylation via a
common diorganyl–Ni(III) intermediate.
We were therefore interested in evaluating whether, by
turning the redox nature of the oxime starting material into
a strong electron acceptor, we could achieve umpolung
ring-opening–functionalisation reactions.
We present here the successful implementation of such
a strategy and its use in the divergent functionalisation of
nitriles through remote alkylation, arylation, vinylation and
alkynylation with organozincs (Scheme 1C, right).
Our proposed mechanism for ring-opening–functional-
isation of iminyl radicals with organozincs (Scheme 2) is
based on a Ni(I)/(II)/(III) redox cycle and starts with the
transmetalation of a Ni(I)–X complex (ligand on Ni not
shown for simplicity) A with the organozinc coupling part-
Table 1 Optimisation of the Ring-Opening–Alkylation Reaction with
9
ner. The corresponding organyl–Ni(I) species B is expected
Use of Oxime 1 and (n-pentyl) Zn
2
ox
10
to be a competent reductant (E ~ +1.1 V vs SCE) and
OAr
N
[Ni]
NC
should undergo facile ground-state single-electron transfer
+
(n-pentyl)2Zn
red
(
SET) with the cyclobutanone oxime C (E ~ –0.8 V vs
THF–DMF, r.t.
Me
11
SCE). This event will deliver the iminyl radical D with si-
multaneous extrusion of a stable aryloxy anion. Subsequent
fast ring-opening reaction will form the distal nitrile radical
E that should have the correct philicity to intercept the oxi-
dised organyl–Ni(II) intermediate F. This radical transmeta-
lation would deliver a diorganyl–Ni(III) species G from
which reductive elimination should be facile. In this way we
should obtain the desired product H and close the nickel
catalytic cycle.
1
2
Entry
[Ni] (mol%)
(n-pentyl)
2
Zn THF–DMF
(M)
Yield
(%)
(
equiv)
1
2
3
4
5
6
7
8
dtbpy·NiBr (20)
2
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
0.05
0.05
0.05
0.05
0.05
65
46
22
64
–
dtbpy·NiBr
dtbpy·NiBr
2
2
(10)
(5)
dtbpy·NiCl
2
(20)
NiBr (20)
2
We began our study analysing the reaction of aryl-ox-
ime 1, easily accessible through a single-step reaction on
multi-gram scale, with freshly prepared dipentylzinc, using
dtbpy·NiBr
dtbpy·NiBr
dtbpy·NiBr
dtbpy·NiBr
2
2
2
2
(20)
(20)
(20)
(20)
0.05
44
24
61
50
0.05a
the preformed NiBr ·dtbpy as the catalyst (Table 1). Pleas-
2
0.025
0.1
9
NC
R
R
ZnY
a
DMA was used instead of DMF.
(
I)
H
R
[
Ni]
X
X–Zn–Y
A
With these optimised conditions in hand, we moved to
explore the scope of this ring-opening–functionalisation
strategy (Scheme 3). Oxime 1 was successfully engaged
with other dialkyl organozincs like the long-chain (3,7-
Me -octyl) Zn leading to nitrile 5 in good yield. More im-
portantly, we were able to utilise a secondary cyclic dialkyl
zinc as coupling partner albeit giving lower yield (6). Spiro-
cyclic and 3-OBn-containing cyclobutanone-oximes 3 and 4
were also evaluated and proved to be efficient precursors
for the ring-opening and coupling with dimethyl (7 and 10),
N
D
+
(III)
(I)
NC
12
[
Ni]
[Ni] R
B
E
OAr
G
N
NC
2
2
+
SET
(
II)
[
Ni]
R
C
Ar = 2,4-(NO2)2-C6H3
F
ArO–
Scheme 2 Proposed mechanism for the divergent Ni-catalysed ring-
opening–functionalisation via iminyl radicals
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
Synlett
L. Angelini et al.
Cluster
diethyl (8 and 11) and dicyclopropyl zinc (9 and 12) thus
enabling the preparation of C-4-disubstituted piperidines
as well as aldol-type nitriles, respectively. The successful in-
troduction of Me as well as cyclopropyl groups represents a
complementarity aspect of this Ni strategy with respect to
our previous dual photoredox-Ni work where coupling
partners like Me–Br/I and cyclopropyl–Br/I were found not
viable.
Finally, we prepared diethynyl zinc from the commer-
cially available Grignard reagent in order to evaluate if this
strategy would also enable the formation of sp –sp C–C
3
bonds.3g Pleasingly, this was possible and both oximes 1 and
3 provided the corresponding alkyne-containing nitriles 19
and 20 in moderate to high yields. To the best of our knowl-
edge, this represents the first example of a strategy able to
introduce a terminal alkyne functionality upon radical
ring-opening of iminyl radicals.
6
OAr
N
This methodology is however not without limitations.
At the moment the major hurdle is represented by the
iminyl radical scope. In fact, while cyclobutanone oximes
can be successfully used, extension of this strategy to cyclo-
pentanone (21) and cyclohexanone (22) oximes was not
possible. As the ring-opening of five- and six-membered-
ring iminyl radicals is feasible, we propose that difficulties
in the radical transmetalation of the corresponding tertiary
and benzylic radicals onto the nickel species or the poten-
tial formation of an aza-enolate by deprotonation of the ox-
ime from the organozinc might be responsible for this lack
of reactivity.
In conclusion, we have demonstrated that highly elec-
tron poor and redox-active cyclobutanone oximes can un-
dergo nickel-catalysed iminyl radical generation followed
by ring-opening and divergent functionalisation with alkyl,
aryl, vinyl and alkynyl organozincs. These results offer an
umpolung alternative for the distal functionalisation of ni-
triles.
dtbpy•NiBr2 (20 mol%)
R
1
2
NC
R1
+
(R ) Zn
R
THF–DMF (1:1), r.t.
1, 3, 4
2, 5–20
(
1.0 equiv)
(1.0 equiv)
ring-opening–alkylation
OAr
OAr
N
Me
CN
NC
Me
CN
CN
Me
2
3%
5
61%
6
1
Me
6
15%
N
Me
Me
NC
NC
N
N
N
N
Boc
7
9%
Boc
8
46%
Boc
9
91%
Boc
3
7
OAr
N
Me
NC
Me
NC
NC
OBn
OBn
OBn
OBn
10
11
12
4
63%
21%
76%
ring-opening–arylation
Me
OMe
Funding Information
S
NC
NC
NC
NC
D.L. thanks EPSRC for a fellowship (EP/P004997/1), and the European
1
3
14
78%
15
84%
16
78%
83%
Research Council for a research grant (758427).
H
2
0
2
0
E
uro
p
e
a
n
R
esearc
h
C
o
u
n
c
i
l(7
5
8
4
2
7)E
n
g
i
n
e
eri
n
g
a
n
d
P
h
ysi
c
a
lS
c
i
e
n
c
es
R
esearc
h
C
o
u
n
c
i
l (EP/P
0
0
4
9
9
7/1)
ring-opening–vinylation
ring-opening–alkynylation
NC
NC
Acknowledgment
N
N
NC
L.A. thanks Eli Lilly for a PhD CASE Award.
NC
Boc
Boc
20
54%
17
18
75%
19
40%
24%
unsuccessful starting materials
OAr
Supporting Information
OAr
N
N
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690690.
Ph
Me
Me
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
21
22
References and Notes
Scheme 3 Scope and limitations for the Ni-catalysed ring-opening–
functionalisations of cyclobutanone oximes
(1) Reviews: (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603.
(b) Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. Synthesis 2018,
Having evaluated the efficiency of this methodology in
50, 1569. (c) Morcillo, S. P. Angew. Chem. Int. Ed. 2019, in press;
DOI: 10.1002/anie.201905218..
(2) (a) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Schiano,
A.-M.; Zard, S. Z. Tetrahedron 1995, 51, 6517. (b) Boivin, J.;
Fouquet, E.; Schiano, A.-M.; Zard, S. Z. Tetrahedron 1994, 50,
3
3
sp –sp C–C bond formation, we decided to test its applica-
3
2
3h,13
bility in the assembly of sp –sp C–C bonds.
the use of diphenyl (13), di-ortho-substituted aromatics
14, 15) as well as a di-hetero-aryl zinc (16) provided the
Specifically,
(
1769.
desired products in high yields. More interestingly, we suc-
ceeded in engaging divinyl zinc in this strategy and ob-
tained 17 and 18 in moderate and high yields, respectively.
(
3) Selected examples: (a) Zhao, J.-F.; Gao, P.; Duan, X.-H.; Guo, L.-
N. Adv. Synth. Catal. 2018, 360, 1775. (b) Wu, J.; Zhang, J.-Y.; Gao,
P.; Xu, S.-L.; Guo, L.-N. J. Org. Chem. 2018, 83, 1046. (c) Yu, X.-Y.;
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2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
Synlett
L. Angelini et al.
Cluster
Zhao, Q.-Q.; Chen, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem. Int. Ed.
018, 57, 15505. (d) Yao, S.; Zhang, K.; Zhou, Q.-Q.; Zhao, Y.; Shi,
(11) (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505.
(b) Davies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. W. A.; Leonori, D.
Angew. Chem. Int. Ed. 2015, 54, 14017.
2
D.-Q.; Xiao, W.-J. Chem. Commun. 2018, 54, 8096. (e) Li, L.; Chen,
H.; Mei, M.; Zhou, L. Chem. Commun. 2017, 53, 11544. (f) Shen,
X.; Zhao, J.-J.; Yu, S. Org. Lett. 2018, 20, 5523. (g) Vaillant, F. L.;
Garreau, M.; Nicolai, S.; Gryn’ova, G.; Corminboeuf, C.; Waser, J.
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L. N. Chem. Commun. 2018, 54, 10738. (j) Zhang, J.-J.; Duan, X.-
H.; Wu, Y.; Yang, J.-C.; Guo, L.-N. Chem. Sci. 2019, 10, 161. (k) Ai,
W.; Liu, Y.; Wang, Q.; Lu, Z.; Liu, Q. Org. Lett. 2018, 20, 409.
(12) Products 2, 5–20; General Procedure
An oven-dried microwave vial equipped with a stirring bar was
charged with the aryl oxime (0.05 mmol, 1.0 equiv) and
dtbpy·NiBr2 (20 mol%). The vial was sealed, evacuated and
refilled with N (3×). DMF was added followed by the organoz-
2
inc (0.1 mmol, 1.0 equiv) as a solution in THF (DMF–THF 1:1,
0.05 M). The reaction was stirred at room temperature for 16 h
and then it was filtered through a silica plug by eluting with
(
l) Ding, D.; Whang, C. ACS Catal. 2018, 8, 11324.
4) Davies, J.; Morcillo, S. P.; Douglas, J. J.; Leonori, D. Chem. Eur. J.
018, 24, 12154.
EtOAc. The solution was washed with H O (3×), and brine (1×),
2
(
(
(
(
dried (MgSO ), filtered and evaporated. Purification by column
4
2
chromatography on silica gel gave the corresponding product.
7,11-Dimethyldodecanenitrile (5)
5) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.;
Leonori, D. Angew. Chem. Int. Ed. 2018, 57, 744.
6) Dauncey, E. M.; Dighe, S. U.; Douglas, J. J.; Leonori, D. Chem. Sci.
Following the general procedure, 1 gave 5 (13 mg, 61%) as a col-
1
orless oil; R 0.90 (PE–EtOAc, 8:2). H NMR (500 MHz, CDCl ):  =
f
3
2
019, 10, 7728.
7) Reviews: (a) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433.
b) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme,
2.33 (t, J = 7.1 Hz, 2 H), 1.66 (quin, J = 7.3 Hz, 2 H), 1.59–1.48 (m,
1 H), 1.47–1.33 (m, 4 H), 1.33–1.18 (m, 5 H), 1.17–0.99 (m, 4 H),
13
(
0.92–0.75 (m, 9 H). C NMR (126 MHz, CDCl ):  = 120.0, 39.5,
3
M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073. (c) Chu, J. C. K.;
Rovis, T. Angew. Chem. Int. Ed. 2017, 45, 62. (d) Yan, M.; Lo, J. C.;
Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692.
8) Angelini, L.; Davies, J.; Simonetti, M.; Malet-Sanz, L.; Sheikh, N.
S.; Leonori, D. Angew. Chem. Int. Ed. 2019, 58, 5003.
37.4, 36.8, 32.8, 29.2, 28.1, 26.4, 25.6, 24.9, 22.9, 22.8, 19.8, 17.3.
HRMS (ASAP): m/z [M + H] calcd for C14H28N: 210.2216; found:
210.2212.
tert-Butyl-4-(cyanomethyl)-4-(prop-2-yn-1-yl)piperidine-1-
carboxylate (20)
+
(
(
9) Phapale, V. B.; Bu ̃n uel, E.; Garc ́i a-Iglesias, M.; C ́a rdenas, D. J.
Angew. Chem. Int. Ed. 2007, 127, 4594.
Following the general procedure, 1 gave 20 (16 mg, 54%) as a
1
colorless oil; R 0.50 (PE–EtOAc, 7:3). H NMR (500 MHz, CDCl ):
f
3
(
10) (a) Jones, G. D.; McFarland, C.; Anderson, T. J.; Vicic, D. A. Chem.
Commun. 2005, 42, 4211. (b) Anderson, T. J.; Jones, G. D.; Vicic,
D. A. J. Am. Chem. Soc. 2004, 126, 8100. (c) Shields, B. J.; Kudisch,
B.; Scholes, G. D.; Doyle, A. G. J. Am. Chem. Soc. 2018, 140, 3035.
 = 3.57–3.44 (m, 2 H), 3.37–3.25 (m, 2 H), 2.53 (s, 2 H), 2.41 (d,
J = 2.7 Hz, 2 H), 2.10 (t, J = 2.6 Hz, 1 H), 1.71–1.59 (m, 4 H), 1.46
13
(s, 9 H). C NMR (126 MHz, CDCl ):  = 154.8, 117.3, 80.1, 79.1,
3
72.6, 34.8, 33.5, 31.1, 28.6, 26.6, 21.2. HRMS (ASAP): m/z [M +
+
H] calcd for C15H23N O : 263.1754; found: 263.1749.
2
2
(13) Yang, H.-B.; Pathipati, S. R.; Selander, N. ACS Catal. 2017, 7, 8441.
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–D