Iminyl-Radicals by Oxidation of α-Imino-oxy Acids: Photoredox-Neutral Alkene Carboimination for the Synthesis of Pyrrolines

Article abstract of DOI:10.1002/anie.201706270

The visible-light-promoted decarboxylation of α-imino-oxy propionic acids for the generation of iminyl radicals has been accomplished through the use of Ir(dFCF₃ppy)₂(dtbbpy)PF₆ as a photoredox catalyst. Different from visible-light-promoted homolysis and single-electron reduction of oxime derivatives, this strategy provides a novel catalytic cycle for alkene carboimination through a sequence comprising N-radical generation, iminyl radical cyclization, intermolecular conjugate addition to a Michael acceptor, and single-electron reduction to afford various pyrroline derivatives in an overall redox-neutral process. The indolizidine alkaloid skeleton could be easily constructed from a pyrroline derivative prepared by this synthetic method.

Full text of DOI:10.1002/anie.201706270

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Title: Iminyl-Radicals via Oxidation of α-Imino-oxy Acids: Photoredox-
Neutral Alkene Carboimination for the Synthesis of Pyrrolines
Authors: Heng Jiang and Armido Studer
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10.1002/anie.201706270
Angewandte Chemie International Edition
COMMUNICATION
Iminyl-Radicals via Oxidation of α-Imino-oxy Acids: Photoredox-
Neutral Alkene Carboimination for the Synthesis of Pyrrolines
Heng Jiang and Armido Studer*
Dedication ((optional))
Abstract: The visible-light-promoted decarboxylation of α-imino-oxy
propionic acids for the generation of iminyl radicals has been
accomplished through the use of Ir(dFCF3ppy)2(dtbbpy)PF6 as a
photoredox catalyst. Different from visible-light promoted homolysis
and single-electron-reduction of oxime derivatives, this strategy
provides a novel catalytic cycle for alkene carboimination through a
sequence comprising N-radical generation, iminyl radical cyclization,
intermolecular conjugate addition to a Michael acceptor, and single
electron reduction to afford various pyrroline derivatives in an overall
redox-neutral process. The indolizidine alkaloid skeleton could be
easily constructed from a pyrroline derivative prepared by this
synthetic method.
photoredox-strategy demands a SET reduction step in the
cascade and we suggested to trap the cyclized C-radical with a
Michael acceptor where the adduct radical should be readily
SET reduced.[9] The overall sequence is redox-neutral and an
additional radical reducing reagent is not required, further
increasing economy of the suggested cascade.
Iminyl radicals are valuable reactive intermediates that can be
used for the construction of various heterocycles.[1] They can be
generated from oxime derivatives but often harsh conditions
such as UV irradiation or high temperature[2] are required.
Generation of iminyl radicals using visible light would enlarge the
synthetic value of these N-radicals.[3] Along these lines, visible-
light induced homolysis of thiohydroxamic esters or ketoxime
xanthates have been achieved (Scheme1, a, left).[4] Recently,
there has been progress using the photoredox strategy to
generate iminyl radicals through single electron reduction of
oxime derivatives (Scheme 1, a, right).[5],[6] However, the
photoredox approach to generate iminyl radicals via single-
electron-oxidation of oxime derivatives has not been reported to
date.
Photoredox-decarboxylation to oxidatively generate C-radicals
from carboxylic acids or oxalates has been investigated by
several groups (Scheme 1, b)[7] and cascades comprising C-
C,[7a-7k] C-N,[7l] C-X,[7m] C-S,[7n] C-B,[7o] C-F[7p],[7q] and C-H[7r],[7s]
bond formation have been developed. We envisioned that iminyl
radicals should also be accessible by the photoredox-
decarboxylation strategy form readily available α-imino-oxy acids
(Scheme1, c). This proposal was further supported by the known
decarboxylation of α-imino-oxy acids to iminyl radicals using
stoichiometric K2S2O8, where, however the strongly oxidizing
and harsh conditions restrict its applicability and practicability.[8]
In our suggested photoredox-decarboxylation, single electron
transfer (SET) oxidation of an α-imino-oxy acid should lead to
the corresponding carboxyl radical that upon sequential CO2 and
aldehyde fragmentation should give an iminyl radical. Radical
cylization will allow constructing N-heterocycles. The
Scheme 1. Visible-light-promoted iminyl radical generation.
We chose α-imino-oxy acetic acid 1a as the model substrate in
combination with methyl acrylate (2a) as the radical acceptor. 1a
is readily prepared from the corresponding ketone by oxime
ether formation (see Supporting Information). Pleasingly, blue
LED light irradiation of a DCE solution containing 1a, 2a,
Ir(dFCF3ppy)2(dtbbpy)PF6 (A, 1 mol%) as a photocatalyst and
K3PO4 as a base for 16 h afforded the desired pyrroline 3a in 31%
yield (Table 1, entry 1). The use of other potassium or sodium
salts such as K2CO3, KOAc, NaOAc, and NaHCO3 provided
worse results (Table 1, entries 2-5). However, with cesium salts
yield further improved and CsF afforded 3a in 56% yield (Table 1,
entries
6-8).
Other
photoredox catalysts such as
Ir(ppy)2(dtbbpy)PF6 (B), Ru(bpy)3(PF6)2 (C) and acridinium (D)
did not catalyze this transformation (Table 1, entries 9-11). Next,
the R-substituent of the acid was varied and with 2-imino-oxy
propionic acid 2b (R = Me), pyrroline 3a was obtained in 79%
yield (Table 1, entry 12). The improved efficiency is likely caused
by the acceleration of the iminyl radical generation (faster
aldehyde expulsion). 2-Imino-oxy phenylacetic acid 2c (R = Ph)
provided a slightly worse result (Table 1, entry 13). In control
[*]
Dr. H. Jiang, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraß 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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experiments, product 3a was not formed in the absence of either
photocatalyst or CsF (Table 1, entries 14, 15) and this cascade
did not proceed in the dark (Table 1, entry 16).
Table 2. Variation of the radical acceptor.[a],[b]
Table 1. Reaction optimization.
entry[a]
PC
base
R
yield (%)[b]
1
A
A
A
A
A
A
A
A
B
C
D
A
A
–
K3PO4
K2CO3
KOAc
NaOAc
NaHCO3
Cs2CO3
CsOAc
CsF
H
31
2
H
27
3
H
17
4
H
N.D.
N.D.
49
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol,
3.0 equiv), photocatalyst A (0.002 mmol, 1.0 mol%), CsF (0.4 mmol, 2.0 equiv)
in DCE (2.0 mL, 0.1 M) was irradiated by a 10 W blue LED at room
temperature for 16 h. [b] Isolated yields. [c] 0.004 mmol photocatalyst A was
used.
5
H
6
H
7
H
47
8
H
56
With the optimal conditions in hand, we examined the scope
by first varying the radical acceptor (Table 2). Various α,β-
unsaturated esters were competent coupling partners affording
pyrrolines 3b-3g in moderate to good yields showing that
substituents at the  and -position of the ester acceptor are
tolerated. As expected, diastereoselectivity was not controlled.
α,β-Unsaturated amides and a phosphonate worked very well to
give the pyrrolines 3h and 3i in high yields. We examined the
reactivity of α,β-unsaturated ketones and found that for such
acceptors, cascades were also efficient using precursor 1d that
results upon cyclization in a primary alkyl radical. Methyl vinyl
ketone, substituted congeners therefrom and a phenyl vinyl
ketone worked well in combination with 1d and 3j-3m were
isolated in good to excellent yields (63-91%). Phenyl vinyl
sulfone could also be used as an acceptor, albeit yield for the
target 3n was slightly lower (42%).
9
CsF
H
N.D.
N.D.
N.D.
79 (73)[c]
53
10
11
12
13
14
15
16[d]
CsF
H
CsF
H
CsF
Me
Ph
Me
Me
Me
CsF
CsF
N.D.
N.D.
N.D.
A
A
–
CsF
[a] Reaction conditions: A mixture of 1 (0.1 mmol, 1.0 equiv), 2a (0.6 mmol,
3.0 equiv), photocatalyst (0.001 mmol, 1.0 mol%), base (0.2 mmol, 2.0 equiv)
in DCE (1.0 mL, 0.1 M) was irradiated by a 10 W blue LED at room
temperature for 16 h. [b] The yield was determined by 1H NMR analysis using
CH2Br2 as an internal standard. [c] Isolated yield at 0.2 mmol scale. [d] The
reaction was conducted in the dark.
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Table 3. Variation of the α-iminyl-oxy acids.[a],[b]
complex that is SET reduced by carboxylate E, formed by
deprotonation of substrate 1, to generate the carboxyl radical F
along with IrII(dFCF3ppy)2(dtbbpy)PF6. Sequential fragmentation
of CO2 and acetaldehyde from F generates the iminyl radical G.
5-exo-Cyclization provides C-radical H that then further reacts
via intermolecular conjugate addition to give the corresponding
electrophilic adduct radical I. The photoredox cycle is closed
through SET reduction of I by IrII(dFCF3ppy)2(dtbbpy)PF6 to
provide J, thereby regenerating the ground-state photocatalyst
IrIII(dFCF3ppy)2(dtbbpy)PF6. Protonation of J eventually affords
the isolated pyrroline 3.
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0
equiv), photocatalyst A (0.002 mmol, 1.0 mol%), base (0.4 mmol, 2.0 equiv) in
DCE (2.0 mL, 0.1 M) was irradiated by a 10 W blue LED at room temperature
for 16 h. [b] Isolated yields.
Scheme 2. Proposed mechanism.
The pyrroline derivatives that are readily accessed using our
alkene carboimination conjugate addition pathway are valuable
precursors for the construction of the core skeleton of
indolizidine alkaloids. This is documented in Scheme 3 by the
highly stereoselective NaBH3CN reduction of pyrroline 3a and
subsequent lactamization to give indolizidine derivative 5 in 87%
overall yield.
We then investigated the scope with respect to the iminyl
radical precursor using methyl vinyl ketone or -styryl phenyl
ketone as acceptors (Table 3). The phenyl group in the oxime
ether could be replaced by electron rich or electron poor para-
substituted phenyl groups and the pyrrolines 4a-4d were
obtained in good yields. 2-Thienyl or 2-naphthyl were also
tolerated as R1-substituents to afford 4e and 4f in 68% and 71%
yield. Oxime ethers bearing substituents R2 and R3 at the α-
position of the C=N double bond were good substrates (see 4g-
4j) but the 1,3-stereoinduction in the cyclization was low (see
4g). The alkene moiety in the oxime ethers can also be charged
with additional substituents R3 and R4 (4k-4n) and reaction
occurred with complete stereoselectivity using the cyclohex-2-
enyl-methyl oxime ether as an N-radical precursor (see 4k).
However, for the non-cyclic substrates, selectivity was low (see
4l, 4m). Importantly, cascade works also efficiently with alkyl
substituted oxime ethers as documented by the preparation of
pyrrolines 4o-4r.
Scheme 3. Synthetic application.
In conclusion, we have applied α-imino-oxy propionic acids
as readily accessible and highly efficient precursors for the
generation of iminyl radicals upon SET oxidation. This approach
has been used to develop a photoredox neutral carboimination
of α-imino-oxy proponic acids with Michael acceptors to give
The proposed mechanism of the cascade is depicted in
Scheme 2. Photo-excitation of IrIII(dFCF3ppy)2(dtbbpy)PF6 by
visible light leads to the excited *IrIII(dFCF3ppy)2(dtbbpy)PF6
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Acknowledgements
This work was supported by the Alexander von Humboldt
Foundation (postdoctoral fellowship to H. J.). We thank Dr.
Xinjun Tang for providing some starting materials and Sherif J.
Kaldas for his support during manuscript preparation.
Conflict of Inerest
The authors declare no conflict of interest.
Keywords: iminyl radicals • photoredox chemistry •
decarboxylation • redox-neutral • pyrroline derivatives
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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H. Jiang, A. Studer*
Page No. – Page No.
Iminyl-Radicals via Oxidation of α-
Imino-oxy Acids - Photoredox-Neutral
Alkene Carboimination for the
Synthesis of Pyrrolines
A redox-neutral radical cascade of α-imino-oxy propionic acids with various
Michael acceptors using Ir-photoredox catalysis to give valuable pyrrolines is
presented. These cascades comprise oxidative iminyl radical generation followed
by cyclizing carbominination and subsequent intermolecular radical conjugate
addition.
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