Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect

Article abstract of DOI:10.1002/anie.201912907

An intermolecular, two-component vicinal carboimination of alkenes has been accomplished by energy transfer catalysis. Oxime esters of alkyl carboxylic acids were used as bifunctional reagents to generate both alkyl and iminyl radicals. Subsequently, addition of the alkyl radical to an alkene generates a transient radical for selective radical–radical cross-coupling with the persistent iminyl radical. Furthermore, this process provides direct access to aliphatic primary amines and α-amino acids by simple hydrolysis.

Full text of DOI:10.1002/anie.201912907

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Accepted Article
Title: Photosensitized intermolecular carboimination of alkenes through
persistent radical effect
Authors: Tuhin Patra, Peter Bellotti, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912907
Angew. Chem. 10.1002/ange.201912907
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10.1002/anie.201912907
Angewandte Chemie International Edition
COMMUNICATION
Photosensitized intermolecular carboimination of alkenes
through persistent radical effect
Tuhin Patra, Peter Bellotti, Felix Strieth-Kalthoff and Frank Glorius*
Dedicated to Prof. Goutam K. Lahiri on the occasion of his 60th birthday
Abstract: An intermolecular, two-component vicinal carboimination of
alkenes has been accomplished via energy transfer catalysis. Oxime
esters of alkyl carboxylic acids are used as bifunctional reagents to
generate both alkyl and iminyl radicals. Subsequently, the addition of
alkyl radical to alkenes generates a transient radical for selective
radical-radical cross coupling with persistent iminyl radical.
Furthermore, this protocol readily allows for direct access to aliphatic
primary amines and α-amino acids through simple hydrolysis.
arylsulfonylacetamide. In this approach, arylsulfonylacetamides
were elegantly used as a single, bifunctional reagent for
diastereoselective, intermolecular carboamination of alkenes via
linear N-addition (Figure 1A).[16]
A. Desulfonative aminoarylation
R1
O O
HN
PC
Ar1
S
R1
+
N
Ar1
H
Ar2
SET
-SO2
Ar2
N-centered initiation
The 1,2-difunctionalization of olefins, which allows simultaneous
construction of two new covalent bonds, is one of the most
powerful and straightforward strategies for the rapid development
of molecular complexity.[1] Given the ubiquity of C−C and C−N
bonds in bioactive compounds, carboamination of alkenes
represents an important subset of such reactions, resulting in
concurrent installation of both carbon and nitrogen functionalities
into the alkenyl framework.[2-4] Ideally, cleavage of a C−N bond,
followed by the addition of two fragments into olefins, would be
the most direct means of carboamination. However, the intrinsic
inertness of C−N bonds, as well as the potential difficulties in
C(sp3)−N reductive elimination over facile β-hydride elimination,
present a formidable challenge.[5] Overcoming these issues,
pioneering work by Wolfe,[6] Rovis,[7] Liu,[8] Engle[9] and our
group[10] have shown the prospect of transition metals in
intermolecular carboamination reactions.
C-centered termination
Ref: 16
B.
Oxime esters as monofunctional reagents
O
R1
or
TM
PC
PC
N
N
R2
R1
R1
O
SET
EnT
R2
R2
iminyl radical
reactivity
carbon radical
reactivity
+
Ref: 17, 19
Ref: 20, 21
+
O
R1
N
•
loss of functionality
• low atom economy
R1
leaving group
O
R2
leaving group
C.
this work
Oxime esters as bifunctional reagents (
O
)
Ph
PC
N
Ph
R2
N
Ph
+
R1
O
EnT
R1
R2
Ph
Alternatively, a radical approach via either an N- or C-centered
initiation has also offered an attractive strategy to circumvent
mechanistic hypothesis
R1
these problems.[11,12] Notwithstanding these
significant
R1
N
breakthroughs, carboamination with general alkyl groups for
easily accessible primary amines remains an unsolved problem.
This can be mainly attributed to the difficulty in generating a broad
range of C-centered radicals from alkylating reagents, such as
alkyl halides.[13] Additionally, the obligation to protect, and later
deprotect, the amine functionality and the requirement for a
radical-polar crossover step emphasizes the retrosynthetic
deficiencies of accessing primary amines through a C-centered
initiation.[14] Similarly, N-centered initiation often requires excess
use of alkene, since N-centered radicals exhibit higher reactivity
and electrophilicity, which makes allylic H-atom abstraction a
kinetically competing process.[15] To address this, Stephenson
and co-workers have targeted alkenes for single-electron
oxidation followed by nucleophilic trapping with an
R2
*
O
R2
III
-CO2
N
Ph
+
+
R1
O
Ph
Ph
N
Ph
Ph
IV
Ph
I
II
triplet triplet
energy transfer
radical cross coupling
(persistent radical effect)
C-centered initiation
N-centered termination
Figure 1. Bifunctional reagents as both C- and N- sources.
Unlike carboamination reactions, the carboimination of
alkenes is still in its infancy and is limited mainly to intramolecular
annulation reactions generating five or six membered N-
heterocycles.[17] Additionally, their high reactivity has been utilized
in a plethora of 1,5-hydrogen atom transfer (HAT) reactions.[18,19]
In all these cases, iminyl radicals are first generated from oxime
esters through a single electron transfer (SET) event (Figure 1B,
left).[19] Alternatively, oxime esters have also been employed
successfully in the photosensitized generation of iminyl radicals
through N−O bond homolysis.[20] Recently, we have utilized this
distinctive energy transfer (EnT) pathway to develop a general
[*]
Dr. T. Patra, P. Bellotti, F. Strieth-Kalthoff, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Supporting information for this article can be found under:
https://doi.org/
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10.1002/anie.201912907
Angewandte Chemie International Edition
COMMUNICATION
radical decarboxylation process applicable to both aromatic and
aliphatic carboxylic acids (Figure 1B, right).[21] Nevertheless, all of
these approaches are plagued by poor atom-economy, since
either the carboxylate unit or the iminyl unit always become part
of the waste stream. The advantageous generation of two
different radicals from N−O bond homolysis, coupled with our
continuous interest in EnT catalysis[22] prompted us to investigate
whether both C-centered and N-centered radicals could
effectively leverage the vicinal carboimination of alkenes (Figure
1C). During our previous investigation concerning the
decarboxylation of oxime esters,[21] we realized relatively long
lifetimes of the benzophenone iminyl radicals through the
observation of iminyl byproducts. Considering the triplet energies
of the oxime esters of aliphatic carboxylic acids (ET = 45.4 kcal
mol-1, SI section 2.1), we envisioned that a triplet-triplet energy
transfer (TTEnT) from the excited photosensitizer (with ET > 46
kcal mol-1) should be thermodynamically favored. This excited
acrylonitrile (2) when [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F], dF-
(CF3)ppy=2-(2,4-difluorophenyl)-5-trifluoromethylpyridine,
dtbbpy=4,4’-di-tert-butyl-2,2’-bipyridine) was used as the
photosensitizer under irradiation with blue LEDs. The desired
carboimination product was afforded in 57% yield (1H NMR) with
complete regioselectivity for the linear C-radical addition (Table 1,
entry 1). Encouraged by this, we evaluated a series of oxime
esters with varying steric and electronic properties (entries 2-6).
Pleasingly, simple benzophenone oxime ester 1b was identified
as the optimal choice in terms of reaction efficiency, affording the
desired product 3a in 71% NMR yield. Control experiments with
respect to the photosensitizer as well as light irradiation further
demonstrated the necessity of each component. Additionally, to
further identify the crucial parameters for our reaction, a
systematic reaction parameters-based sensitivity screening was
performed (Table 1, radar diagram).[29] Notably, the reaction was
found to be sensitive towards low light intensity and high oxygen
concentration, but robust in respect of water content and
temperature fluctuations (SI section 3.2).
oxime
ester
I
would
participate
in
a
concerted
decarboxylation/fragmentation process to generate a C-centered
alkyl radical and an N-centered diphenyliminyl radical pair II.[21, 23]
Long lifetime of the diphenyliminyl radical IV should allow the
transient alkyl radical to escape the solvent cage and add to the
terminal position of the alkene to generate a stabilized radical III.
Lastly, a highly selective radical-radical cross coupling between
III and IV would be kinetically feasible based on the persistent
radical effect (PRE).[24] However, such radical-radical cross-
coupling approach possesses numerous challenges connected to
potentially unproductive pathways outperforming the desired
reaction.
Notably,
a critical distinction between an EnT and a
hypothetical SET pathway is that the EnT-induced reactivity
should also be accessible via direct excitation with high energy
light sources in absence of any photocatalyst or any electron
source. Indeed, the desired carboiminated product 33 was
observed upon direct photoirradiation with 365 nm LED source,
albeit in reduced yield (SI, section 2.3). Additionally, use of
different photocatalysts revealed a direct correlation of the
product yield with the triplet energies of the photocatalysts (SI
section 2.4). All these observations further substantiate the
involvement of an EnT-mediated carboimination process.
Herein we report an unprecedented intermolecular radical
carboimination of alkenes involving benzophenone oxime
carboxylates as a bifunctional source of both N- and C-centered
radicals with excellent regioselectivity for linear C-radical addition.
In the majority of the reported protocols, N-centered radicals are
known to be highly reactive species favoring linear N-radical
additions.[11] In our study, the use of benzophenone oxime esters
is key to the generation of a persistent iminyl radical in order to
achieve the inverted selectivity. Benzophenone imines are
synthetic equivalents to ammonia and have been used in a variety
of transition metal-catalyzed coupling reactions.[25] The
diarylmethylene protecting group can be easily removed by
hydrolysis or transamination to release primary amines or can be
converted to a wide range of valuable amine building blocks.[26,27]
Importantly, the use of benzophenone-based oxime esters is also
crucial to shut down unwanted SET reduction pathways, owing to
Table 1. Effect of activators and sensitivity assessment.[a]
O
[Ir-F]
(0.5 mol %)
Ph
A
[
]
EtOAc (0.1 M)
[A]
+
O
CN
hν (λmax= 455 nm)
CN
Ph
rt, 5 h
1
2
3
entry
activator ([A])
yield (%)
sensitivity assessment
1
2
3
4
5
6
1a
57
71
14
19
0
1b
1c
1d
1e
1f
7
red
their high reduction potential (Eirr = -2.05 V, SI section 2.2),
R
1a
, R= 4-F
1b
, R= H
N
N
N
which is inaccessible by commonly used photo(redox) catalysts.
The use of an EnT pathway is also inimitable for two reasons: (1)
concurrent generation of two different radicals in equal rates from
the N−O bond homolysis of the oxime ester and (2) overall
decarboxylation/fragmentation and carboamination steps should
be independent of the intrinsic regeneration/turnover of the
catalyst in the absence of any redox event. Expediently, this
method uses highly abundant and stable aliphatic carboxylic
acids (via their oxime ester derivative) in a highly atom economic
fashion, generating carbon dioxide as the sole byproduct.[28]
Upon exploring the various reaction parameters in line with
our previous experience with oxime esters,[21] we found that the
oxime ester 1a provided the desired carboimination product with
1c, R= 4-Cl
1d
, R= 3-CF3
R
1e
1f
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), [Ir-F] (0.5 mol %) in ethyl
acetate (1 mL), irradiating with 30 W blue LEDs (λmax= 455 nm) under an argon
atmosphere at room temperature for 5 h. Yields were determined by 1H NMR.
Next, with these optimized conditions, the generality of the
carboimination reaction was evaluated by exploring different
substrates. First, we explored a range of alkenes with different
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10.1002/anie.201912907
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COMMUNICATION
Table 2. Scope for decarboxylative intermolecular carboimination of alkenes.[a]
N
Ph
PF6
F3C
[N] :
Ar :
F
F
Ph
tBu
N
Ir
N
[Ir-F] (0.5 mol %)
EtOAc (0.1 M)
O
[N]
N
N
F
F
N
Ph
R2
+
R1
O
R1
:
[Ir-F]
R2
hν (λmax= 455 nm), 5 h
Ph
tBu
OAc
[N]
F3C
Alkenes
[N]
Cl
[N]
7
, R= F: 73%
4, R= CN: 70%
Ph
Ph
[N]
NO2
[N]
R
Ph
8, R= Br: 61%
5
, R= COMe: 56%
Ph
t
9
, R= O Bu: 57%
6, R= Ph: 73%
10
R
, R= OAc: 69%
11
, 67%
12, 49%
[N]
F
F
[N]
O
O
[N]
Ph
F
F
[N]
O
[N]
Ph
Ph
Ph
Ph
CN
CN
CO2Me
N
F
13
, 81%
14
15
, 66%
16
, 74%
17
, 41% (d.r. 1:1)
18
, 46%
from Tulipalin A
, 76%
Primary acids
[N]
[N]
[N]
[N]
[N]
Br
F3C
R
CN
CN
Cl
Ph
CN
Ar
Ar
, R= CO2Et: 57%
24, R= N3: 37%
19
20
21
22
23
, 53%
, 63%
, 72%
, 74%
α-oxyacids
N
[N]
N
N
[N]
[N]
[N]
[N]
N
Ph
Ph
O
Ar
Ph
O
28
O
Ar
Ph
25
, 59%
26
27
29
, 65%
, 71%
, 62%
, 67%
55% (2 mmol)b,c
[N]
Secondary acids
[N]
Boc
[N]
[N]
O
[N]
N
[N]
[N]
O
Ar
30, 46%
CN
CN
CN
Ar
CN
31, 72%
32, 86% (d.r. 1:1)
33, 83%
34, 63%
35, 68% (d.r. 1:1)
81% (gram scale)b,d
[N]
Tertiary acids
[N]
[N]
Ar
[N]
[N]
CN
O
Ar
37, 55%
F3C
Ar
Ar
36, 61%
TBDPSO
40, 71%
Ar
38, 64%
39, 68%
41, 73%
Natural products and drugs
O
S
O
H
Ar
[N]
O
Cl
Cl
O
Boc
O
[N]
N
[N]
CN
O
N
O
H
O
O
CN
CN
O
O
[N]
[N]
NC
e
e
42
from Gabapentin
43
from (1S)-(-)-Camphanic acid
44
45
, 64%
from 2,4-D
46
, 63% (d.r. 1:1)
from diprogulic acid
, 67%
, 67% (d.r. 1:1)
, 36% (d.r. 1:1)
from Sulbactam
[N]
[N]
Ar
O
NC
Cl
Cl
O
[N]
CN
[N]
H
Ph
O
NHBoc
, 70% (d.r. 1:1)
from Boc-Glu-Obzl
O
Ar
H
H
e
47
48
49
, 65%
from Gemfibrozil
50
, 66%
from Lithocholic acid
, 64%
from Ciprofibrate
AcO
[a] Reaction conditions: alkene (0.3 mmol), oxime ester (0.45 mmol), [Ir-F] (0.5 mol %) in ethyl acetate under an argon atmosphere, irradiating with 30 W blue LEDs
λmax= 455 nm) at room temperature for 5 h. Isolated yields. [b] Reaction time 16 h. [c] 1.25 equiv. of oxime ester was used. [d] 1.1 equiv. of oxime ester was used.
[e] 1.0 equiv. of oxime ester was used.
(
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10.1002/anie.201912907
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COMMUNICATION
A.
Synthetic diversifications
electronic and steric properties (Table 2, entries 4-18). Electron
deficient alkenes such as acrylonitrile (4), vinyl ketone (5) and
acrylate (15) reacted smoothly providing the desired
carboimination products. While styrenes bearing meta- and para-
substitutions worked efficiently, ortho-substituted styrenes
returned diminished yields (7-12). Delightfully, electron-poor
nitrostyrene (11), pentafluorostyrene (13) as well as heterocyclic
2-vinylpyridine (14) effectively delivered the desired products in
good yields. Substituents at either the α- or the β-positions on the
alkene could be accommodated (16-18) despite their greater
•
O
O
NH2 HCl
(a)
(b)
(c)
CN
51
, 89%
Ph
NH2
CO2H
N
Ph
R1
52, 81%
R2
Ph
HN
Ph
O
steric demand and lower electrophilicity, with
a
1:1
53, 59%
OH
, 53%
diastereoselectivity for 17. Naturally occurring Tulipalin A was
successfully utilized to generate sterically congested imine 18 in
moderate yield. However, cyclic alkenes and alkynes proved to
be incompatible with our conditions.
B.
Decarboxylative imination
standard
conditions
54, R=
Ph
O
O
N
Ph
N
Ph
R
O
R
55
, R=
, 66%
Ph
Subsequently, we explored the carboxylic acid scope including
two large scale demonstrations. A plethora of carboxylic acids
featuring primary, secondary and tertiary carbon centers were
found effective for carboimination reaction. Simple halides (20
and 21), trifluoromethyl (22), ester (23), azide (24) or ether (25)
containing primary carboxylic acids were employed without any
problem. Similarly, primary carboxylic acids comprising
heterocycles such as pyridine (26) and 1,2,4-triazole (27) were
tolerated under the optimized conditions. Both aliphatic (28) and
aromatic α-oxyacids (29) could be applied successfully to form γ-
amino ethers. Different cyclic (30 and 31) and heterocyclic
secondary carboxylic acids (32, 33 and 34) with varying ring sizes
could be easily accommodated. Tertiary carboxylic acids starting
from simple pivalic acid (36) to adamantane (38) or heterocyclic
3-methyloxetane (41) derivatives reacted smoothly to generate
quaternary carbon centers. Pleasingly, comparable reactivity was
also observed in the case of sterically demanding acids (37-40).
Unfortunately, carboimination with oxime esters of aromatic
carboxylic acids and phenyl acetic acids were unsuccessful.
We next probed the range of densely functionalized
substrates amenable to our reaction condition. Pharmaceuticals
and agrochemicals like gabapentin, sulbactam, ciprofibrate,
gemfibrozil and 2,4-D afforded the desired carboiminated
products (42, 44, 45, 47 and 49) in synthetically useful yields.
Naturally occurring carboxylic acids such as diprogulic acid,
lithocholic acid, chiral auxiliary (1S)-(-)-camphanic acid and
natural amino acid derived Boc-Glu-Obzl also reacted smoothly
(43, 46, 48 and 50).
Finally, after developing a convenient method for alkene
carboimination, we sought to explore their reactivity and synthetic
utility (Figure 2A). Simple hydrolysis of the carboimination product
33 with 1.5 equiv. of HCl in wet MeOH delivered the
corresponding primary ammonium chloride salt in 89% isolated
yield (Figure 2A, entry 51).[25b] Similarly, concomitant hydrolysis of
both the nitrile and iminyl functionality produced the valuable α-
amino acid 52 in racemic fashion. Furthermore, the biologically
relevant diarylmethylamine class[27] of compounds could be easily
generated from simple reduction of the iminyl moiety (53). Most
interestingly, direct radical-radical cross coupled iminyl products
were isolated in the absence of an alkene acceptor (Figure 2B,
entries 54 and 55). Remarkably, expensive iridium-based
photosensitizers could be replaced by simple organic sensitizers,
albeit with diminished efficiency (Figure 2C). As a result, a metal-
free, intermolecular carboimination process can be developed
based on this study.
Ph
C.
Organic photosensitizer
O
Ph
thioxanthone (10 mol %)
EtOAc (0.1 M)
N
Ph
+
O
N
Ph
CN
O
CN
hν (λmax= 400 nm)
O
Ph
rt, 12 h
33
, 49%
Figure 2. Synthetic utilities and ramifications. (a) 1N HCl (1.5 equiv.) in MeOH.
(b) 6N HCl. (c) NaBH4 (3 equiv.) in MeOH/CH2Cl2.
In summary, using oxime esters of readily available alkyl
carboxylic acids as bifunctional reagent an intermolecular, two-
component carboimination of olefins was developed.
photosensitized energy transfer strategy was used for effective
generation of both C- and N-centered radicals in a highly atom-
economic fashion. The persistency of iminyl radical underpins
their exquisite regioselectivity. In addition, the mild reaction
conditions, operational simplicity and a broad scope provide an
easy gateway towards unprotected alkyl amines.
A
Acknowledgements
Generous financial support from the Alexander von Humboldt
Foundation (T.P.) and the Deutsche Forschungsgemeinschaft
(Leibniz Award; SFB 858 for P.B. and SPP2102 for F.S.-K.) are
gratefully acknowledged. The authors thank Julian Heuer and
Max Lübbesmeyer for experimental support, Frederik Sandfort,
Toryn Dalton, Dr. Zackaria Nairoukh and Dr. Anup Bhunia (all
WWU Münster) for helpful discussions.
Keywords: photocatalysis • amination • cross coupling •
carboxylic acids • energy transfer
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COMMUNICATION
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10.1002/anie.201912907
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Tuhin Patra, Peter Bellotti, Frank
Ph
R2
O
PC
Glorius*
N
Ph
Ph
R2
N
Ph
+
R1
O
Energy Transfer
Catalysis
R1
Page No. – Page No.
C-centered initiation
N-centered termination
Selective radical-radical cross-coupling
Primary, secondary and tertiary carboxylic acids
Photosensitized intermolecular
carboimination of alkenes through
persistent radical effect
Two birds, one stone: Oxime esters of aliphatic carboxylic acids is used as a
bifunctional source of both C- and N-radicals. Persistency of N-radicals enables
intermolecular radical carboamination of alkenes in a highly selective fashion.
This article is protected by copyright. All rights reserved.