catalysts
Review
α -Functionalization of Imines via Visible Light Photoredox Catalysis
Alberto F. Garrido-Castro1 , M. Carmen Maestro1,* and José Alemán1,2,*
1 Department of Organic Chemistry, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
2 Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain
* Correspondence: [email protected] (M.C.M.); [email protected] (J.A.); Tel.:+34914973875 (J.A.)
Received: 6 May 2020; Accepted: 16 May 2020; Published: 19 May 2020
Abstract:The innate electrophilicity of imine building blocks has been exploited in organic synthetic chemistry for decades. Inspired by the resurgence in photocatalysis, imine reactivity has now been redesigned through the generation of unconventional and versatile radical intermediates under mild reaction conditions. While novel photocatalytic approaches have broadened the range and applicability of conventional radical additions to imine acceptors, the possibility to use these imines as latent nucleophiles via single-electron reduction has also been uncovered. Thus, multiple research programs have converged on this issue, delivering creative and practical strategies to achieve racemic and asymmetric α-functionalizations of imines under visible light photoredox catalysis.
Keywords: amines; imines; photoredox catalysis; radical additions; radical–radical couplings;
stereoselectivity; umpolung chemistry; visible light
1. Introduction
Visible light photoredox catalysis has been at the forefront of organic chemistry research for over a decade, establishing itself as a sustainable and multifaceted synthetic tool [1]. Irradiation of catalytic amounts of polypyridyl complexes and organic sensitizers under mild conditions has proven to be an excellent activation pathway to access a wide variety of radical intermediates (Figure1). Spurred by this resurgence, long-standing challenges in the field have been resolved, while a plethora of transformations continue to be developed in an effort to revamp organic synthesis.
Catalysts 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts
Review
1 α-Functionalization of Imines via Visible Light
2
Photoredox Catalysis
3
Alberto F. Garrido-Castro 1, M. Carmen Maestro 1,*, and José Alemán 1,2,*
4
1 Department of Organic Chemistry, Universidad Autónoma de Madrid, Madrid 28049, Spain;
5
6
2 Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid,
7
Madrid 28049, Spain
8
* Correspondence: [email protected] (M.C.M.), [email protected] (J.A.); Tel.: +34914973875 (J.A.)
9
Received: 6 May 2020; Accepted: 16 May 2020; Published: date
10
Abstract: The innate electrophilicity of imine building blocks has been exploited in organic synthetic
11
chemistry for decades. Inspired by the resurgence in photocatalysis, imine reactivity has now been
12
redesigned through the generation of unconventional and versatile radical intermediates under
13
mild reaction conditions. While novel photocatalytic approaches have broadened the range and
14
applicability of conventional radical additions to imine acceptors, the possibility to use these imines
15
as latent nucleophiles via single-electron reduction has also been uncovered. Thus, multiple
16
research programs have converged on this issue, delivering creative and practical strategies to
17
achieve racemic and asymmetric α-functionalizations of imines under visible light photoredox
18
catalysis.
19
Keywords: amines; imines; photoredox catalysis; radical additions; radical–radical couplings;
20
stereoselectivity; umpolung chemistry; visible light
21
22
1. Introduction
23
Visible light photoredox catalysis has been at the forefront of organic chemistry research for over
24
a decade, establishing itself as a sustainable and multifaceted synthetic tool [1]. Irradiation of catalytic
25
amounts of polypyridyl complexes and organic sensitizers under mild conditions has proven to be
26
an excellent activation pathway to access a wide variety of radical intermediates (Figure 1). Spurred
27
by this resurgence, long-standing challenges in the field have been resolved, while a plethora of
28
transformations continue to be developed in an effort to revamp organic synthesis.
29
30
Figure 1. Visible light photoredox catalysts (λ = local absorbance maximum for lowest energy
31
absorption).
32
O CO2Et
NEt
Me Me
EtHN
· HCl
Rhodamine 6G λ = 530 nm RuII
N N
N N N N
[Ru(bpy)3]2+
λ = 452 nm
CN NC
N
N N N
4CzIPN λ = 435 nm IrIII
N N
N N
[Ir{dF(CF3)ppy}2(dtbbpy)]+ λ = 380 nm tBu
tBu F3C
F3C F
F F F
Visible Light Photoredox Catalysts
Figure 1.Visible light photoredox catalysts (λ= local absorbance maximum for lowest energy absorption).
The reactivity of imines has certainly undergone a complete makeover, as different strategies involving these key building blocks have been developed (Scheme1). The classical approach still relies
Catalysts 2020, 10, 562; doi:10.3390/catal10050562 www.mdpi.com/journal/catalysts
Catalysts 2020, 10, 562 2 of 22
on the innate electrophilic nature of imines to undergo standard alkyl radical addition (pathway A in Scheme1, left). Thanks to photoredox catalysis, the generation of nucleophilic radicals starting from mild alkylating reagents [2] has provided a broader range to a severely limited transformation in the past due to hazardous reagents and impractical conditions.
Catalysts 2020, 10, x FOR PEER REVIEW 2 of 21
The reactivity of imines has certainly undergone a complete makeover, as different strategies
33
involving these key building blocks have been developed (Scheme 1). The classical approach still
34
relies on the innate electrophilic nature of imines to undergo standard alkyl radical addition
35
(pathway A in Scheme 1, left). Thanks to photoredox catalysis, the generation of nucleophilic radicals
36
starting from mild alkylating reagents [2] has provided a broader range to a severely limited
37
transformation in the past due to hazardous reagents and impractical conditions.
38
Alternatively, the photocatalytic single-electron reduction of imines has emerged as a powerful
39
technology to generate radical anion intermediates which exist as two different resonant forms
40
(pathway B in Scheme 1, right) [3,4]. The α-amino radical species can engage in radical–radical
41
couplings with a large pool of reacting partners (pathway B1 in Scheme 1),while also displaying a
42
complementary nucleophilic behavior to their corresponding electrophilic imine precursors. Indeed,
43
they can be trapped by electron-deficient π-systems, a combination which would not be feasible using
44
polar chemistry (pathway B2 in Scheme 1). Interestingly, the N-centered radical species can be
45
quickly quenched by an H atom donor to yield a stable carbanion capable of reacting with a
46
traditional electrophile in polar fashion (pathway B3 in Scheme 1).
47 48
49
Scheme 1. Photocatalytic functionalization of imines: pathway A, alkyl radical addition (left);
50
pathway B, single-electron reduction (right).
51
The single-electron reduction event (pathway B in Scheme 1, right) can be a challenging redox
52
process which often requires assistance [4]. While some electron-poor imines can undergo a
53
straightforward photocatalytic reduction (such as N-sulfonyl- or α-keto-imines), other neutral imines
54
feature a reduction potential which falls out of range of most photocatalysts. The addition of an
55
external Lewis acid can increase the reduction potential of the imine (less negative) through
56
coordination. Moreover, hydrogen-bonding via Brønsted acid can make this reduction a
57
thermodynamically favorable process thanks to proton-coupled electron transfer (PCET), wherein an
58
electron transfer from the photocatalyst to the imine takes place in concert with a proton transfer
59
from the Brønsted acid to the imine.
60 61
Pathway B2 Giese Radical Addition Photocatalytic Functionalization of Imines
HN N
HN Alk
HN broader range of
reacting partners diverse reactivity:
electrophile
&
nucleophile
N N
HN E Pathway A
Alkyl Radical Addition
Pathway B Single-Electron
Reduction
Pathway B1 Radical-Radical
Coupling
EWG Pathway B3 Nucleophilic Attack
Scheme 1.Photocatalytic functionalization of imines: pathway A, alkyl radical addition (left); pathway B, single-electron reduction (right).
Alternatively, the photocatalytic single-electron reduction of imines has emerged as a powerful technology to generate radical anion intermediates which exist as two different resonant forms (pathway B in Scheme1, right) [3,4]. The α-amino radical species can engage in radical–radical couplings with a large pool of reacting partners (pathway B1 in Scheme1), while also displaying a complementary nucleophilic behavior to their corresponding electrophilic imine precursors. Indeed, they can be trapped by electron-deficient π-systems, a combination which would not be feasible using polar chemistry (pathway B2 in Scheme1). Interestingly, the N-centered radical species can be quickly quenched by an H atom donor to yield a stable carbanion capable of reacting with a traditional electrophile in polar fashion (pathway B3 in Scheme1).
The single-electron reduction event (pathway B in Scheme 1, right) can be a challenging redox process which often requires assistance [4]. While some electron-poor imines can undergo a straightforward photocatalytic reduction (such as N-sulfonyl- or α-keto-imines), other neutral imines feature a reduction potential which falls out of range of most photocatalysts. The addition of an external Lewis acid can increase the reduction potential of the imine (less negative) through coordination.
Moreover, hydrogen-bonding via Brønsted acid can make this reduction a thermodynamically favorable process thanks to proton-coupled electron transfer (PCET), wherein an electron transfer from the photocatalyst to the imine takes place in concert with a proton transfer from the Brønsted acid to the imine.
Catalysts 2020, 10, 562 3 of 22
2. Photocatalytic Radical Additions to Imines—Pathway A
2.1. Racemic Photocatalytic Radical Additions to Imines
Racemic radical additions to imines under visible light photocatalysis began to appear in 2016, when Bode reported the cyclization of silicon amine protocol (SLAP) reagents with an imine moiety (Scheme2, left) [5]. These α-silyl amine precursors could undergo mild single-electron oxidation to render α-amino radicals, which could then engage with the imine to yield a wide variety of piperazine derivatives. The protocol was expanded further with α-silyl ether and thioether precursors to access morpholines, oxazepanes, thiomorpholines and thiazepanes (Scheme2, right) [6,7]. It should be noted that, in this case, a Lewis acid was required to activate the imine, and the photocatalytic cycle could start with an initial Lewis acid-assisted single-electron reduction of the imine.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 21
2. Photocatalytic Radical Additions to Imines—Pathway A
62
2.1. Racemic Photocatalytic Radical Additions to Imines
63
Racemic radical additions to imines under visible light photocatalysis began to appear in 2016,
64
when Bode reported the cyclization of silicon amine protocol (SLAP) reagents with an imine moiety
65
(Scheme 2, left) [5]. These α-silyl amine precursors could undergo mild single-electron oxidation to
66
render α-amino radicals, which could then engage with the imine to yield a wide variety of
67
piperazine derivatives. The protocol was expanded further with α-silyl ether and thioether
68
precursors to access morpholines, oxazepanes, thiomorpholines and thiazepanes (Scheme 2, right)
69
[6,7]. It should be noted that, in this case, a Lewis acid was required to activate the imine, and the
70
photocatalytic cycle could start with an initial Lewis acid-assisted single-electron reduction of the
71
imine.
72
73
Scheme 2. Cyclization of SLAP reagents developed by Bode for the synthesis of piperazines (left) and
74
morpholines, oxazepanes, thiomorpholines and thiazepanes (right).
75
The first intermolecular photocatalytic radical addition was published in 2017 by Molander’s
76
group [8]. The design of a general and modular approach based on the swift single-electron oxidation
77
of ammonium alkyl bis(catecholato)silicates enabled the alkylation of different N-sulfonyl- and N-
78
aryl-imines (Scheme 3, top left) [9]. In addition, Friestad employed these silicon reagents to perform
79
the alkylation of N-acyl hydrazones in the presence of a Lewis acid (Scheme 3, top right) [10]. Alkyl
80
silicates have also been utilized by Kelly and Molander to achieve the synthesis of various saturated
81
N-heterocycles via radical alkylation and subsequent cyclization in a radical polar crossover (RPC)
82
process (Scheme 3, bottom) [11].
83
More radical precursors have also been deployed in an attempt to expand the synthetic prowess
84
of this transformation. For instance, Hanna, Jr. and Molander disclosed the photocatalytic activation
85
of alkyl trifluoroborates, enabling the radical alkylation of non-activated imines (Scheme 4) [12,13].
86
when Y =
up to 93% yield
Y NH [Ir(ppy)2dtbbpy]PF6 (1 mol%)
MeCN/TFE, r.t.
Y N
TMS N
NH
n
n when Y = O, S
[Ir(ppy)2dtbbpy]PF6 (1 mol%) or TPP (5 - 10 mol%)
Lewis acid MeCN, r.t.
n = 1, 2 up to 84% yield [batch]
up to 94% yield [flow]
Bode
[alkenyl, alkyl, (het)aryl imines]
N
N
NH
46% yield 94% yield [flow]
O
NH NMe N
O
NH
NH Me O
70% yield [flow] 72% yield [flow]
S NH
Cl
F S
NH N 68% yield [batch]
selected examples Ph
Scheme 2.Cyclization of SLAP reagents developed by Bode for the synthesis of piperazines (left) and morpholines, oxazepanes, thiomorpholines and thiazepanes (right).
The first intermolecular photocatalytic radical addition was published in 2017 by Molander’s group [8]. The design of a general and modular approach based on the swift single-electron oxidation of ammonium alkyl bis(catecholato)silicates enabled the alkylation of different N-sulfonyl- and N-aryl-imines (Scheme3, top left) [9]. In addition, Friestad employed these silicon reagents to perform the alkylation of N-acyl hydrazones in the presence of a Lewis acid (Scheme3, top right) [10]. Alkyl silicates have also been utilized by Kelly and Molander to achieve the synthesis of various saturated N-heterocycles via radical alkylation and subsequent cyclization in a radical polar crossover (RPC) process (Scheme3, bottom) [11].
More radical precursors have also been deployed in an attempt to expand the synthetic prowess of this transformation. For instance, Hanna, Jr. and Molander disclosed the photocatalytic activation of alkyl trifluoroborates, enabling the radical alkylation of non-activated imines (Scheme4) [12,13].
Catalysts 2020, 10, 562 4 of 22
Catalysts 2020, 10, x FOR PEER REVIEW 4 of 21
87
Scheme 3. Intermolecular photocatalytic radical additions to imines using alkyl silicates developed
88
by Molander (top left), Friestad (top right) and Kelly and Molander (bottom).
89
90
Scheme 4. Photocatalytic radical additions to imines using alkyl trifluoroborates developed by
91
Hanna, Jr (left) and Molander (right).
92
O Si
O H2NiPr2
2 N
HN
(1.1 - 3.0 equiv.) 4CzIPN (1 mol%)
DMSO, r.t.
up to 91% yield
Molander
(0.5 equiv.) Br 2
n
[Ir{dF(CF3)ppy}2bpy]PF6 (1 mol%) DMSO, r.t.
N +
O Si
O H2NiPr2
N n
n = 1 - 3 up to 84% yield
N
Br
N
Br RPC
SET
Intramolecular SN2 Alkyl Radical
Addition
Kelly, Molander
N N O
4CzIPN (5 - 15 mol%) MgCl2, DMSO, r.t.
HN N O
up to 94% yield Friestad
[(het)aryl imines] [alkyl, aryl imines]
[(het)aryl imines]
N Ph N
N Me2N S
O O
Br
Ph N
Cl N
Ph Ph
MeO
38% yield 66% yield 66% yield 24% yield
selected examples HN S
Me O O
O O
HN Ph
MeO2C
OMe HN
Ph N O O
Me HN NHBz
Ph
69% yield 69% yield 63% yield 45% yield
selected examples
N
[(het)aryl, glyoxyl imines]
[in situ formation]
[Ir{dF(CF3)ppy}2bpy]PF6 (2 mol%) NaHSO4, 1,4-dioxane, r.t.
KF3B
(1.5 equiv.) Ph
N Ph
Ph HN Ph
[Ir{dF(CF3)ppy}2dtbbpy]PF6 (2.5 mol%) DCM, r.t.
HN
up to 73% yield up to 95% yield
Molander Hanna, Jr.
Ph HN Ph
Ph HN Ph
Me MeMe
HN Ph
MeO2C NBoc
EtO2C HN Ph
70% yield 60% yield 83% yield 77% yield
selected examples
Scheme 3.Intermolecular photocatalytic radical additions to imines using alkyl silicates developed by Molander (top left), Friestad (top right) and Kelly and Molander (bottom).
Catalysts 2020, 10, x FOR PEER REVIEW 4 of 21
87
Scheme 3. Intermolecular photocatalytic radical additions to imines using alkyl silicates developed
88
by Molander (top left), Friestad (top right) and Kelly and Molander (bottom).
89
90
Scheme 4. Photocatalytic radical additions to imines using alkyl trifluoroborates developed by
91
Hanna, Jr (left) and Molander (right).
92
O Si
O H2NiPr2
2 N
HN
(1.1 - 3.0 equiv.) 4CzIPN (1 mol%)
DMSO, r.t.
up to 91% yield
Molander
(0.5 equiv.) Br 2
n
[Ir{dF(CF3)ppy}2bpy]PF6 (1 mol%) DMSO, r.t.
N +
O Si
O H2NiPr2
N n
n = 1 - 3 up to 84% yield
N
Br
N
Br RPC
SET
Intramolecular SN2 Alkyl Radical
Addition
Kelly, Molander
N N O
4CzIPN (5 - 15 mol%) MgCl2, DMSO, r.t.
HN N O
up to 94% yield Friestad
[(het)aryl imines] [alkyl, aryl imines]
[(het)aryl imines]
N Ph N
N Me2N S
O O
Br
Ph N
Cl N
Ph Ph
MeO
38% yield 66% yield 66% yield 24% yield
selected examples HN S
Me O O
O O
HN Ph
MeO2C
OMe HN
Ph N O O
Me HN NHBz
Ph
69% yield 69% yield 63% yield 45% yield
selected examples
N
[(het)aryl, glyoxyl imines]
[in situ formation]
[Ir{dF(CF3)ppy}2bpy]PF6 (2 mol%) NaHSO4, 1,4-dioxane, r.t.
KF3B
(1.5 equiv.) Ph
N Ph
Ph HN Ph
[Ir{dF(CF3)ppy}2dtbbpy]PF6 (2.5 mol%) DCM, r.t.
HN
up to 73% yield up to 95% yield
Molander Hanna, Jr.
Ph HN Ph
Ph HN Ph
Me MeMe
HN Ph
MeO2C NBoc
EtO2C HN Ph
70% yield 60% yield 83% yield 77% yield
selected examples
Scheme 4.Photocatalytic radical additions to imines using alkyl trifluoroborates developed by Hanna, Jr (left) and Molander (right).
Catalysts 2020, 10, 562 5 of 22
Alkyl carboxylic acids hold a preferred position among radical precursors due to their versatility and ubiquity. Indeed, these alkylating agents can be implemented into mechanistically distinct photoredox pathways. Deprotonation of the acid can render a carboxylate species which can then undergo single-electron oxidation and subsequent decarboxylation to afford the alkyl radical intermediate.
Alternatively, these acids can be activated with N-hydroxyphthalimide (NHPI) or its tetrachlorinated derivative (TCNHPI) through a simple esterification process to provide redox-active esters (RAEs). In this case, single-electron reduction can deliver the alkyl radical intermediate. This flexible behavior has been exploited by several research groups attempting to perform the alkyl radical addition to imines (Scheme5). Weng and Lu reported the decarboxylative benzylation process following the oxidative pathway (Scheme5, left) [14,15], while Mariano and Wang published a reductive version. In this later case, the decarboxylative glycosylation of imines was featured, although a Hantzsch ester (HEH) derivative was needed as a stoichiometric photosensitizer (Scheme5, right) [16,17].
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 21
Alkyl carboxylic acids hold a preferred position among radical precursors due to their versatility
93
and ubiquity. Indeed, these alkylating agents can be implemented into mechanistically distinct
94
photoredox pathways. Deprotonation of the acid can render a carboxylate species which can then
95
undergo single-electron oxidation and subsequent decarboxylation to afford the alkyl radical
96
intermediate. Alternatively, these acids can be activated with N-hydroxyphthalimide (NHPI) or its
97
tetrachlorinated derivative (TCNHPI) through a simple esterification process to provide redox-active
98
esters (RAEs). In this case, single-electron reduction can deliver the alkyl radical intermediate. This
99
flexible behavior has been exploited by several research groups attempting to perform the alkyl
100
radical addition to imines (Scheme 5). Weng and Lu reported the decarboxylative benzylation process
101
following the oxidative pathway (Scheme 5, left) [14,15], while Mariano and Wang published a
102
reductive version. In this later case, the decarboxylative glycosylation of imines was featured,
103
although a Hantzsch ester (HEH) derivative was needed as a stoichiometric photosensitizer (Scheme
104
5, right) [16,17].
105 106
107
Scheme 5. Photocatalytic radical additions to imines using alkyl carboxylic acids developed by Weng
108
and Lu (left) and Mariano and Wang (right).
109
Notably, the radical fluoroalkylation of imines had remained inaccessible in the field until
110
Maestro and Alemán recently reported the direct difluoromethylation of imine moieties (Scheme 6)
111
[18]. This general procedure was predicated on the single-electron oxidation of readily available zinc
112
difluoromethane sulfinate (DFMS) in the presence of an organophotoredox catalyst (Rhodamine 6G).
113
114
HO O O
[glycosyl carboxylic acids]
[activation with TCNHPI]
(0.75 equiv.) [benzyl carboxylic acids]
(2.0 equiv.) N
[(het)aryl imines]
O HN
up to 95% yield [Ir{dF(CF3)ppy}2bpy]PF6
or 4CzIPN (2 mol%) K2HPO4, MeCN, r.t.
HEH iPr2NEt·HBF4, MeCN, r.t.
Weng, Lu Mariano, Wang
HO
O Ar
HN Ar
up to 80% yield
Ph
BocHN OMe
Ph NH
S pTol S
O
O EtO2C
HN O
F
OBz OMe
OBz BzO
HN O S pTol
O O
OMe
O O
Me Me
80% yield 51% yield 81% yield 66% yield
selected examples
Cl
N HN
[(het)aryl imines]
O S CHF2H O OZn HF2C S
O
DFMS (0.5 - 1.0 equiv.)
CF2H
up to 94% yield
+ Rhodamine 6G (2 mol%)
MeCN, r.t.
Maestro, Alemán
NH
CO2Et CF2H HN
O
O NH
CF2H Br
S NH
CF2H
pTol MeO HN Ph
CF2H
73% yield 71% yield 73% yield 60% yield
selected examples
Scheme 5.Photocatalytic radical additions to imines using alkyl carboxylic acids developed by Weng and Lu (left) and Mariano and Wang (right).
Notably, the radical fluoroalkylation of imines had remained inaccessible in the field until Maestro and Alemán recently reported the direct difluoromethylation of imine moieties (Scheme 6) [18].
This general procedure was predicated on the single-electron oxidation of readily available zinc difluoromethane sulfinate (DFMS) in the presence of an organophotoredox catalyst (Rhodamine 6G).
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 21
Alkyl carboxylic acids hold a preferred position among radical precursors due to their versatility
93
and ubiquity. Indeed, these alkylating agents can be implemented into mechanistically distinct
94
photoredox pathways. Deprotonation of the acid can render a carboxylate species which can then
95
undergo single-electron oxidation and subsequent decarboxylation to afford the alkyl radical
96
intermediate. Alternatively, these acids can be activated with N-hydroxyphthalimide (NHPI) or its
97
tetrachlorinated derivative (TCNHPI) through a simple esterification process to provide redox-active
98
esters (RAEs). In this case, single-electron reduction can deliver the alkyl radical intermediate. This
99
flexible behavior has been exploited by several research groups attempting to perform the alkyl
100
radical addition to imines (Scheme 5). Weng and Lu reported the decarboxylative benzylation process
101
following the oxidative pathway (Scheme 5, left) [14,15], while Mariano and Wang published a
102
reductive version. In this later case, the decarboxylative glycosylation of imines was featured,
103
although a Hantzsch ester (HEH) derivative was needed as a stoichiometric photosensitizer (Scheme
104
5, right) [16,17].
105 106
107
Scheme 5. Photocatalytic radical additions to imines using alkyl carboxylic acids developed by Weng
108
and Lu (left) and Mariano and Wang (right).
109
Notably, the radical fluoroalkylation of imines had remained inaccessible in the field until
110
Maestro and Alemán recently reported the direct difluoromethylation of imine moieties (Scheme 6)
111
[18]. This general procedure was predicated on the single-electron oxidation of readily available zinc
112
difluoromethane sulfinate (DFMS) in the presence of an organophotoredox catalyst (Rhodamine 6G).
113
114
HO O O
[glycosyl carboxylic acids]
[activation with TCNHPI]
(0.75 equiv.) [benzyl carboxylic acids]
(2.0 equiv.) N
[(het)aryl imines]
O HN
up to 95% yield [Ir{dF(CF3)ppy}2bpy]PF6
or 4CzIPN (2 mol%) K2HPO4, MeCN, r.t.
HEH iPr2NEt·HBF4, MeCN, r.t.
Weng, Lu Mariano, Wang
HO
O Ar
HN Ar
up to 80% yield
Ph
BocHN OMe
Ph NH
S pTol S
O
O EtO2C
HN O
F
OBz OMe OBz BzO
HN O S pTol
O O
OMe O O Me Me
80% yield 51% yield 81% yield 66% yield
selected examples
Cl
N HN
[(het)aryl imines]
O S CHF2H O OZn HF2C S
O
DFMS (0.5 - 1.0 equiv.)
CF2H up to 94% yield
+ Rhodamine 6G (2 mol%)
MeCN, r.t.
Maestro, Alemán
NH CO2Et
CF2H HN
O
O NH
CF2H Br
S NH
CF2H
pTol MeO HN Ph
CF2H
73% yield 71% yield 73% yield 60% yield
selected examples
Scheme 6.Photocatalytic difluoromethyl radical addition to imines using DFMS developed by Maestro and Alemán.
Catalysts 2020, 10, 562 6 of 22
Lastly, hydrogen atom transfer (HAT) has also been used in order to perform the C-H activation of different alkyl radical precursors and perform the desired alkylation reaction with activated imines (Scheme7). Lu and Gong reported the α-oxyalkyl radical addition of 1,3-dioxolane to fluoroalkyl imines (Scheme7, top) [19,20], while Dilman managed to install different alkyl and acyl radicals into N-sulfonyl imines (Scheme7, bottom) [21–23].
Catalysts 2020, 10, x FOR PEER REVIEW 6 of 21
Scheme 6. Photocatalytic difluoromethyl radical addition to imines using DFMS developed by
115
Maestro and Alemán.
116
Lastly, hydrogen atom transfer (HAT) has also been used in order to perform the C-H activation
117
of different alkyl radical precursors and perform the desired alkylation reaction with activated imines
118
(Scheme 7). Lu and Gong reported the α-oxyalkyl radical addition of 1,3-dioxolane to fluoroalkyl
119
imines (Scheme 7, top) [19,20], while Dilman managed to install different alkyl and acyl radicals into
120
N-sulfonyl imines (Scheme 7, bottom) [21–23].
121
122
Scheme 7. Photocatalytic radical additions to imines using HAT developed by Lu and Gong (top) and
123
Dilman (bottom).
124
2.2. Stereoselective Photocatalytic Radical Additions to Imines
125
In the field of asymmetric photocatalytic additions to imines, Knowles first described in 2013 an
126
elegant intramolecular example in which a hydrazone trapped a ketyl radical intermediate—
127
generated by PCET—in enantioselective fashion thanks to the chiral induction exerted by a chiral
128
phosphoric acid (Scheme 8) [24].
129
N
O
O HN
O O BD (10 mol%)
NHS (10 mol%) r.t.
Me
O Me
O H
O N O
O
Me
O Me
OH O N
O
O
BD + NHS HAT
active species SET
active species [solvent]
(150 equiv.) +
up to 96% yield
hν, ISC then HAT or PCET
Lu, Gong H
N S pTol O O
+
[ethers]
[alkanes]
[aldehydes]
(10 equiv.)
H [W10O32]N(nBu)4 (2 mol%) MeCN, r.t.
HN S pTol O O
up to 92% yield Dilman
[fluoroalkyl imines]
[alkyl, aryl imines]
HN S pTol O O
MeO
HN Ph
S pTol O O
HN S pTol O O
Ph
HN Ph
S pTol O O
O Me
70% yield 70% yield 54% yield 45% yield
selected examples HN
F3C O
O Br
HN
O O
Ph HN
O O
Ph F3C
EtO2C
HN Ph
O F3C O
Me
86% yield 89% yield 74% yield
F3C F F
77% yield selected examples
O O O
Scheme 7.Photocatalytic radical additions to imines using HAT developed by Lu and Gong (top) and Dilman (bottom).
2.2. Stereoselective Photocatalytic Radical Additions to Imines
In the field of asymmetric photocatalytic additions to imines, Knowles first described in 2013 an elegant intramolecular example in which a hydrazone trapped a ketyl radical intermediate—generated by PCET—in enantioselective fashion thanks to the chiral induction exerted by a chiral phosphoric acid (Scheme8) [24].
Catalysts 2020, 10, 562 7 of 22
Catalysts 2020, 10, x FOR PEER REVIEW 7 of 21
130
Scheme 8. Asymmetric intramolecular photocatalytic radical addition to hydrazones developed by
131
Knowles.
132
No further reports were published on this topic until Maestro and Alemán disclosed in 2017 an
133
asymmetric intermolecular radical alkylation of imines based on the use of chiral sulfoxides (Scheme
134
9) [25]. The photocatalytic reduction of NHPI-derived RAEs delivered the alkyl radical, which then
135
engaged with the enantiopure N-sulfinimine in diastereoselective fashion to afford α-branched
136
benzyl amine derivatives.
137
138
Scheme 9. Asymmetric intermolecular photocatalytic radical addition to N-sulfinimines developed
139
by Maestro and Alemán.
140
Moreover, Gong’s research group developed a series of transformations in 2018 and 2019 based
141
on chiral Lewis acid-catalyzed radical alkylations of different imine scaffolds (Scheme 10, top) [26,27].
142
When using redox-active alkyl trifluoroborates and silanes, the Cu-BOX complexes acted as
143
bifunctional chiral photocatalysts, performing both the asymmetric induction and the single-electron
144
oxidation of the radical precursors, while suppressing the need for an external photocatalyst. In the
145
latest report published by Gong, an HAT-photocatalyst (5,7,12,14-pentacenetetrone, PT) was required
146
to perform the C-H activation of benzyl and allyl positions, as well as non-activated alkanes (Scheme
147
10, bottom) [28].
148
The generality observed throughout this section noticeably stands out, wherein an assortment
149
of radical precursors has been inserted into mechanistically similar protocols based on their
150
photocatalytic activation to render the nucleophilic radical intermediate. Most notably, the range of
151
imine building blocks employed in these reactions is quite impressive, as both activated and non-
152
activated substrates have proven to be suitable acceptors to the different radical additions.
153
Y HO HN NMe2 N NMe2
* * [Ir(ppy)2dtbbpy]PF6 (2 mol%)
CPA (10 mol%)
HEH, 1,4-dioxane, –30 ºC - r.t. O
P O
OH O SiPh3
SiPh3 CPA O Y
Y = CH2, O up to 96% yield
up to 95% ee
>98:2 dr Knowles
HO HN NMe2
58% yield 90% ee
>98:2 dr F3C
HO Ph
HN NMe2
Me Me
O HO Ph
HN NMe2
HO HN NMe2 S
Br
78% yield 90% ee
>98:2 dr
85% yield 83% ee
>98:2 dr
69% yield 85% ee
>98:2 dr selected examples
fac-Ir(ppy)3 (1 mol%) iPr2NEt, HEH, DMSO, r.t.
N S Mes
* O
Maestro, Alemán
HN S Mes
* O
*
up to 79% yield
>98:2 dr +
[activation with NHPI]
(1.5 equiv.) [(het)aryl imines]
Me Me
Me
-Mes HO
O
HN S Mes
O Me Me
HN S Mes
O Me Me S
HN S Ph
Mes O Me MeMe
HN S Ph
Mes O
Me 70% yield
>98:2 dr 64% yield
>98:2 dr 36% yield
>98:2 dr 41% yield
>98:2 dr selected examples
Br
Scheme 8. Asymmetric intramolecular photocatalytic radical addition to hydrazones developed by Knowles.
No further reports were published on this topic until Maestro and Alemán disclosed in 2017 an asymmetric intermolecular radical alkylation of imines based on the use of chiral sulfoxides (Scheme9) [25]. The photocatalytic reduction of NHPI-derived RAEs delivered the alkyl radical, which then engaged with the enantiopure N-sulfinimine in diastereoselective fashion to afford α-branched benzyl amine derivatives.
Catalysts 2020, 10, x FOR PEER REVIEW 7 of 21
130
Scheme 8. Asymmetric intramolecular photocatalytic radical addition to hydrazones developed by
131
Knowles.
132
No further reports were published on this topic until Maestro and Alemán disclosed in 2017 an
133
asymmetric intermolecular radical alkylation of imines based on the use of chiral sulfoxides (Scheme
134
9) [25]. The photocatalytic reduction of NHPI-derived RAEs delivered the alkyl radical, which then
135
engaged with the enantiopure N-sulfinimine in diastereoselective fashion to afford α-branched
136
benzyl amine derivatives.
137
138
Scheme 9. Asymmetric intermolecular photocatalytic radical addition to N-sulfinimines developed
139
by Maestro and Alemán.
140
Moreover, Gong’s research group developed a series of transformations in 2018 and 2019 based
141
on chiral Lewis acid-catalyzed radical alkylations of different imine scaffolds (Scheme 10, top) [26,27].
142
When using redox-active alkyl trifluoroborates and silanes, the Cu-BOX complexes acted as
143
bifunctional chiral photocatalysts, performing both the asymmetric induction and the single-electron
144
oxidation of the radical precursors, while suppressing the need for an external photocatalyst. In the
145
latest report published by Gong, an HAT-photocatalyst (5,7,12,14-pentacenetetrone, PT) was required
146
to perform the C-H activation of benzyl and allyl positions, as well as non-activated alkanes (Scheme
147
10, bottom) [28].
148
The generality observed throughout this section noticeably stands out, wherein an assortment
149
of radical precursors has been inserted into mechanistically similar protocols based on their
150
photocatalytic activation to render the nucleophilic radical intermediate. Most notably, the range of
151
imine building blocks employed in these reactions is quite impressive, as both activated and non-
152
activated substrates have proven to be suitable acceptors to the different radical additions.
153
Y HO HN NMe2 N NMe2
** [Ir(ppy)2dtbbpy]PF6 (2 mol%)
CPA (10 mol%)
HEH, 1,4-dioxane, –30 ºC - r.t. O
P O
OH O SiPh3
SiPh3 CPA O Y
Y = CH2, O up to 96% yield
up to 95% ee
>98:2 dr Knowles
HO HN NMe2
58% yield 90% ee
>98:2 dr F3C
HO Ph
HN NMe2
Me Me
O HO Ph
HN NMe2
HO HN NMe2 S
Br
78% yield 90% ee
>98:2 dr
85% yield 83% ee
>98:2 dr
69% yield 85% ee
>98:2 dr selected examples
fac-Ir(ppy)3 (1 mol%) iPr2NEt, HEH, DMSO, r.t.
N S Mes
* O
Maestro, Alemán
HN S Mes
* O
*
up to 79% yield
>98:2 dr +
[activation with NHPI]
(1.5 equiv.) [(het)aryl imines]
Me Me
Me
-Mes HO
O
HN S Mes
O Me Me
HN S Mes
O Me Me S
HN S Ph
Mes O Me MeMe
HN S Ph
Mes O
Me 70% yield
>98:2 dr 64% yield
>98:2 dr 36% yield
>98:2 dr 41% yield
>98:2 dr selected examples
Br
Scheme 9.Asymmetric intermolecular photocatalytic radical addition to N-sulfinimines developed by Maestro and Alemán.
Moreover, Gong’s research group developed a series of transformations in 2018 and 2019 based on chiral Lewis acid-catalyzed radical alkylations of different imine scaffolds (Scheme10, top) [26,27].
When using redox-active alkyl trifluoroborates and silanes, the Cu-BOX complexes acted as bifunctional chiral photocatalysts, performing both the asymmetric induction and the single-electron oxidation of the radical precursors, while suppressing the need for an external photocatalyst. In the latest report published by Gong, an HAT-photocatalyst (5,7,12,14-pentacenetetrone, PT) was required to perform the C-H activation of benzyl and allyl positions, as well as non-activated alkanes (Scheme10, bottom) [28].