Photoredox Imino Functionalizations of Olefins

Article abstract of DOI:10.1002/anie.201708497

Shown herein is that polyfunctionalized nitrogen heterocycles can be easily prepared by a visible-light-mediated radical cascade process. This divergent strategy features the oxidative generation of iminyl radicals and subsequent cyclization/radical trapping, which allows the effective construction of highly functionalized heterocycles. The reactions proceed efficiently at room temperature, utilize an organic photocatalyst, use simple and readily available materials, and generate, in a single step, valuable building blocks that would be difficult to prepare by other methods.

Full text of DOI:10.1002/anie.201708497

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Photoredox Imino-Functionalizations of Olefins
Authors: Jacob Davies, Nadeem S. Sheikh, and Daniele Leonori
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708497
Angew. Chem. 10.1002/ange.201708497
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10.1002/anie.201708497
Angewandte Chemie International Edition
COMMUNICATION
Photoredox Imino-Functionalizations of Olefins
Jacob Davies,a Nadeem S. Sheikhb and Daniele Leonoria*
Abstract: Herein, we show that poly-functionalized nitrogen
heterocycles can be easily prepared by a visible-light-mediated
radical cascade process. This divergent strategy features the
oxidative generation of iminyl radicals and their cascade cyclization–
radical trapping, which allows the effective construction of highly
functionalized heterocycles. The reactions proceed efficiently at
room temperature, utilize an organic photocatalyst, use simple and
readily available materials and generate, in a single step, valuable
building blocks that would be difficult to prepare by other methods.
involved in any bond-forming event, controls the fate of our
photoredox manifold. In fact, owing to the required polarization
of X–Y for efficient reaction with B, Y• is expected to be
electrophilic. This generates an electronic mismatch in our first-
generation photoredox cycle, whereby [PC•+ + Y• ! PC + Y+] is
a
endothermic process (Scheme 1D, left). Therefore, we
reasoned that should the iminyl A be generated by oxidative
SET from the visible-light-excited photocatalyst (*PC), a facile
SET between Y• and PC•– ought to take place, ensuring catalytic
activity (Scheme 1D, right). An additional challenge associated
with the realization of this approach concerns the nature of the
SOMOphile X–Y.[12] In fact, many of these species are excellent
SET quenchers for *PC, they have been exploited in many
powerful atom/group-transfer reactions and they can lead to the
formation of “onium” ions.[12b] As a result, we would require the
oxidative generation of the iminyl radical, its intramolecular
cyclization and the following intermolecular radical reaction to
supersede any other possible photoredox and ionic pathway.
Small-molecule nitrogen heterocycles constitute the core of
many drugs and agrochemicals and are one of the key epitopes
evaluated in biological screenings.[1] As a result, the invention of
methods enabling their rapid construction is
a topic of
continuous scientific endeavour. An overarching goal in the
design of these methodologies is the identification of divergent
approaches whereby simple starting materials are converted into
a broad array of products that contain different functional groups
and efficiently tap into chemical space.
A) Previous work: Hydroimination via iminyl radicals
R2
Nitrogen radicals are
a
class of versatile synthetic
R1
X
eosin Y
1,4-cyclohexadiene, K2CO3
H
intermediates, and their reactivity encompasses a series of
powerful bond-forming reactions, like intramolecular cyclization
and 1,5-H abstraction.[2] In recent years, owing to the power of
visible-light photoredox catalysis[3] in realizing single electron
transfer (SET) processes,[4] the chemistry of nitrogen-radicals
has witnessed a remarkable resurgence in scientific interest.[5]
We have developed a class of electron-poor O-aryl oximes
and aryloxy amides which allows, upon reductive SET, access to
iminyl[6] and amidyl[7] radicals to use in radical hydroaminations
(Scheme 1A). However, despite all our efforts, we have not been
able to harness this reactivity mode for the development of much
sought after, but also more challenging, amino-functionalization
processes.[2i, 8] Herein, we describe our work towards this goal,
which has led to the development of a powerful platform for the
divergent assembly of poly-functionalized nitrogen heterocycles
(Scheme 1B).[9]
OAr
N
N
vs
N
acetone, rt
green LEDs
R
R
R
Ar = 2,4-(NO2)2-C6H3
not possible
B) Aim of the work: Divergent assembly of poly-functionalized nitrogen heterocycles
R2
N
R1
X
n highly valuable imine motif
n easy to modify
n divergent platform for
imino-funcionalization
R
R1
iminyl radical
n
N
n difficult to construct
n nitrogen-radical cascade
R
C) Polar effects in radical cascade reactions of nitrogen-radicals
R2
R1 –δ
R1
R2
X
+δ
–δ
5-exo-trig
+δ –δ
N
R2
N
N
+
Y•
X
Y
R
R1
R
R
SOMOphile
A
B
C
electrophilic
electrophilic
nucleophilic
D) Mechanistic analysis for reductive and oxidative photoredox cycles (PC = photocatalyst)
difficult SET
easy SET
Y
Y
PC
PC
vs
–δ
–δ
SET
SET
While facing the difficulties of developing cascade photoredox
imino-functionalizations of electron poor O-aryl oximes,[6] we
realized that an inherent chemical reactivity issue was
associated with the envisaged catalytic cycle. Nitrogen radicals
Y•
Y•
*PC
PC•+
PC•–
*PC
SET
SET
A
are electrophilic species and undergo facile exo-trig
cyclizations (Scheme 1C).[10] However, upon ring closure, they
generate nucleophilic carbon radical B, which benefits from
polar effects[11] in the reaction with SOMOphiles X–Y. This
process leads to the formation of the imino-functionalized
product C and the radical Y•. This radical, even though it is not
OAr
?
N
R2
N
R2
N
R2
R
R1
Ar = 2,4-(NO2)2-C6H3
A generated by SET reduction
R
R1
R
R1
A
A generated by SET oxidation
Scheme 1. Nitrogen-heterocycles and mechanistic analysis of the divergent
functionalization processes developed in this work.
[a]
[b]
Jacob Davies and Dr. Daniele Leonori
School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, UK
E-mail: daniele.leonori@manchester.ac.uk
Website: http://leonoriresearchgroup.weebly.com
Prof. Nadeem S. Sheikh
Department of Chemistry, Faculty of Science, King Faisal University,
P.O. Box 380, Al-Ahsa 31982, Saudi Arabia.
Inspired by the pioneering work of Forrester[13] and Zard,[2h] we
speculated that oxime I might serve as a traceless (n+σ+σ)
electrophore[13] and undergo a sequence of two β-scissions upon
in situ deprotonation (II) and SET oxidation (Scheme 2A). This
would deliver an iminyl radical in conjunction with the release of
CO2 and HCOH (III " IV).[14] As α-hydroxy-acids (e.g., 1) have
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708497
Angewandte Chemie International Edition
COMMUNICATION
ox
been employed in many photoredox decarboxylations,[12c, 15] we
were confident that such a substrate design would be feasible.
Surprisingly, electrochemical analysis of model substrate 2a
revealed its oxidation potential to be almost outside the range for
displayed E1/2 = 1.65 V (vs SCE), a value that can be reached
by some organic photoredox catalysts.[16]
Having identified
a suitable electrophore, we prepared
substrate 3a and begun our investigations by looking at
developing an oxidative hydroimination (Scheme 3). To
accomplish this goal, we selected methyl acridinium perchlorate
4 (E*1/2 = +2.06 V vs SCE)[3c, 17] as the photoredox catalyst and
evaluated a range of solvents and bases under blue LEDs
irradiation. Pleasingly, in the presence of an aryl-disulfide as H-
atom relay catalyst,[18] and 2,6-lutidine as the base, 5a was
obtained in 81% yield, which, to the best of our knowledge,
represents the first fully catalytic radical hydroimination of olefins.
Control experiments established the requirement for 4 and
continuous irradiation and the calculated quantum yield[19] Φ =
0.09 supports the photoredox nature of the process.[16]
ox
photoredox oxidation (E1/2 = 2.10 V vs SCE) (Scheme 2B). In
fact, previous activation methods required the use of strong
oxidants under forcing conditions, or the formation of the
corresponding Barton ester.[2h]
A) Substrate design for oxidative generation of iminyl radiclas
CO2
CO2
CO2H
O
O
O
– CO2
– H+
– e–
N
II
N
N
N
I
R
R1
R
R1
– HCOH
R
R1
R
R1
III
IV
B) Electrochemical scale (vs SCE in CH3CN)
1.0 V
1.2 V
1.4 V
1.6 V
1.8 V
2.0 V
We next turned our attention to defining the capacity for imino-
functionalization in the presence of external coupling partners.
By employing NCS, diethyl-bromo-malonate, NIS and NFSI, we
developed all olefin imino-halogenations in excellent to good
yield (5b–e). Interestingly, the use of Selectfluor as radical
fluorinating agent,[20] provided 5e in considerably lower yield.
Imino-iodinations and imino-fluorinations have not been reported
previously. The use of arylsulfonyl azide and DEAD as coupling
partners enabled the preparation of substrates with two nitrogen-
based functional groups in different oxidation states (imine and
azide (5f) or hydrazine (5g)) and with orthogonal reactivity. This
opens the potential for further functionalization and application in
click chemistry ligation. As thioethers motifs are frequently found
in pharmaceutical and agrochemical compounds,[21] we
evaluated their introduction as part of our strategy. Pleasingly,
we were able to form imines 5h–i that incorporated S-CF3 and
S-Ph groups. In this case, CsOBz[12h] proved to be uniquely
effective in promoting good conversions.
O
O
O
O
O
Me
Me
Ph
Me
OCs
OCs
OCs
OCs
OCs
O
O
O
O
O
N
N
N
N
Ph
2d: 1.65 V
Me
Ph
2c: 1.75 V
Me
Ph
Me
2b:1.80 V
Ph
2a: 2.10 V
Me
1: 1.1 V
Scheme 2. Substrate design and electrochemical studies.
Hence, we speculated that the addition of organyl groups at
the methylenic position might inductively increase the electron
density at the carboxylate, and lower its E1/2ox. Pleasingly, the
addition of a methyl (2b) and a phenyl (2c) group lowered the
ox
E1/2
by 0.25 and 0.3 V, respectively. More importantly,
substrate 2d, which was prepared by condensation of
acetophenone with a commercially available hydroxylamine,
Mes
Me
Me
Me
Me
X–Y (2.0 equiv.)
4 (5 mol%), base (1.0 equiv.)
CO2H
X
O
N
Me
Me
N
solvent, N2, rt
blue LEDs
N
Ph
Me ClO4
Ph
3a
5a–n
4
O
S
O
O
CO2Et
N N
PhO2S
SO2Ph
Ar
N3
ArS SAr
N
O
O
O
O
N
N
EtO
OEt
EtO2C
O
F
(50 mol%)
Cl
I
Br
n hydroimination
n iminochlorination
n iminobromination
n iminoiodination
n iminofluorination
n iminoazidation
n iminoamination
NHCO2Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Cl
Br
I
F
Me
N3
N
CO2Et
N
N
N
N
N
N
N
Ph
5a, 81%a,e
Ph
Ph
5c, 62%b,g
Ph
5d, 67%c,h
Ph
Ph
5f, 95%c,e
Ph
O
5b, 80%b,f,k
5e, 80%b,i,k
5g, 82%c,e
O
O
O
O
O
O
O
O
I
MeO2C
Me
CO2Me
I
CN
I
TIPS
N
SePh
N
SCF3
N
SPh
SPh
Ph
O
O
O
n iminothioetherification
n iminoselenation
n iminoMichael
Me
n iminocyanation
n iminoolefination
n iminoalkynylation
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
TIPS
Me
CN
Me
SCF3
SePh
CO2Me
CO2Me
Ph
N
N
N
N
N
N
N
Ph
5k, 66%, dr 1.5:1c,j,l
Ph
5l, 63%c,e
Ph
Ph
Ph
5h, 55%d,e
Ph
Ph
5j, 75%c,f
5m, 83%c,e
5n, 63%c,e
5i, 56%d,e,k
a
b
c
d
e
f
g
h
Scheme 3. Scope of the imino-functionalization strategy. Base used: 2,6-lutidine, K2CO3, Cs2CO3, CsOBz. Solvent used: CH2Cl2, toluene, i-PrOH,
MeOH, i hexafluoro-i-PrOH, j CH3CN–H2O (2:1). Equivalents of X–Y: k 3.0 equiv., n 4.0 equiv. Bn = benzyl, TIPS = triisopropylsilyl,
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10.1002/anie.201708497
Angewandte Chemie International Edition
COMMUNICATION
The formation of 5h is particularly relevant because the
introduction of the S-CF3 group in organic molecules is a
significant but challenging task in medicinal chemistry.[22] This
reactivity was also successfully extended to the introduction of a
Se-functionality (5j). Finally, we evaluated this approach for the
installation of organic groups based on the cascade formation of
C–N and C–C bonds. By using a Michael acceptor, we obtained
product 5k, which represents a radical imino-Michael cascade.
Furthermore, by using hypervalent IBX-reagents[23], we have
efficiency. In general, we have found that the inorganic bases
Cs2CO3 and K2CO3 and the solvents CH2Cl2 and toluene
provided the best results.[16] We have also conducted additional
electrochemical, Stern-Volmer and quantum yield (Φ) studies,
which corroborate our working hypothesis for the reaction
mechanism.[16] According to these studies we believe that, in
general, the iminofunctionalizations proceed via
a single
photoredox catalytic cycle starting with the SET oxidation of 3a.
However, in the case of the IBX reagents (imino-cyanation 5l
and alkynylation 5m), quantum yields 2<Φ<5 suggest that very
short-lived productive radical chain processes might be
operating together with the main photoredox manifold. It is worth
mentioning, that none of these processes provided the desired
products using our first generation iminyl-radical precursors.
developed unprecedented radical imino-cyanation (5l),
-
olefination (5m) and -alkynylation (5n) processes. The
successful formation of 5l is interesting, as recent literature
reports described the cyanating reagent to be able to react with
only α-heteroatom sp3 C-radicals.[12i] The reagent used for the
formation of 5m[24] has not been used before in radical manifolds, This clearly highlights the importance of polar effects and redox
which makes this example the first use of IBX-reagents as
vinylation partners in free-radical processes.
balance in the development of cascade reactions of nitrogen
radicals.
Regarding the optimization of these 14 different imino-
functionalizations, we were able to use 4 as the photocatalyst
across all the systems but the base, the solvent and the reaction
concentration had to be adjusted to maximise the reaction
Having developed a platform for the divergent assembly of
poly-functionalized nitrogen heterocycles, we expanded the
reaction
scope.
R1
Me
Me
CO2H
X–Y (2.0-4.0 equiv)
4 (5 mol%), base (1.0 equiv.)
R2
X
n 55 examples
O
R2
n functionalization of 1º, 2º and 3ª radicals
n late-stage modifications
N
N
blue LEDs
R
R1
R
3a–h
6a–k, 7a–r, 8a–i, 10a–c
Starting Materials
OR
OR
3b
OR
OR
OR
OR
3f
OR
3g
N
Me
Me
N
N
N
N
N
N
Me
Me
Ph
Ph
Ph
Ph
Ph
CO2Me
Ph
MeO2C
3a
3c
3d
3e
N
Scope of the Process
CO2Et
CO2Et
Ph
H
Cl
Br
N
SePh
Cl
N
CO2Et
CO2Bn
Ph
CO2Et
N
N
H
H
N
N
N
N
N
N
N
N
N
N
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6a, 68%
6b, 87%
6c, 69%
6d, 65%
6e, 74%
6f, 61% dr 1:1
6g, 51%
MeO2C
6h, 58%
6i, 64%
6j, 60%
N
N
CO2Et
CO2Et
Ph
Ph
Ph
Ph
Ph
MeO2C
MeO2C
MeO2C
H
Br
F
N
H
Br
N
SePh
CO2Et
Ph
Ph
CO2Et
N
N
H
H
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
7e, 48%, dr 9:1
Ph
Ph
Ph
Ph
6k, 41%
7a, 66% 7b, 40%, dr 2.3:1 7c, 38%, dr 9:1
7d, 62%
7f, 82%
7g, 44%, dr 2.3:1
7h, 61%, dr 2:1
7i, 78%, dr 1:1
Ph
N
BnO2C
Ph
Me
Me
Cl
F
N3
F3CS
H
NC
MeO2C
H
H
H
H
H
H
H
Me
Ph
CO2Bn
N
N
N
N
N
N
N
N
N
N
Me
H
H
H
H
H
H
H
H
Ph
Ph
Ph
7l, 53%, dr 4:1
Ph
Ph
Ph
Ph
7p, 66%, dr 4:1
Ph
Ph
Ph
8a, 48%, dr 3:1
7j, 63%, dr 9:1
7k, 75%, dr 20:1
7m, 72%, dr 4:1
7n, 66%, dr 8:1
7o, 61%, dr 3:1
7q, 61%, dr 2:1
7r, 53%, dr 1.5:1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
TIPS
Cl
SPh
N3
O
N
N
N
N
N
N
N
N
MeO2C
MeO2C
Ph
Ph
Ph
Ph
MeO2C
MeO2C
8b, 51%, dr 1:1
8c, 35%
8d, 77%
8e, 64%
8f, 48%
8g, 55%
8h, 44%
8i, 68%
Late-Stage Modifications
Me
Me
Me
Me
HN
Me
N
CO2Et
N
N
N
N
N3
N
SePh
CO2Et
N
via
N
N
O
Me
N
Me
Me
Me
H
OMe
Me
H
H
OMe
H
OMe
H
O
O
O
O
O
MeO
OMe
thevinone, 9
MeO
OMe
MeO
MeO
MeO
10a, 43%
10b, 41%
10c, 61%
Scheme 4. Reaction Scope. See Scheme 3 for solvent and base used in each imino-functionalization reaction.[17] Bn = benzyl.
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10.1002/anie.201708497
Angewandte Chemie International Edition
COMMUNICATION
[5]
(a) J.-R. Chen, X.-Q. Hu, L. Q. Lu, W.-J. Xiao, Chem. Soc. Rev. 2016,
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As shown in Scheme 5, we were able to implement substrates
containing terminal olefins (3b), which lead, via the intermediacy
of a primary radical, to imines 6a–h. Pyridine substituents were
tolerated thus providing nicotine analogues 6i–k. Substrates
containing di-substituted olefins (3d,e) were also successfully
engaged proving that the strategy is amenable to the formation
and functionalization of secondary benzylic (7a–e) and α-ester
(7f–j) radicals. By embedding the olefin into a cycle (3f), we
generated poly-functionalized bicyclic molecules in good yield
and good to moderate diastereoselectivity favouring the all-syn
isomer (7j–q). We also expanded the scope of coupling partners
in terms of Michael acceptors (8a,b) and IBX-reagents for imino-
olefination (8c) and -alkynylation (8d,e). Substrates prepared
from α-ketoacids could also be employed leading to the
formation of proline-like products (8f–i). Lastly, this radical
platform was evaluated as an enabling tool for the late-stage
imino-functionalization of biologically active molecules.
Therefore, we tested the structurally complex and densely
functionalized morphane derivative thevinone (9),[25] which was
successfully engaged in the formation of products derived from
imino-azidation (10a), imino-amination (10b) and imino-
selenation (10c) of the olefin moiety.
[6]
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[8]
In conclusion, we have developed a general method for the
fast and divergent assembly of poly-functionalized nitrogen
heterocycles. The reaction involves the organo-photoredox
generation of iminyl radicals by oxidative SET of a traceless
[9]
Studer has recently reported a photoredox imino-Michael reaction, H.
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Acknowledgements
D. L. thanks the European Union for a Career Integration Grant
(PCIG13-GA-2013-631556) and EPSRC for a research grant
(4500284613). N. S. S. acknowledges the support offered by the
Department of Chemistry, King Faisal University, Saudi Arabia.
Keywords: nitrogen radicals • divergent functionalization •
photoredox • cascade • nitrogen molecules
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