Photoinduced Remote Functionalisations by Iminyl Radical Promoted C?C and C?H Bond Cleavage Cascades

Article abstract of DOI:10.1002/anie.201710790

A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp³)?(sp³) and C(sp³)?H bond cleavage gives access to distal carbon radicals that undergo S_H2 functionalisations. These mild, visible-light-mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.

Full text of DOI:10.1002/anie.201710790

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Photoinduced Remote Functionalizations via Iminyl Radical-
Promoted C-C and C-H Bond Cleavage Cascades.
Authors: Elizabeth M. Dauncey, Sara P. Marcillo, James J. Douglas,
Nadeem S. Sheikh, and Daniele Leonori
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710790
Angew. Chem. 10.1002/ange.201710790
Link to VoR: http://dx.doi.org/10.1002/anie.201710790
http://dx.doi.org/10.1002/ange.201710790

10.1002/anie.201710790
Angewandte Chemie International Edition
COMMUNICATION
Photoinduced Remote Functionalizations via Iminyl Radical-
Promoted C–C and C–H Bond Cleavage Cascades
Elizabeth M. Dauncey,#[a] Sara P. Morcillo,#[a] James J. Douglas,[b] Nadeem S. Sheikh,[c] and Daniele
Leonori*[a]
Abstract: A photoinduced cascade strategy leading to a variety of
differentially functionalized nitriles and ketones has been developed.
A) Radical Transposition Processes
These protocols rely on the oxidative generation of iminyl radicals
from simple oximes. Radical transposition by sp3–sp3 C–C and sp3
C–H bond cleavages gives access to distal carbon-radicals that
undergo SH2-functionalizations. These mild, visible-light-mediated
protocols allow remote fluorinations, chlorinations and azidations
and have been applied to the modification of bioactive and
structurally complex molecules.
n sp3-sp3 C–C cleavage
n sp3 C–H cleavage
Me
Me
radical
transposition
H
Ts
R
Ts
R
NH
N
RT
RT
RT
H
Me
Me
Me
Me
B) Previous work: Visible-Light-Mediated Generation and Cyclizations of Iminyl Radicals
NO2
+ e–
SET
– e–
SET
Me
Me
CO2H
NO2
R2
N
R2
O
O
N
N
R2
reduction
oxidation
R
R1
iminyl radical
The development of methods for the selective functionalization
of non-activated sp3 carbons is a longstanding endeavor in
organic synthesis.[1] Radical strategies are attractive options
owing to the ability of odd-electron species to undergo
R
R1
R
R1
C) This work: Photoinduced Remote Functionalizations – Oxidative SET
N
NC
( )n
R1
R2
Me
Me
R2
R1
RT [X]
CO2H
n( )
X
transposition processes.[2] If
a suitably reactive radical is
O
SET
N
O
generated in a specific position of an organic molecule, then sp3-
sp3 C–C and sp3 C–H bond cleavages can be triggered leading
to remote functionalizations. Classical examples are the ring-
opening of α-cyclopropyl radicals (radical clock)[3] and the 1,5-H-
atom abstractions of nitrogen-radicals – the key step of the
Hofmann-Löffler-Freytag reaction (HLF)[4] (Scheme 1A).[5]
N
H
R1
R2
R1
R
R1
RT [X]
R
R
X
R2
Scheme 1. Radical transpositions processes and current work using iminyl
radicals.
We have recently developed two classes of oximes that provide
access to iminyl radicals by both reductive and oxidative visible-
light-mediated single electron transfers (SETs) and used them in
intra-molecular cyclization processes (Scheme 1B).[6] Whereas
amidyl and N-Ts-aminyl radicals have been extensively
exploited in visible-light-mediated transposition reactions,[5, 7] the
implementation of iminyl radicals has been considerably
overlooked.[8] Inspired by the pioneering work of Zard[8e-g] and
Forrester[8a-c], we wondered if the key transposition steps of the
radical clock and the HLF processes could be harnessed as part
of a general interrupted cascade strategy from an iminyl radical,
leading to a variety of functionalized molecules. Herein, we
report the development of two photoinduced manifolds that
enable the preparation of remotely functionalized nitriles and
ketones via a tandem iminyl radical generation, sp3-sp3 C–C/sp3
C–H bond cleavage, functionalization cascade (Scheme 1C).
At the outset, we realized that our reductive SET approach for
iminyl radical generation and cyclization was electronically
mismatched as illustrated in Scheme 2 using a ring-opening–
functionalization process. In fact, upon SET reduction and
fragmentation of precursor A, the iminyl radical B should
undergo a fast β-fission generating the δ-CN-radical C. As this
species is expected to be nucleophilic, it benefits from the
reaction with polarized SOMOphiles (X–Y) where the X-
atom/group has a partial positive character. Following radical
atom/group transfer reaction (SH2), D is generated together with
the radical Y•. Owing to its electrophilic nature, a final SET
oxidation will be highly endergonic, thus thwarting the
development of a redox neutral process. We therefore selected
the carboxylic acid-containing oxime E as the starting point. We
were hopeful that upon deprotonation, a sequence of SET
oxidation, followed by CO2 and acetone extrusion would lead to
the formation of B. Following β-fission–SH2 cascade would
generate the product D and the electrophilic radical Y• that
Me
Me
CO2H
OAr
O
+ e–
– e–
N
A
N
B
N
R1
R1
R1
SET
SET
R
R
R
– ArO–
– CO2, acetone
[a]
Elizabeth M. Dauncey, Dr. Sara P. Morcillo and Dr. Daniele Leonori
School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL (UK)
E
Ar = 2,4-NO2-C6H3
R1
+δ –δ
NC
E-mail: daniele.leonori@manchester.ac.uk
Website: http://leonoriresearchgroup.weebly.com
Dr. James J. Douglas
X
Y
R
–δ
C
– e–
+ e–
SET
[b]
[c]
#
Early Chemical Development, Pharmaceutical Sciences, IMED
Biotech Unit, AstraZeneca, Macclesfield SK10 2NA (UK)
Prof. Nadeem S. Sheikh
Department of Chemistry, Faculty of Science, King Faisal University
P.O. Box 380, Al-Ahsa 31982 (Saudi Arabia)
These authors contributed equally to the work.
SET
Y
Y•
Y•
Y
exergonic
endergonic
X
R1
NC
R
D
Scheme 2. Mechanistic analysis of iminyl radical transposition–
functionalization.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710790
Angewandte Chemie International Edition
COMMUNICATION
should undergo exergonic SET reduction, ensuring efficient
reactivity.
We started our investigation by preparing oxime 1a by
(1d,e!3d,e), cyclohexanones (1f,g!3f–g and 1k–m!3k–m),
and, remarkably, cycloheptanone (1h!3h), obtaining a broad
range of fluorinated products in good yields. The methodology
was also implemented as part of a strategy for the preparation of
C-4 fluorinated 4-aryl-piperidines (1n,o!3n,o) that constitute the
structural core of many opioid analgesic and antipsychotics such
as pethidine and haloperidol. In this case, upon iminyl radical
generation the fragmentation process expels acetonitrile.
condensation
of
2,2-dimethylcyclopentanone
with
a
commercially available hydroxylamine on a gram-scale (Scheme
3A).[9] Using Fukuzumi’s acridinium 2 as the photoredox catalyst
10]
(E*1/2 = 2.2 V vs SCE),[6b,
we evaluated several potential
radical fluorinating agents (X–Y),[11] bases and solvents under
blue LEDs irradiation. While NFSI resulted in unreacted 1a
(entry 1), we were pleased to see that using selectfluor the
desired iminyl radical generation–ring-opening–fluorination
We were particularly interested in applying this strategy to the
structural modification of natural products. As these unique
architectures are tuned to allow optimal interactions with specific
cascade could be achieved albeit in low yield (entry 2). However, bio-targets, a methodology enabling access to compounds with
by using H2O as the co-solvent (entry 3) and K2CO3 as the base
(entry 4), 3a was obtained in high yield in just 15 minutes. This
natural product-like cores has great promise in phenotypic-
based drug discovery.[14] Pleasingly, we were able to
deconstruct and fluorinate (+)-camphor (13!3p), the steroids
represents
a radical “abnormal” Beckmann fragmentation–
fluorination process.[12] Control experiments confirmed the
requirement for base, 2 and continuous blue light irradiation. A
quantum yield[13] Φ = 2.8 was determined for this transformation,
which suggests that productive short-lived radical chain
propagation processes are operating together with the
photoredox pathway.[9]
With an optimized set of conditions in hand, the scope of the
reaction was evaluated (Scheme 3B). We successfully carried
the oxidation–ring-opening–fluorination of oximes deriving from
cyclobutanones (1b,c!3b,c and 1i,j!3i,j), cyclopentanones
estrone (1q!3q) and androsterone (1r!3r), a synthetic
intermediate of the oral contraceptive drospirenone (1t!3s) and
the diterpene isosteviol (1u!3t).
Furthermore, N-chloro-succinimide (NCS) and tri-i-Pr-sulfonyl–
azide[15] were effective among a range of reagents investigated
to achieve a novel cascade approach towards chlorinated (4a–j)
and azidated (5a–e) nitriles.[9] Here, the optimum base and
solvent were identified as KOAc–CH3CN and Cs2CO3–CH2Cl2
for the chlorination and azidation processes respectively.
By a combination of DFT and experimental studies, we have
A) Optimisation of the photoinduced cascade ring opening–fluorination
Mes
Entry
F–Y
Base
Solvent
Time Yield (%)
F–Y (2.0 equiv.)
2 (5 mol%), base (1.0 equiv.)
Cl
OR
PhO2S
SO2Ph
N
N
N
F
Me
Me
N
Me
Me
1
2
3
4
NFSI
Cs2CO3
CH3CN
CH3CN
1h
1h
1h
–
Me
Me
CO2H
NC
R =
F
N
selectfluor Cs2CO3
selectfluor Cs2CO3 CH3CN–H2O (1:1)
selectfluor K2CO3 CH3CN–H2O (1:1) 15 min
13
67
84
(BF4)2
solvent (0.2 M), time, r.t.
F
NFSI
3a
ClO
blue LEDs
Me
2
4
selectfluor
1a
B) Scope for the photoinduced fragmentation-fluorination/chlorination/azidation Processes
Starting Materials
R1
n
1b: 0
1c: 0 Ph
1d: 1 Ph
R
H
R1
H
H
R
NOR
NOR
NOR
NOR
R1
Me
H
Me
H
Me
H
Me
H
R
NOR
1k: Me H
1l: Me Me
Me
Me
NOR
NOR
Me
H
Me
H
Me
H
Me
H
Me
NOR
H
1i
R
1m:
NOR
H
H
H
H
H
H
H
1 1e: 1
N
Boc
R1O
AcO
AcO
AcO
R
NOR
Me
H
OH
1t
( )n
NOR
Ph
1p
MeO2C Me
1u
R1 = Ac: 1q
R1 = Me: 1v
estrone
1r
1s
1n: R = Ts
1o: R = Boc
1f:
2
Ph
H
(+)-camphor
Me
androsterone
prasterone
drospirenone
intermediate
isosteviol
H
N
1g: 2 Ph Me
1h: 3 Ph
N
Ts
1j
H
R
Reaction Products
Ph
F
NC
CN
F
NC
Me
Me Me
F
NC
CN
F
F
NC
F
NC
F
F
F
F
F
Me
Ph
CN
F
N
N
F
N
CN
Ph
Ph
Boc
NC
Ph
Ph
Ts
CN
CN
CN Ts
3b, 76% 3c, 63%
3d, 68%
3e, 35%
3f, 61%
3g, 63%
3h, 72%
3i, 62%, dr 4:1 3j, 44%, dr 3:1
3k, 46%
3l, 70%
3m, 56%
3n, 60%
Me
F
Me
F
Me
Me
F
N
Ph
F CN
Me
Ph
Ph
F
Me
H
Me
H
H
H
CN
Me
Me Me
CN
AcO
H
H
NC
via
CN
H
H
H
Me
Cl Me
Me
CN Cl
4b, 59%
– MeCN
N
N
N
F
AcO
MeO2C Me
Boc
AcO
H
HO
R
R
3o, 64%
3p, 72%, dr 4:1
3q, 72%, dr 1.3:1
3r, 52%, dr 3:1
3s, 51%, dr 3:1
3t, 31%*
4a, 94%
Me
Cl
Me
ClCN
Me
Cl
Me
Cl
Ph
Ph
Cl
Cl
NC
Me
H
Me
H
Me Me
N3
Cl
H
Me
H
Me Me
NC
CN
NC
CN
H
CN
H
H
Me
N3 Me
Me
H
H
N
N
N
Cl
AcO
AcO
Boc Ts
Boc
MeO
H
AcO
HO
4j, 40%, dr 3:1
CN
4c, 50%
4d, 71%
4e, 66%
4f, 69%, dr 4:1
4g, 53%*
4h, 87%*
4i, 62%, dr 4:1
5a, 64%
5b, 52%
Reaction Parameters: ΔG‡ and ΔGº: (Kcal mol–1) [UB3LYP/6-31+G(d,p)
= experimentally successful
Ph
N3
R1
H
ΔGº
n
2
2
2
2
R
H
R1
H
ΔGº
7.9
5.4
–5.7
2.4
ΔG‡
9.6
7.9
4.2
5.1
ΔG‡
18.7
15.7
11.2
13.0
ΔGº
n
1
1
1
1
R
H
n
R
H
H
H
Me
R1
H
Me
Ph
Me
ΔG‡
ΔGº
13.8
9.1
–1.8
5.9
n
4
4
4
4
R
H
R1
H
ΔG‡
24.0
19.9
15.4
18.7
Me Me
N
NC
9.4
4.4
–7.3
0.8
–10.2
–11.8
–22.8
–14.4
3
3
3
3
22.7
19.8
15.7
16.7
N3
Me
R
R1
N
H
H
Me
Me
Ph
Me
H
H
Me
Me
Ph
Me
H
H
Me
Me
Ph
Me
N3
CN
Ts
( )n
5c, 63%
5d, 64%
5e, 86%*
Scheme 3. Development and scope for the photoinduced ring-opening fluorination, chlorination, azidation reactions via iminyl radicals. * = isolated as single
diastereomer.
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10.1002/anie.201710790
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COMMUNICATION
determined that while cyclobutanones derived oximes undergo
very facile fragmentation, the radical ring-openings of higher
cycles are considerably more difficult. However, by placing either
an α-aromatic substituent or two α-alkyl groups (e.g. gem-Me2),
we were able to effectively engage cyclopentanone derivatives.
In the case of cyclohexanone and cycloheptanone-derived
oximes, the radical fragmentations are increasingly challenging,
but could be achieved in good yields when α-aromatic
substituents were present.[9]
concerns, we started our investigations by preparing oxime 6a
and exposing it to various SOMOphiles using
2 as the
photocatalyst under blue LEDs irradiation (Scheme 4B).[9] We
were pleased to see that in the presence of NCS γ-chlorination
occurred smoothly.[17] However, upon isolation and full
characterization of the reaction product we realized that the
imine intermediate I had reacted with the excess NCS providing
the N-Cl imine 7a which was stable and could be purified by
column chromatography.[18] We then hoped to expand this
strategy and develop a sought-after γ-fluorination process. We
were particularly interested by the fact that going via an iminyl
radical would by-pass some of the limitations of approaches
based on the photo-excitation of ketones, which are mostly
suited for the fluorination of structurally congested molecules as
elegantly demonstrated by Lectka.[19] In this case however,
screening of several radical F-donors, bases, photocatalysts and
solvents, lead to very low product formation (entry 1). Pleasingly,
by using selectfluor as the F-source and Ag2CO3 as a co-
catalyst,[20] γ-fluorinated ketone 8a was obtained in high yield in
just 15 min (entry 3). Control experiments confirmed the
necessity of 2, Ag(I) and continuous blue LEDs irradiation. For
this reaction, a calculated quantum yield Φ = 4.8 is consistent
with the presence of productive radical chain propagations along
with the photoredox manifold.[9]
Having achieved tandem iminyl radical generation and sp3-sp3
C–C bond fragmentation–functionalization, we evaluated the
development of a strategy based on sp3 C–H bond cleavage.
Success here would deliver a method for the selective γ-
functionalization of ketones[16] via iminyl radicals that is
underdeveloped. Specifically, we envisaged a cascade process
starting with the oxidative SET–fragmentation of precursor F
leading to the iminyl G. In this case, as C–C bond fragmentation
is not favorable;
a
1,5-H-abstraction[2d] would deliver the
nucleophilic γ-carbon radical H (Scheme 4A). Polarity matched
SH2 reaction with the SOMOphiles (to give I) and hydrolysis
would provide the γ-functionalized ketone J which would be
unreactive under classical ionic reactions. We were however
concerned by the fact that (i) 1,5-H abstractions involving iminyl
radicals are known to require acidic conditions,[8b, 8c] which would
not allow decarboxylation in our system, and (ii) that radical H is
With these set of conditions in hand, we evaluated the scope of
the processes using a range of oximes with different substitution
patterns. This enabled the divergent preparation of a variety of
prone to undergo intramolecular cyclization when R = aromatic
8c, 8k]
as reported by Forrester and Nevado.[8b,
Despite these
A) γ-Functionalizations of ketones via cascade reaction of iminyl radiclas
Me
Me
CO2H
challenging transformation
H
O
F
R1
R2
+δ –δ
– e–
O
O
O
N
N
NH
NH
–δ
γ
X
Y
R1
R1
R1
R1
R1
R2
R1
R2
SET
R
R
β
R
R
R
R
R
α
R2
X
R2
R2
R2
G
H
I
J
X
X
B) Development of γ-chlorination and γ-fluorination and scope of the two processes
Entry Ag Catalyst Yield (%)
NCS (4 equiv.)
2 (5 mol%), Cs2CO3 (1.0 equiv.)
selectfluor (2.0 equiv.)
2 (5 mol%), Cs2CO3 (1.0 equiv.)
OR
N
NCl
OR
6a
Me
Me
N
O
Ag catalyst (25 mol%)
1
2
3
4
–
17
60
81
19
CO2H
Me
Me
Cl Me
7a
R =
Ph
Ph
toluene, r.t., 45 min
blue LEDs
69%
AgNO3
Ag2CO3
AgO
Me
Me
Me
Me
Ph
Ph
Me
CH3CN–H2O, r.t., 15 min
6a
F
blue LEDs
8a
Starting Materials
Me
Me
Me
NOR
NOR
NOR
6g: R = t-Bu
6h: R = Ad
6i: R = Bn
6j: R = Cy
6k: R = EtO2C
6b: R = p-OMe-C6H4
6c: R = p-CN-C6H4
6d: R = 2-napthyl
6e: R = 2-furyl
Cl
6f: R =
N
NOR
X
Me
OH Me
N
Me
6l: X = Br
H
Bn
R
R
Me
Boc
R
6t
Me
6s
6m: X = N3
6n: X = CN
6o: X = OPh
6p: X = SPh
Me
Me
Me
6q: R = Ph
6r: R = Bn
Me
H
H
HO
6v
6w
6u
Me
H
Reaction Products
NCl
NCl
NCl
NCl
NCl
NCl
NCl
NCl
Me
Cl Me
Me
Me
Me
Me
Me Cl
Me Me
Me
Me
Cl Me
Cl Me
Cl Me
Cl Me
7c, 49%
Cl Me
Cl Me
7e, 66%
Cl Me
EtO2C
O
N
Me
7g, 58%
MeO
Br
NC
7h, 91%
7b, 70%
7d, 65%
7f, 45%
7i, 36%
NCl
NCl
O
O
O
O
O
O
Ph
Me
Me Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
Me N3
Me
Me
Me
Ph
Cl Me
Cl Me
7k, 34%
F
F
F
F
OH
8d, 57%
EtO2C
O
F
F
7j, 53%
8b, 88%
8c, 74%
8e, 71%
8f, 59%
8g, 79%
O
O
O
O
O
O
F
F
PhS
NC
Me
Me
PhO
Me
Me
Me
Me
Ph
Me
Ph
Me
Me
Ph
Ph
F
F
F
F
Me
F
Me
8l, 59%
N
Boc
8h , 66%
8i, 68%
8j, 52%
8k, 63%
8m, 82%
8n, 82%, dr 3:1
F
O
Me
Me
BDEs (Kcal mol–1) [(RO)B3P86 6-311G(d,p)]
Reaction Parameters: ΔG‡ and ΔGº (Kcal mol–1) [UB3LYP/6-31+G(d,p)]
H
Me
Ha
H
Hc
N–Ha = 93.2
C–Hb = 95.6
N–Hc = 121.2
C–Hd = 92.5
H
H
H
H
H
Me
H
N
N
vs
H
Me
Me
H
H
H
H
Me
Me
Hb
Me
ΔG‡
ΔGº
13.1
–2.1
13.7
4.2
15.7
6.7
18.2
11.0
n.d.
–24.9
Hd
Me
N
N
N
N
N
Ph
Me
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HO
Me
Me
H
8o, 71%, dr 1.3:1
Scheme 4. Development and scope for the photoinduced γ-chlorination and γ -fluorination reactions via iminyl radicals.
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10.1002/anie.201710790
Angewandte Chemie International Edition
COMMUNICATION
Suarez, J. Org. Chem. 2003, 68, 1012; (c) L. R. Reddy, B. V. S. Reddy,
E. J. Corey, Org. Lett. 2006, 8, 2819; (d) K. Chen, J. M. Richter, P. S.
Baran, J. Am. Chem. Soc. 2008, 130, 7247.
γ-Cl-N-Cl imines (7b–k) and -F ketones (8b–n) in good yields.
Overall, the reactions were largely undeterred by a variety of
functionalities as demonstrated by the successful formation
ofproducts containing electron rich and poor (hetero)aromatics,
nitrile, azide, ester, free alcohol, (thio)ether, and N-Boc groups.
Furthermore, we were able to apply the -fluorination to the
modification of a structurally complex lithocolic derivative (7o).
The challenges associated to the development of these radical
transpositions can be appreciated by evaluating the reaction
parameters. According to our calculations, there is a very small
gain in BDEs[21] going from the iminyl G to the carbon radical H
(compare BDE for N–Ha and C–Hb) and these 1,5-abstraction
process are generally endergonic (for ΔGº = 4.2 kcal mol–1)
(Scheme 4).[9] This is in line with our experimental results
showing the ability of these γ-chlorination and γ-fluorination
cascades to functionalize tertiary centres, which are the most
activated.[22] Our results also explain while previous methods
required a stoichiometric acid that, by protonating the iminyl
radical, renders the reaction extremely exergonic and imposes a
significant gain in BDEs to the abstraction process (compare
BDEs for N–Hc and C–Hd).[23]
[5]
Selected examples of visible-light-mediated HLFs: (a) C. Martinez, K.
Muniz, Angew. Chem. Int. Ed. 2015, 54, 8287; (b) J. Richers, M.
Heilmann, M. Drees, K. Tiefenbacher, Org. Lett. 2016, 18, 6472; (c) E.
A. Wappes, S. C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem. Int.
Ed. 2016, 128, 9974; (d) P. Becker, T. Duhamel, C. J. Stein, M. Reiher,
K. Muniz, Angew. Chem. Int. Ed. 2017, 56, 8004; (e) H. Zhang, K.
Muniz, ACS Catal. 2017, 7, 4122.
[6]
[7]
[8]
(a) J. Davies, S. G. Booth, S. Essafi, R. W. A. Dryfe, D. Leonori, Angew.
Chem. Int. Ed. 2015, 54, 14017; (b) J. Davies, N. S. Sheikh, D. Leonori,
Angew. Chem. Int. Ed. 2017, 56, 13361. For reviews on nitrogen
radicals, see: (c) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603; (d) J.-R.
Chen, X.-Q. Hu, L. Q. Lu, W.-J. Xiao, Chem. Soc. Rev. 2016, 2044.
(a) Q. Quin, S. Yu, Org. Lett. 2015, 17, 1894; (b) J. C. K. Chu, T. Rovis,
Nature 2016, 539, 272-275; (c) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu,
R. R. Knowles, Nature 2016, 539, 268-271; (d) D. Meng, Y. Tang, J.
Wei, X. Shi, M. Yang, Chem. Commun. 2017, 53, 5744; (e) W. Shu, A.
Genoux, Z. Li, C. Nevado, Angew. Chem. Int. Ed. 2017, 56, 10521.
Selected examples: (a) A. R. Forrester, M. Gill, R. H. Thomson, J.
Chem. Soc. Chem. Commun. 1976, 677; (b) A. R. Forrester, M. Gill, R.
J. Napier, R. H. Thomson, J. Chem. Soc., Perkin Trans. 1 1979, 632;
(c) A. R. Forrester, R. J. Napier, R. H. Thomson, J. Chem. Soc., Perkin
Trans. 1 1981, 984; (d) D. S. Watt, J. Am. Chem. Soc. 1976, 98, 271;
(e) J. Boivin, E. Fouquet, S. Z. Zard, J. Am. Chem. Soc. 1991, 113,
1055; (f) J. Boivin, E. Fouquet, S. Z. Zard, Tetrahedron 1991, 32, 4299;
(g) J. B. Boivin, E. Fouquet, S. Z. Zard, Tetrahedron 1994, 50, 1745; (h)
A. L. J. Beckwith, D. M. O'Shea, S. W. Westwood, J. Am. Chem. Soc.
1976, 110, 2565; (i) L. Zhang, G. Y. Ang, S. Chiba, Org. Lett. 2011, 13,
1622; (j) A. Faulkner, N. J. Race, J. S. Scott, J. F. Bower, Chem. Sci.
2014, 5, 2416; (k) H.-B. Yang, N. Selander, Chem. Eur. J. 2017, 23,
1779; (l) B. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2017, 56, 12727. For
visible-light-mediated examples, see: (m) W. Shu, C. Nevado, Angew.
Chem. Int. Ed. 2017, 56, 1881; (n) E. A. Wappes, K. M. Nakafuku, D. A.
Nagib, J. Am. Chem. Soc. 2017, 139, 10204; (o) J. Li, P. Zhang, M.
Jiang, H. Yang, Y. Zhao, H. Fu, Org. Lett. 2017, 19, 1994; (p) L. Li, H.
Chen, M. Meia, L. Zhou, Chem. Commun. 2017, 53, 11544.
In conclusion, we have developed a photoinduced strategy for
the preparation of remotely functionalized nitriles and ketones.
These protocols are triggered by the organo-photoredox
generation of iminyl radicals that, upon transposition via sp3–sp3
C–C or sp3 C–H bond cleavage, give access to distal carbon-
radicals.
Acknowledgements
D.L. thanks the European Union for a Career Integration Grant
(PCIG13-GA-2013-631556), the Leverhulme Trust for
a
research grant (RPG-2016-131) and EPSRC for a research
grant (EP/P004997/1). E.D. thanks AstraZeneca for a PhD
CASE Award. N.S.S. gratefully acknowledges the support by the
Department of Chemistry, King Faisal University.
[9]
See SI for more information.
[10] N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075.
[11] (a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320; (b) C. Chatalova-Sazepina, R. Hemelaereb, J.-F.
Paquin, G. M. Sammis, Synthesis 2015, 47, 2554; (c) M. Rueda-
Becerril, C. C. Sazepin, J. C. T. Leung, T. Okbinoglu, P. Kennepohl, J.-
F. Paquin, G. M. Sammis, J. Am. Chem. Soc. 2012, 134, 4026.
[12] M. Kirihara, K. Niimi, M. Okumura, T. Momose, Chem. Pharm. Bull.
2000, 48, 220.
Keywords: fluorination • azidation • chlorination • remote
radical functionalization cascade • photoinduced
[1]
[2]
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(a) Y. Qin, L. Zhu, S. Luo, Chem. Rev. 2017, 117, 9433; (b) P. A.
Champagne, J. Desroches, J.-D. Hamel, M. Vandamme, J.-F. Paquin,
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S. Maity, N. Zheng, Angew. Chem. Int. Ed. 2012, 51, 222; (b) J. W.
Beatty, C. R. J. Stephenson, J. Am. Chem. Soc. 2014, 136, 10270; (c)
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Xu, Y. Chen, Angew. Chem. Int. Ed. 2017, 59, 12619.
[16] Radical cascades leading to γ-functionalizaed ketones have been
reported by the ring-opening of cyclobutanols using Ag- and Mn-based
catalysts. For a recent review, see: (a) R. Ren, C. Zhu, Synthesis 2016,
27, 1139. For relevant examples, see: (b) R. Ren, H. Zhao, L. Huan, C.
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[18] Radical chlorination of alkanes is generally difficult owing to the poor
selectivity offered by the chlorine radical. For succesful visible-light- and
Ag(I)-mediated examples, see (a) R. K. Quinn, Z. A. Könst, S. E.
Michalak, Y. Schmidt, A. R. Szklarski, A. R. Flores, S. Nam, D. A.
[4]
(a) C. G. Francisco, A. J. Herrera, A. Martin, I. Perez-Martin, E. Suarez,
Tetrahedron 2007, 48, 6384; (b) C. G. Francisco, A. J. Herrera, E.
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K. F. Chin, M. W. Wongb, C.-H. Tan, Chem. Commun. 2014, 50, 8211.
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[22] According to our DFT studies, the 1,5-H abstraction from benzylic
positions should be feasible. However, under experimental conditions
complex reaction mixtures were obtained which thwarted the
implementation of this class of substrates.[9]
For
a Fe-catalysed 1,5-HAT–fluorination cascade, see: (f) B. J.
Groendyke, D. I. AbuSalim, S. P. Cook, J. Am. Chem. Soc. 2016, 138,
12771.
[23] The use of an acid additive is not possible here as photoredox
decarboxylations under protic conditions are extremely challenging. For
a review, see: J. Xuan, Z.-G. Zhang, W.-J. Xiao, Angew. Chem. Int. Ed.
2015, 54, 15632.
[20] For a recent review, see: (a) T. Liang, C. N. Neumann, T. Ritter, Angew.
Chem. Int. Ed. 2013, 52, 8214. For selected examples on Ag-mediated
fluorination of C-radicals, see: (b) T. Xu, X. Mu, H. Peng, G. Liu, Angew.
Chem. Int. Ed. 2011, 50, 8176; (c) F. Yin, Z. Wang, Z. Li, C. Li, J. Am.
Chem. Soc. 2012, 134, 10401; (d) S. Mizuta, I. S. R. Stenhagen, M.
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Nadeem S. Sheikh,[c] and Daniele
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Photoinduced Remote
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Functionalizations via Iminyl Radical-
Promoted C–C and C–H Bond
Cleavage Cascades
[1]
[2]
(a) Y. Qin, L. Zhu, S. Luo, Chem. Rev. 2017, 117, 9433; (b) P. A. Champagne, J. Desroches, J.-
D. Hamel, M. Vandamme, J.-F. Paquin, Chem. Rev. 2015, 115, 9073.
(a) P. Dowd, W. Zhang, Chem. Rev. 1993, 93, 2091; (b) A. Gansäuer, T. Lauterbach, S.
Narayan, Angew. Chem. Int. Ed. 2003, 42, 5556; (c) Z. Cekovic, J. Serb. Chem. Soc. 2005, 70,
287; (d) M. Nechab, S. Mondal, M. P. Bertrand, Chem. Eur. J. 2014, 20, 16034.
(a) S. Maity, N. Zheng, Angew. Chem. Int. Ed. 2012, 51, 9562; (b) J. W. Beatty, C. R. J.
Stephenson, J. Am. Chem. Soc. 2014, 136, 10270; (c) C. R. Pitts, M. S. Bloom, D. D. Bume, Q.
A. Zhang, T. Lectka, Chem. Sci. 2015, 6, 5225; (d) H. Jiang, X. An, K. Tong, T. Zheng, Y.
Zhang, S. Yu, Angew. Chem. Int. Ed. 2015, 54, 4055; (e) J.-J. Guo, A. Hu, Y. Chen, J. Sun, H.
Tang, Z. Zuo, Angew. Chem. Int. Ed. 2016, 128, 15319; (f) H. G. Yayla, H. Wang, K. T.
Tarantino, H. S. Orbe, R. R. Knowles, J. Am. Chem. Soc. 2016, 138, 10794; (g) J. Zhang, Y. Li,
R. Xu, Y. Chen, Angew. Chem. Int. Ed. 2017, 59, 12619.
[3]
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[4]
(a) C. G. Francisco, A. J. Herrera, A. Martin, I. Perez-Martin, E. Suarez, Tetrahedron 2007, 48,
6384; (b) C. G. Francisco, A. J. Herrera, E. Suarez, J. Org. Chem. 2003, 68, 1012; (c) L. R.
Reddy, B. V. S. Reddy, E. J. Corey, Org. Lett. 2006, 8, 2819; (d) K. Chen, J. M. Richter, P. S.
Baran, J. Am. Chem. Soc. 2008, 130, 7247.
[5]
(a) C. Martinez, K. Muniz, Angew. Chem. Int. Ed. 2015, 54, 8287; (b) J. Richers, M. Heilmann,
M. Drees, K. Tiefenbacher, Org. Lett. 2016, 18, 6472; (c) E. A. Wappes, S. C. Fosu, T. C.
Chopko, D. A. Nagib, Angew. Chem. Int. Ed. 2016, 128, 9974; (d) P. Becker, T. Duhamel, C. J.
Stein, M. Reiher, K. Muniz, Angew. Chem. Int. Ed. 2017, 56, 8004; (e) H. Zhang, K. Muniz,
ACS Catal. 2017, 7, 4122.
[6]
[7]
[8]
(a) J. Davies, S. G. Booth, S. Essafi, R. W. A. Dryfe, D. Leonori, Angew. Chem. Int. Ed. 2015,
54, 14017; (b) J. Davies, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2017, 56, 13361; (c) S.
Z. Zard, Chem. Soc. Rev. 2008, 37, 1603-1618; (d) J.-R. Chen, X.-Q. Hu, L. Q. Lu, W.-J. Xiao,
Chem. Soc. Rev. 2016, 2044-2056.
(a) Q. Quin, S. Yu, Org. Lett. 2015, 17, 1894; (b) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272-
275; (c) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268-271;
(d) D. Meng, Y. Tang, J. Wei, X. Shi, M. Yang, Chem. Commun. 2017, 53, 5744; (e) W. Shu, A.
Genoux, Z. Li, C. Nevado, Angew. Chem. Int. Ed. 2017, 56, 10521.
(a) A. R. Forrester, M. Gill, R. H. Thomson, J. Chem. Soc. Chem. Commun. 1976, 677; (b) A. R.
Forrester, M. Gill, R. J. Napier, R. H. Thomson, J. Chem. Soc., Perkin Trans. 1 1979, 632; (c) A.
R. Forrester, R. J. Napier, R. H. Thomson, J. Chem. Soc., Perkin Trans. 1 1981, 984; (d) D. S.
Watt, J. Am. Chem. Soc. 1976, 98, 271; (e) J. Boivin, E. Fouquet, S. Z. Zard, J. Am. Chem. Soc.
1991, 113, 1055; (f) J. Boivin, E. Fouquet, S. Z. Zard, Tetrahedron 1991, 32, 4299; (g) J. B.
Boivin, E. Fouquet, S. Z. Zard, Tetrahedron 1994, 50, 1745; (h) A. L. J. Beckwith, D. M.
O'Shea, S. W. Westwood, J. Am. Chem. Soc. 1976, 110, 2565; (i) L. Zhang, G. Y. Ang, S. Chiba,
Org. Lett. 2011, 13, 1622; (j) H.-B. Yang, N. Selander, Chem. Eur. J. 2017, 23, 1779; (k) W.
Shu, C. Nevado, Angew. Chem. Int. Ed. 2017, 56, 1881; (l) E. A. Wappes, K. M. Nakafuku, D.
A. Nagib, J. Am. Chem. Soc. 2017, 139, 10204; (m) J. Li, P. Zhang, M. Jiang, H. Yang, Y. Zhao,
H. Fu, Org. Lett. 2017, 19, 1994; (n) L. Li, H. Chen, M. Meia, L. Zhou, Chem. Commun. 2017,
53, 11544.
[9]
, See SI for more information.
[10] N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075.
[11] (a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; (b) C.
Chatalova-Sazepina, R. Hemelaereb, J.-F. Paquin, G. M. Sammis, Synthesis 2015, 47, 2554; (c)
M. Rueda-Becerril, C. C. Sazepin, J. C. T. Leung, T. Okbinoglu, P. Kennepohl, J.-F. Paquin, G.
M. Sammis, J. Am. Chem. Soc. 2012, 134, 4026.
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[13] M. A. Cismenia, T. P. Yoon, Chem. Sci. 2015, 6, 5426.
[14] J. Kim, H. Kim, S. B. Park, J. Am. Chem. Soc. 2014, 136, 14629.
[15] (a) P. Panchaud, L. Chabaud, Y. Landais, C. Ollivier, P. Renaud, S. Zigmantas, Chem. Eur. J.
2004, 10, 3606; (b) C. Ollivier, P. Renaud, J. Am. Chem. Soc. 2000, 122, 6496; (c) X. Huang, J.
T. Groves, ACS Catal. 2016, 6, 751; (d) X. Zhang, H. Yang, P. Tang, Org. Lett. 2015, 17, 5828.
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Chem. Int. Ed. 2015, 127, 12883.
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D. A. Horne, C. D. Vanderwal, E. J. Alexanian, J. Am. Chem. Soc. 2016, 138, 696; (b) J. Ozawa,
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Lectka, Chem. Sci. 2017, 8, 6918; (c) S. Bloom, J. L. Knippel, T. Lectka, Chem. Sci. 2014, 5,
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1175; (d) J.-B. Xia, C. Chen, Chem. Commun. 2014, 50, 11701; (e) C. W. Kee, K. F. Chin, M.
W. Wongb, C.-H. Tan, Chem. Commun. 2014, 50, 8211; (f) B. J. Groendyke, D. I. AbuSalim, S.
P. Cook, J. Am. Chem. Soc. 2016, 138, 12771.
[20] (a) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214; (b) T. Xu, X. Mu,
H. Peng, G. Liu, Angew. Chem. Int. Ed. 2011, 50, 8176; (c) F. Yin, Z. Wang, Z. Li, C. Li, J. Am.
Chem. Soc. 2012, 134, 10401; (d) S. Mizuta, I. S. R. Stenhagen, M. O’Duill, J. Wolstenhulme, A.
K. Kirjavainen, S. J. Forsback, M. Tredwell, G. Sandford, P. R. Moore, M. Huiban, S. K. Luthra,
J. Passchier, O. Solin, V. Gouverneur, Org. Lett. 2013, 15, 2648; (e) P. Xu, X. Guo, L. Wang, P.
Tang, Angew. Chem. Int. Ed. 2014, 53, 5955.
[21] T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011, 50, 3362.
[22] , benzylic.
[23] , acid.
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