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A dual photoredox-nickel strategy for remotefunctionalization via iminyl radicals: radical ringopening-arylation, -vinylation and -alkylationcascades†Elizabeth M. Dauncey, ‡a Shashikant U. Dighe,and Daniele Leonori *a

Received 29th May 2019
Accepted 26th June 2019‡a James J. Douglasb

A divergent strategy for the remote arylation, vinylation and alkylation of nitriles is described. These
processes proceed through the photoredox generation of a cyclic iminyl radical and its following ring-

DOI: 10.1039/c9sc02616a

opening reaction. The distal nitrile radical is then engaged in nickel-based catalytic cycles to form C–C

rsc.li/chemical-sciencebonds with aryl bromides, alkynes and alkyl bromides.

The selective functionalization of unactivated sp3 carbons
streamlines access to molecules that can be diﬃcult to prepare
using classical disconnections.1 Radical strategies are powerfulplatforms to achieve this goal owing to the ability of oddelectron species to undergo fast transpositions by s-bondcleavage.2 Processes based on 1,5-H-atom transfer (1,5-HAT) arefrequently adopted as they allow selective functionalization at
precise carbon sites in already assembled substrates.3 Methodologies centred on radical ring-opening reactions4 lead toskeletal rearrangements and as a result use diﬀerent classes ofstarting materials. Most importantly they can functionalize sp3
carbons that are elusive by HAT-based protocols.
Following the pioneering work of Forrester5 and Zard,6 we haverecently developed a photo-induced methodology where readily
prepared oximes undergo SET (single-electron transfer) oxidationand fragmentation en route to cyclic iminyl radicals (Scheme 1A).7
With the correct juxtaposition of a-substituents and ring-size,
eﬃcient ring opening-functionalization cascades were developed
accessing remotely uorinated, chlorinated and azidated nitriles.
Other groups have also been active in the area and several
photo-induced strategies have been subsequently developed
enabling radical ring-opening followed by reaction with, mostnotably, Michael acceptors,8 styrenes8c,9 and alkynylbenziodoxolone reagents10 (Scheme 1B).11 These methodologies haveprovided signicant synthetic capacity as they enabled distal
C–C bond formations, albeit with structurally specic coupling
partners.

Despite these advances, the possibility to use related radicaltranspositions as a tool for the general and modular construction of C–C bonds at remote sites is still an unmet goal.

aSchool of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
UK. E-mail: daniele.leonori@manchester.ac.ukb

Early Chemical Development, Pharmaceutical Sciences, AstraZeneca, R&D,
Maccleseld SK10 2NA, UK† Electronic supplementary information (ESI) available: Full experimental details
and characterisation. See DOI: 10.1039/c9sc02616a‡ These authors have contributed equally to this work.

7728 | Chem. Sci., 2019, 10, 7728–7733

Scheme 1 Strategies for the photo-induced ring-opening functionalizations of cyclic iminyl radicals. (A) Previous work: photoredox ringopening functionalizations. (B) Photoredox strategies for radical ringopening C–C bond formation. (C) This work: photoredox-Ni ringopening arylations, vinylations and alkylations.

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We speculated that one way to partially address this fundamental challenge would be to incorporate the concept of metallaphotoredox catalysis12 in these radical transpositions. In
principle, this strategy would enable the use of readily available
coupling partners, like aryl/alkyl bromides and alkynes, andaccess products currently elusive by other methodologies. In
this paper, we demonstrate the successful development of
a divergent dual photoredox–nickel process that gives access toremotely arylated, vinylated and alkylated nitriles by means ofradical ring-opening–cross coupling cascades (Scheme 1C).
The proposed mechanism for this divergent strategy wascentred on our previously developed reductive quenching photoredox cycle for iminyl radical generation.13 As shown in
Scheme 2, we would use a visible-light excited photocatalyst(*PC) to promote the SET oxidation of oxime-carboxylate A.
Following extrusion of CO2 and acetone, the iminyl radical B
should undergo facile ring-opening delivering the distal nitrile
radical C. At this point, we hoped that a Ni(0) co-catalyst would
simultaneously undergo oxidative addition on an aryl bromide
coupling partner to give an aryl–Ni(II) species D.14 Radicaltransmetalation between C and D ought to be possible thus
delivering an aryl,alkyl–Ni(III) complex E from which reductive
elimination is facile. This step would generate the remotely
arylated nitrile F and a Ni(I) species. A nal SET between the
reduced photocatalyst (PCc) and the Ni(I)-complex (Ered Ni(II)/Ni(0) ¼ 1.2 V vs. SCE, DMF)15 would re-initiate both the Ni
and the photoredox cycle. Related mechanistic frameworks
should enable the use of alkynes and alkyl halides and therefore
allow the remote installation of vinyl and alkyl groups
respectively.
We started our investigation using the cyclobutanone-oxime
1 (one-step preparation on gram-scale)16 and p-Br-acetophenone
2 as the coupling partner (Scheme 3). Pleasingly, using the Irphotocatalyst PC1, NiCl2$glyme, dtbbpy ligand and K2CO3 in
DME under blue light irradiation, we obtained the desired
product 3 in 15% yield (entry 1). Diﬀerent photocatalysts were
evaluated and while Fukuzumi's acridinium (PC2) was notsuitable (entry 2), the organic dye 4CzIPN (PC3) and the Ircomplex PC4 provided 3 in 24 and 41% yield respectively(entries 3 and 4). Using PC4 we tested diﬀerent inorganic and

Proposed dual photoredox-Ni catalytic cycle for the radical
ring-opening-arylation cascades.

Scheme 2

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Chemical Science

Development of dual photoredox–Ni ring-opening-arylation process.

Scheme 3organic bases and identied tetramethyl guanidine (TMG) as
optimum (entries 4–8). The nal elements of reaction optimization involved the evaluation of a selection of Ni-catalysts(entries 9–11) as well as solvents from which EtOAc resulted
ideal (entries 12–14). Control experiments conrmed therequirement for all reaction components (entries 15–18) anda quantum yield F ¼ 0.19 is in agreement with the observed
requirement for continuous light irradiation.
With these optimised reaction conditions, we evaluated thescope of the aromatic partner in conjunction with the cyclobutanone oxime 1 (Scheme 4). Pleasingly the process exhibitedbroad scope and tolerated a wide variety of common functionalities such as ketone (3 and 4), ester (5), nitrile (6), aldehyde (7),sulfone (8), triuoromethyl (9) as well as groups that can beused as a handle for further functionalization like pinacol
boronic ester (10) and aryl chloride (11) albeit in lower yields.17
Electron rich aryl bromides are a limitation of the protocol (12),possibly due to a more diﬃcult oxidative addition process fromthe Ni(0) catalyst. Moreover, while meta-substituted aryl
bromides were successfully engaged in this protocol (13 and14), the presence of an ortho-substituent was detrimental to thereactivity and, for example, 15 was obtained in low yield. Wethen evaluated the use of hetero-aromatic coupling partners asthese systems are frequently encountered in medicinal chemistry programs. Pleasingly the reaction enabled ring-openingarylation with diﬀerentially functionalized pyridines at either
C-2 (16 and 17) and C-3 (18), as well as quinoline (19), electronrich benzothiazole (20) and benzoimidazole (21) and Br–
caﬀeine, which gave 22 in good yield.
Other cyclobutanone oximes were tested and we used
a substrate containing an OBn ether at C-3 (23) as well as

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Scheme 4

Scope of the dual photoredox–Ni ring-opening-arylation

process.

a spirocyclic N-Boc-piperidine (24). This gave access to a C-4
benzylated piperidine, which is a common pharmacophoric
unit in many NMDA antagonist drugs like ifenprodil.
As the ring-opening of cyclic iminyl radicals is thermodynamically feasible on larger rings with the correct juxtapositionof a-substituents,7 we evaluated the use of gem-dimethyl cyclopentanone and 2-Ph-cyclohexanone oxime starting materials.
While the arylation cascade leading to 25 could not be implemented, we successfully extended it to the deconstruction of thesix-membered ring and access the 3-di-arylated nitriles 26–28 ingood to moderate yields. We propose the failure in obtaining 25
to be due to the known diﬃculty of tertiary C-radical to undergotransmetalation processes.
Flow chemistry has emerged as an eﬀective solution to thescale up of visible light-mediated processes.18 Dual photoredox–nickel catalysis can be challenging to conduct in ow,
due to the typically heterogenous mixtures and long reaction
times. We initiated the attempted scale-up of the ring-opening-

7730 | Chem. Sci., 2019, 10, 7728–7733

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arylation cascade by developing homogenous reaction conditions amenable to continuous ow (Scheme 4B). This allowed
the preparation of 3 on a useful preparative scale (4 mmol over4 h) with yield comparable to the small-scale (0.1 mmol) batch
reaction (56% in ow vs. 61% batch). The developed ow
process compared favourably to the original batch conditions
employed at large-scale. Using these without further optimization gave reduced yield with increasing scale aer 18 h
(0.1 mmol scale 59%, 2 mmol 45%, 4 mmol 22%). The use of
the developed homogenous conditions in batch gave a comparable 52% yield (0.1 mmol scale), however at increased scale
resulted in <10% yield, indicating the benet of the ow
process.19
Having developed an oxidative cascade for ring-openingarylation, we tested the feasibility of using terminal alkynes ascoupling partners to construct gem-disubstituted olens.20 The
optimization of this process was performed using oxime 1 and1-heptyne 29 (Scheme 5). In this case, conditions used for thearylation cascade failed to provide the desired product (entry 1)
but, by switching the base to K2CO3 and the solvent to DMF, 30
was obtained in an encouraging 10% yield (entry 2 and 3). The
eﬃciency of the process was improved to 33% by lowering theamount of base (entry 4) and adding 20 equiv. of H2O as anadditive (entry 5). Other nickel–ligand combinations were
tested but they provided 30 in generally lower yield, if any(entries 6–8). Evaluation of other photocatalysts and solvents
identied PC3 (entry 9) and CH3CN (entry 10) as optimum.
Finally, with the use of the preformed NiCl2$dttbpy catalyst andCs2CO3 as the inorganic base, 30 was obtained in 73% yield(entries 11 and 12). Also in this case, control experimentsconrmed the requirement for all reaction components as wellas continuous blue-light irradiation (entries 13–16).
The scope of terminal alkynes that can be engaged in thisreactivity pattern is illustrated in Scheme 6. Pleasingly, coupling
partners containing linear (30 and 31) as well as cyclic (32) alkyl
groups could be used including a substrate containing a cyclopropyl unit (33) albeit in lower yield.17 The methodology tolerated several important functionalities like nitrile (34), N-Bocprotected amine (35), alkyl chloride (36) and a phthalamide
unit (37). Expansion of this chemistry to N-Boc-azetidone anda spirocyclic N-Boc-piperidine based oximes gave access toallylic (38 and 39) as well as a C-4 disubstituted piperidine (40),which are useful building blocks for further derivatization.
Current limitations are the use of aryl-substituted alkynes (e.g.
41) and also its expansion to higher ring-size iminyl precursors(42 and 43).
This radical ring-opening-vinylation strategy could also be
performed in intra-molecular settings as demonstrated by the
successful conversion of 44 into 45. Control experiments in theabsence of the Ni-catalyst or H2O demonstrated that a radical
ring-opening followed by 5-exo-dig and nal H-abstraction was
not operating,19 thus leaving the proposed dual photoredox–Niprocess as the likely pathway for the formation of 45. This
reaction product is an interesting building block that, using
literature methods, was converted into the bicyclic ketone 46 ingood yield and as the single syn-diastereomer.

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Scheme 5 Development of dual photoredox–Ni ring-opening-vinylation process.

As this dual photoredox-Ni approach has enabled theconstruction of sp3–sp2 C–C bonds with both aromatic and vinyl
substituents we questioned if alkyl halides could also be used
and therefore achieve the very challenging assembly of sp3–sp3
C–C bonds.21 Indeed, remote alkylations via radical

Scheme 6

Scope of the dual photoredox–Ni ring-opening-vinylation

process.

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Chemical Sciencetransposition are still very diﬃcult to perform, with the exception of strategies involving the use of Michael acceptors as
SOMOphiles.
We started the optimization of this process using the oxime 1
and the simple alkyl bromide 47 (Scheme 7). Reaction conditions similar to the one developed for the ring-openingarylation cascade did not provide the desired product (entry1). However, evaluation of photoredox catalysts (entries 2–4),
solvents (entry 5) and bases (entries 5–7) showed that theprocess could be achieved and 48 obtained in 25% yield using
PC1 and Cs2CO3 in CH3CN (entry 9). Pleasingly, we have beenable to increase the yield to 66% by adopting the preformed
nickel catalyst NiCl2$dtbpy (entry 10) and by increasing theequivalents of base (entry 10). Also in this case, all reaction
components as well as continuous blue-light irradiation wererequired (entries 11–14).
With this set of conditions in hand, we evaluated the scope of
the process (Scheme 8). Pleasingly, using cyclobutanone oxime 1
we succeeded in engaging several primary alkyl bromides with
diﬀerent substitution patterns. This included ester (49), nitrile(50), alkyl chloride (51), N-phthalimide (52) and an acetal (53). At
the moment this reactivity is limited to primary alkyl electrophiles as secondary ones (e.g. 54) did not react.
In analogy to the ring-opening-arylation cascades we havenot been able to engage the gem-dimethyl-cyclopentanone
oxime (55) but we successfully used the 2-Ph-cyclohexanone
starting material, which gave access to 3-alkylated nitriles 56
and 57 in good yield.
To showcase the potential of the methodology, we have usedcommercially available L-Br-serine 58 as the coupling partner.
This functionalized building block provided access to theunnatural amino acid 59 that was converted into the 1-carbon
elongated L-lysine analogue 60.22

Scheme 7 Development of dual photoredox–Ni ring-opening-alkylation process.

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Scheme 8

Scope of the dual photoredox–Ni ring-opening-alkylation

process.

Conclusions
In conclusion, we have reported the rst example of a photoredox strategy where the ring-opening of iminyl radicals has
been merged with Ni-catalysis. This divergent platform hasenabled the development of distal arylation, vinylation and, forthe rst time, alkylation of nitrile-containing molecules.
Current interest in our laboratory is towards rendering theseprocesses asymmetric.

Conﬂicts of interest
There are no conicts to declare.

Acknowledgements
D. L. thanks EPSRC for a Fellowship (EP/P004997/1), and theEuropean Research Council for a research grant (758427). E. M.
D. thanks AstraZeneca for a PhD CASE Award. S. U. D. thanks
the Marie Curie Actions for a Fellowship (791349). We thank S.
Wells, T. Churchill and P. Gillespie (AstraZeneca Process Safety)
for safety testing.

Notes and references
1 (a) Y. Qin, L. Zhu and S. Luo, Chem. Rev., 2017, 117, 9433; (b)P. A. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme
and J.-F. Paquin, Chem. Rev., 2015, 115, 9073.
2 (a) P. Dowd and W. Zhang, Chem. Rev., 1993, 93, 2091; (b)A. Gansäuer, T. Lauterbach and S. Narayan, Angew. Chem.,
Int. Ed., 2003, 42, 5556; (c) Z. Cekovic, J. Serb. Chem. Soc.,
2005, 70, 287; (d) M. Nechab, S. Mondal and
M. P. Bertrand, Chem.–Eur. J., 2014, 20, 16034; (e)J. C. K. Chu and T. Rovis, Angew. Chem., Int. Ed., 2017, 45, 62.
3 (a) C. G. Francisco, A. J. Herrera, A. Martin, I. Perez-Martin
and E. Suarez, Tetrahedron, 2007, 48, 6384; (b)7732 | Chem. Sci., 2019, 10, 7728–7733

Edge Article

C. G. Francisco, A. J. Herrera and E. Suarez, J. Org. Chem.,
2003, 68, 1012; (c) H. Zhang and K. Muniz, ACS Catal.,
2017, 7, 4122; (d) C. Martinez and K. Muniz, Angew. Chem.,
Int. Ed., 2015, 54, 8287; (e) J. C. K. Chu and T. Rovis,
Nature, 2016, 539, 272–275; (f) G. J. Choi, Q. Zhu,
D. C. Miller, C. J. Gu and R. R. Knowles, Nature, 2016, 539,
268–271.
4 For a review, see: (a) S. P. Morcillo, Angew. Chem., Int. Ed.,
2019, DOI: 10.1002/anie.201905218. For selected examples,
see: (b) S. Maity and N. Zheng, Angew. Chem., Int. Ed., 2012,
51, 9562; (c) J. W. Beatty and C. R. J. Stephenson, J. Am.
Chem. Soc., 2014, 136, 10270; (d) C. R. Pitts, M. S. Bloom,
D. D. Bume, Q. A. Zhang and T. Lectka, Chem. Sci., 2015, 6,5225; (e) H. Jiang, X. An, K. Tong, T. Zheng, Y. Zhang and
S. Yu, Angew. Chem., Int. Ed., 2015, 54, 4055; (f) J.-J. Guo,
A. Hu, Y. Chen, J. Sun, H. Tang and Z. Zuo, Angew. Chem.,
Int. Ed., 2016, 128, 15319; (g) H. G. Yayla, H. Wang,
K. T. Tarantino, H. S. Orbe and R. R. Knowles, J. Am. Chem.
Soc., 2016, 138, 10794; (h) J. Zhang, Y. Li, R. Xu and
Y. Chen, Angew. Chem., Int. Ed., 2017, 59, 12619.
5 (a) A. R. Forrester, M. Gill, J. S. Sadd and R. H. Thomson, J.
Chem. Soc., Perkin Trans. 1, 1979, 1, 612; (b) A. R. Forrester,M. Gill and R. H. Thomson, J. Chem. Soc., Chem. Commun.,
1976, 677.
6 (a) J. B. Boivin, E. Fouquet and S. Z. Zard, Tetrahedron, 1994,
50, 1745; (b) J. Boivin, E. Fouquet, A.-M. Schiano and
S. Z. Zard, Tetrahedron, 1994, 50, 1769; (c) J. Boivin,
E. Fouquet and S. Z. Zard, J. Am. Chem. Soc., 1991, 113, 1055.
7 E. M. Dauncey, S. P. Morcillo, J. J. Douglas, N. S. Sheikh and
D. Leonori, Angew. Chem., Int. Ed., 2018, 57, 744.
8 (a) J.-F. Zhao, P. Gao, X.-H. Duan and L.-N. Guo, Adv. Synth.
Catal., 2018, 360, 1775; (b) J. Wu, J.-Y. Zhang, P. Gao,
S.-L. Xu and L.-N. Guo, J. Org. Chem., 2018, 83, 1046; (c)L. Li, H. Chen, M. Mei and L. Zhou, Chem. Commun., 2017,
53, 11544; (d) P.-Z. Wang, X.-Y. Yu, C.-Y. Li, B.-Q. He,
J.-R. Chen and W.-J. Xiao, Chem. Commun., 2018, 54, 9925.
9 (a) X.-Y. Yu, Q.-Q. Zhao, J. Chen, J.-R. Chen and W.-J. Xiao,
Angew. Chem., Int. Ed., 2018, 57, 15505; (b) S. Yao,
K. Zhang, Q.-Q. Zhou, Y. Zhao, D.-Q. Shi and W.-J. Xiao,
Chem. Commun., 2018, 54, 8096; (c) X. Shen, J.-J. Zhao and
S. Yu, Org. Lett., 2018, 20, 5523; (d) X.-Y. Yu, J.-R. Chen,
P.-Z. Wang, M.-N. Yang, D. Liang and W.-J. Xiao, Angew.
Chem., Int. Ed., 2018, 57, 738.
10 F. L. Vaillant, M. Garreau, S. Nicolai, G. Gryn'ova,
C. Corminboeuf and J. Waser, Chem. Sci., 2018, 9, 5883.
11 (a) H.-B. Yang and N. Selander, Chem.–Eur. J., 2017, 23, 1779;(b) L. Yang, P. Gao, X.-H. Duan, Y.-R. Gu and L. N. Guo,
Chem. Commun., 2018, 54, 10738; (c) J.-J. Zhang,
X.-H. Duan, Y. Wu, J.-C. Yang and L.-N. Guo, Chem. Sci.,
2019, 10, 161; (d) W. Ai, Y. Liu, Q. Wang, Z. Lu and Q. Liu,
Org. Lett., 2018, 20, 409; (e) D. Ding and C. Whang, ACS
Catal., 2018, 8, 11324.
12 (a) J. Twilton, C. C. Le, P. Zhang, M. H. Shaw, R. W. Evans
and D. W. C. MacMillan, Nat. Rev. Chem., 2017, 1, 0052; (b)V. Corcé, L. M. Chamoreau, E. Derat, J.-P. Goddard,
C. Ollivier and L. Fensterbank, Angew. Chem., Int. Ed.,
2015, 54, 11414; (c) J. C. Tellis, D. N. Primer andThis journal is © The Royal Society of Chemistry 2019

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G. A. Molander, Science, 2014, 345, 433; (d) Z. Zuo,
D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle andD. W. C. MacMillan, Science, 2014, 345, 437.
13 J. Davies, N. S. Sheikh and D. Leonori, Angew. Chem., Int. Ed.,2017, 56, 13361.
14 (a) D. N. Primer, I. Karakaya, J. C. Tellis and G. A. Molander,
J. Am. Chem. Soc., 2015, 137, 2195; (b) S. Z. Tasker,
E. A. Standley and T. F. Jamison, Nature, 2014, 509, 299.
15 M. Durandetti, M. Devaud and J. J. Perichon, New J. Chem.,
1996, 20, 659.
16 Starting material 1, and its precursor (aminooxy)-2methylpropanoic acid hydrochloride, were subjected tosafety testing and found not to be explosive. See ESI† formore information.

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17 In this case we have observed the formation of butyronitrile,
possibly from radical ring-opening followed by H-atom
abstraction from the solvent.
18 D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel and
T. Noël, Chem. Rev., 2016, 116, 10276–10341.
19 See ESI† for more information.
20 N. A. Till, R. T. Smith and D. W. C. MacMillan, J. Am. Chem.
Soc., 2018, 140, 5701.
21 C. P. Johnston, R. T. Smith, S. Allmendinger and
D. W. C. MacMillan, Nature, 2016, 536, 322.
22 T. P. Boyle, J. B. Bremner, J. A. Coates, P. A. Keller and G. P. S,
Tetrahedron, 2005, 61, 7271.

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