Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

Article abstract of DOI:10.1021/acscatal.0c03089

A strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska's complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants, and late-stage functionalization of an active pharmaceutical ingredient. Density functional theory analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction's efficiency.

Full text of DOI:10.1021/acscatal.0c03089

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Article
Reverse Polarity Reductive Functionalization of Tertiary Amides
via a Dual Iridium Catalyzed Hydrosilylation & SET Strategy
Tatiana Rogova, Pablo Gabriel, Stamatia Zavitsanou, Jamie
Alexander Leitch, Fernanda Duarte, and Darren J. Dixon
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c03089 • Publication Date (Web): 27 Aug 2020
Downloaded from pubs.acs.org on August 27, 2020
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ACS Catalysis
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Reverse Polarity Reductive Functionalization of Tertiary
Amides via a Dual Iridium Catalyzed Hydrosilylation & SET
Strategy
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Tatiana Rogova, Pablo Gabriel‡, Stamatia Zavitsanou‡, Jamie A. Leitch‡, Fernanda Duarte*,
Darren J. Dixon*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1
3TA, United Kingdom
KEYWORDS Vaska reduction, photocatalysis, iminium ion, umpolung, α-amino radical
ABSTRACT: A strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide
building blocks has been developed. By combining Vaska’s complex-catalyzed tertiary amide reductive activation and
photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were
successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive
intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis
of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The
utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage
functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and
elements of the chemical system that were responsible for the reaction’s efficiency.
its
untapped
synthetic
potential,
reductive
INTRODUCTION
functionalization of tertiary amides by reversing their
natural polarity (umpolung) remains unreported.
α-Functionalized amines and their derivatives are an
integral part of
a vast array of natural products,
pharmaceutical agents and agrochemicals.1 Traditionally,
these valuable structures are accessed through C–N bond
forming strategies and numerous protocols have been
developed for this purpose.2 Alternatively, C–C bond
formation provides a complementary avenue towards
these biologically-relevant architectures.3
To this end, we reasoned that if single electron transfer
(SET) to the metastable silylated hemiaminal or iminium
ion could be realized, entry to the nucleophilic α-amino
radical and therefore umpolung reactivity would be
enabled (Scheme 2). Of the techniques available for such a
single electron reduction, photoredox catalysis has
emerged as the most versatile, and in related works,15 the
resulting free radical species have been shown to engage in
a range of transformations, including reaction with
electrophilic species such as Michael acceptors.16
Within the scope of the latter approach, the reductive
functionalization of ubiquitous amides is a powerful access
point towards decorated α-branched amines. It is equally
applicable for the elaboration of simple building blocks
into valuable products as well as expediting natural
product synthesis.4-11 To this end, Vaska’s complex
(IrCl(CO)(PPh3)2), in conjunction with TMDS (1,1,3,3-
tetramethyldisiloxane) as terminal reductant, has come to
the fore as an effective system for generating iminium ions
in situ, via the hydrosilylation of tertiary amide and lactam
reactants (Scheme 1).12 The mild reaction conditions,
exquisite chemoselectivity, and broad functional group
tolerance of this approach have contributed to its growing
application as a synthetic strategy in the elaboration of
simple building blocks and in late stage functionalization
of complex molecular architectures including alkaloid
natural products.13
Scheme 1. α-Functionalization strategies for amine
synthesis from tertiary amides
Reductive functionalization of amides - state of the art and challenges
Vaska's complex
CO
[Si]
Ph3P Ir PPh3
Nu
O
O
Cl
(cat.)
Nu
N
N
N
Me
Me
O
Me
Me
Si
H
Si
H
-functionalized
silyl
hemiaminal
tertiary amide
[robust]
amine
TMDS
reductive umpolung functionalization of tertiary amide derivatives?
amide
activation
E
Nevertheless, and without exception, all Vaska’s complex
catalysed amide activation methods that enable
functionalization at the α-position14 exploit the
electrophilicity of iminium ion intermediates, generated in
situ by ionization of the silyl hemiaminal. To date, despite
O
e
E+
N
N
N
N
[challenge
remains]
tertiary amide
[robust]
reverse polarity
functionalization
electrophilic
nucleophilic
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Scheme 2. Proposed concept for accessing α-amino tandem process, the nucleophilic α-amino radical species
1
2
3
4
5
6
7
8
radicals via reverse polarity amide activation. Red=
reductant
could indeed be generated and therefore access to new
chemical space for the abundant tertiary amide would be
granted. Herein we wish to report our findings.
Concept design - reductive reverse polarity functionalization of amides
RESULTS & DISCUSSION
[Si]
[Si]
O
O
O
over-reduction
Optimization Studies. Our initial investigation focused
on sequentially establishing a general set of experimental
conditions for both the tertiary amide hydrosilylation and
the photocatalytic reductive coupling. For this purpose,
the fluorinated N-methyl anilide (1a) was chosen as a
model tertiary amide substrate and protected
dehydroalanine (DHA) derivative (2) was chosen as a
suitably reactive nucleophilic radical acceptor that would
ultimately afford medicinally relevant amino acid products
(3a) (Scheme 3).16f, 17
Following exploration of reduction conditions commonly
utilized with Vaska’s complex, smooth hydrosilylation of
the tertiary amide (1a) to the hemiaminal species (1aa) was
achieved in under an hour using the addition of 2 mol% of
Vaska’s complex, and 2 equivalents of TMDS in anhydrous
toluene18 (Scheme 3A, Table 1, entry 2; see Supporting
Information for further details). Following the full
consumption of the starting material, it was found that
addition of dimethylsulfoxide not only quenched the
catalytic activity of the Vaska’s complex (for further details
cat. Ir
N
N
N
N
[Si]-H
[Si]-H
hemiaminal
iminium ion
[electrophilic]
9
Ir hydrosilylation manifold
10
11
12
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Ir
photocatalytic manifold
H
NH
Red
N
O
hydrolysis
IrII
Red
*IrIII
SET
R
N(Boc)2
CO2Me
HO
N
IrIII
electrophilic
acceptor
-amino radical
synthon creation
over-reduction
O
N
N(Boc)2
N(Boc)2
CO2Me
H+
CO2Me
e
N
N
N
-functionalized
amine
see Supporting Information), thereby suppressing
competitive over-reduction pathway of 1aa to the amine
side-product (3ac), but also served as a suitable
a
Accordingly, we reasoned that if both reductive
processes could be streamlined into an effective one-pot,
Scheme 3. Optimization studies for (A) Vaska’s catalyzed amide hydrosilylation. (B) The photocatalytic reductive
coupling of the silyl hemiaminal intermediate with DHA derivative.
Hydrosilylation optimization
Photocatalytic coupling optimization
A
B
N(Boc)2
CO2Me
CO
N(Boc)2
CO2Me
3ab
[PC]
HE
(1 mol%)
(1.5 eq)
[Si]
Ar
Me Me Me Me
Ph3P Ir PPh3
Cl
Vaska's Complex
O
N(Boc)2
CO2Me
O
Si
Si
Ph
O
H
O
HO
Ar
N
Ph
Ph
PhMe/DMSO
(1:1)
30 °C, 16 h
(x mol%)
N
Ph
N
Ar
3a
Ph
Me
N
N
Ar
Me
Me
Me
Me
Si
Me
F
Me
Me
3ac
O
TMDS
(y eq)
F
1aa
2
Me
1a
Si
H
(4 eq.)
1aa
H
blue LEDs
HE
solvent [0.2 M], rt
solvent Vaska (mol%) TMDS (eq) time (h)
entry
photocatalyst [PC]
3a (%)a
drb
3ab (%)a 3ac (%)a
entry
1aa (%)a
1
2
3
4
[PC-Ir1]
[PC-Ir2]
HE1
HE1
HE1
HE1
25 (17)c
42
2.0:1
1.8:1
1.9:1
1.8:1
44
49
57
31
32
9
1
2
3
4
CH2Cl2
PhMe
PhMe
PhMe
2
2
2
1
2
2
2.5
1.0
1.0
1.0
43
100
73
fac-Ir(ppy)3
4-CzIPN
38
5
20
38
1.5
2
81
5d
[PC-Ir2]
[PC-Ir2]
[PC-Ir2]
[PC-Ir2]
HE2
HE3
HE4
HE5
75 (75)c
81 (75)c,f
54
1.8:1
2.0:1
1.6:1
1.8:1
24
7
1
7
6d,e
7d,e
8d,e
Table 1: Iridium-catalyzed tertiary amide hydrosilylation
.
General
1a
conditions:
(0.1 mmol), IrCl(CO)(PPh3)2 (x mol%), 1,1,3,3-
42
25
3
tetramethyldisiloxane (y eq), solvent (0.5 mL), under a nitrogen atmopshere a
Calculated using19F{1H} NMR analysis of the crude reaction mixture.
56
19
change from entry 5
0 g
0 g
0 h
-
-
-
-
-
9
no photocatalyst
10
11
no light
F3C
-
-
-
-
F
(PF6)
R2
R3
R2
1a
(amide) as starting material
R1
HE
N
Ir
R3O2C
Me
CO2R3
Me
N
N
Table 2: Photocatalytic coupling of hemiaminal species
.
Ar
(0.4 mmol), photocatalyst (PC, 0.001
mmol, 1 mol%), Hantzsch ester (0.15 mmol), DMSO/PhMe (1 mL, 1:1), 16 h, under a nitrogen
= 4-fluorophenyl. General
F
F
HE1
HE2
HE3
HE4
H
Et
Me
Me
Et
1aa
2
(from hydrosilylation step, ~0.1 mmol),
conditions:
Me
Cy
Ph
R1
N
H
N
a
atmopshere under blue light irradiation using 18
W
LED lamp. Calculated by 19F{1H} NMR
analysis of the crude reaction mixture. Calculated by 1H NMR analysis of the crude reaction
F
b
F3C
c
d
HE5 4-CO2MePh Et
mixture. Isolated yield after silica gel column chromatography. DHA (0.2 mmol, 2 eq) was used.
Hantzsch ester
R1 = tBu: [PC-Ir1]
e
f
g
Hantzsch ester (0.1 mmol,
1
eq) used.
Difficult chromatographic separation.
4-
R1 = H: [PC-Ir2]
fluorobenzaldehyde was formed as the sole product. h No conversion from amide
was observed.
1a
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ACS Catalysis
Scheme 4. Substrate scope of the reductive photocatalytic functionalization of tertiary amides. [a] HE2 used as
the terminal reductant. [b] HE5 used as the terminal reductant
1
2
3
4
5
6
7
8
N(Boc)
CO2Me
CO
2 (2.0 eq)
CO2Me
[PC-Ir2]
F3C
F
(PF6)
Ph3P Ir PPh3
N(Boc)2
N
Ir
Me
Cl
(2 mol%)
(2 eq)
(1 mol%)
HE2 HE5
O
N
N
MeO2C
Me
CO2Me
Me
F
F
CO2Me
Ar2
Ar1
TMDS
or
(1 eq)
Ar1
EtO2C
Me
CO2Et
Me
N
R
Ar2
N
R
N
N
H
PhMe/DMSO (1:1)
30 °C, 16 h
PhMe
rt, 1 h
N
H
F
3a-r
1a-r
F3C
9
HE2a
HE5b
[PC-Ir2]
blue LEDs
10
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60
N(Boc)2
N(Boc)2
N(Boc)2
CO2Me
N(Boc)2
N(Boc)2
N(Boc)2
CO2Me
MeO
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
N
N
Me
Me
Me
F
F
F
F
F
3a a
75%, 2.0:1 dr
3b a
55%, 1.6:1 dr
3c b
3d b
61%, 1.8:1 dr
3e b
40%, 2.1:1 dr
3f b
51%, 1.5:1 dr
55%, 1.8:1 dr
N(Boc)2
CO2Me
N(Boc)2
CO2Me
N(Boc)2
CO2Me
N(Boc)2
CO2Me
N(Boc)2
N(Boc)2
CO2Me
CO2Me
O
N
N
N
N
N
N
Me
Me
Me
Me
O
OMe
Me
Me
N
Bpin
N
Me
3h b
38% 2.0:1 dr
3g b
78%, 1.2:1 dr
3i b
3j b
44%, 1.8:1 dr
3k b
66%, 1.5:1 dr
3l b
61%, 1.6:1 dr
40%, 2.0:1 dr
N(Boc)2
CO2Me
N(Boc)2
N(Boc)2
N(Boc)2
N(Boc)2
N(Boc)2
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
N
N
Me
Me
Me
Me
F
tBu
Ph
Br
Me
F
Me
3r a
35%, 2.2:1 dr
3m b
54%, 1.5:1 dr
3n b
44% 1.8:1 dr
3o b
59% 1.8:1 dr
3p b
24%, 1.1:1 dr
3q a
50%, 2.5:1 dr
co-solvent for the subsequent photocatalytic step.16b,f,m
absence of photocatalyst, or light, or from the unactivated
amide (entries 9-11).
A survey of compatible photocatalysts gave a promising
lead result of 17% yield of 3a as a mixture of diastereomers
when a system of [Ir(dF(CF3)(ppy)2(dtbbpy)]PF6 and
commercially-available Hantzsch ester (HE1) terminal
reductant under blue LED irradiation was employed. The
desired product was however accompanied by significant
quantities of undesired secondary alcohol coupled product
(3ab) and over-reduction by-products (3ac) (Scheme 3B,
Table 2, entry 1). Minimization of these background
processes was achieved through fine-tuning of the reaction
Scope Development. With optimal reaction conditions
in hand, the scope of the method with respect to the
aniline portion of the tertiary amides was investigated
(Scheme 4). Anisidine-derived amides (3c) were shown to
be applicable to this methodology, as well as heterocyclic
indoline (3d), tetrahydroquinoline (3e), and benzazepane
(3f) structures, affording the decorated tertiary amine
products in good yields. Notably in these cases, HE5
outperformed the previous optimal reductant (HE2).
Through diversification of the acyl unit on the amide, it
was identified that tetrahydroisoquinoline derivative was
an excellent substrate in this methodology delivering C–C
coupled product 3g in 78% yield. Furthermore, challenging
architectures such as indazole (3h), and Ar-BPin (3i) motifs
were well-tolerated. In addition, a variety of substituted
arenes were explored under the reaction conditions (3j-
3p). These studies revealed that electron donating
substituents including alkoxy, alkyl, and aryl substituents
were most effective in this transformation, forming the
tertiary amine products in good yields, whereas electron-
withdrawing substrates (3p) showed a reduction in
efficacy. The length of the alkyl chain on nitrogen was then
conditions
by
employing
structurally
modified
photocatalysts and 4-substituted Hantzsch esters. After
extensive screening, it was found that the combination of
[Ir(dF(CF3)(ppy)2(bpy)](PF6) [PC-Ir] with methyl-
substituted HE2 (Scheme 3B, Table 2 entry 5) gave the 1,3-
diamine product in a 75% isolated yield. The addition of
other Hantzsch-based reductants (HE3 and HE5, Scheme
3B, Table 2, entries 6 and 8) produced similarly high-
yielding results and allowed for greater flexibility in the
choice of reductant in further substrate scope
development.
Importantly,
deletion
experiments
demonstrated that the reaction did not proceed in the
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studied, and we were pleased to observe that ethyl and Scheme 5. Extension of the Vaska-photoredox system
1
2
3
4
5
6
7
8
propyl substituted structures delivered tertiary amine
products, although a steric increase vs. reaction efficiency
trend was observed.19
for reductive cyclization of tertiary amides
CO
(PhO)3P Ir P(OPh)3
O[Si]
N
O
Cl
(2 mol%)
(2 eq)
Ph
n
Ph
n
Intramolecular Cyclization. We recognized the
opportunity that this tandem amide activation protocol –
through tethering an alkene acceptor to the alkyl chain of
the amide starting material – could be suitably leveraged
towards the synthesis of complex heterocyclic amine
frameworks. Accordingly, model substrates bearing a
pendant α,β-unsaturated ester (1s-1t) were prepared, but
initial studies demonstrated that these motifs did not
readily undergo hydrosilylation using Vaska’s catalyst
(only around 80% conversion was achieved after 8 hours of
reaction time), and furthermore significant quantities of
over reduction side-product were isolated following the
photocatalytic step.20 Nevertheless, these initial challenges
were circumvented when a derivative of Vaska’s complex
bearing triphenylphosphite ligands – previously reported
by Nagashima21 – was employed in the hydrosilylation step
instead (Scheme 5). Pleasingly, clean conversion to a stable
silyl hemiaminal species was achieved within one hour,
and subsequent subjection to the optimized photoredox
conditions delivered the desired cyclic pyrrolidine (4s) and
piperidine (4t) products in good yields.
N
TMDS
MeO
MeO
PhMe
rt, 1 h
silyl
hemiaminal
CO2Me
CO2Me
1s-t
(n = 1,2)
[PC-Ir2]
HE5
(1 mol%)
(1 eq)
9
PhMe/DMSO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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59
60
blue LEDs
CO2Me
30 °C, 16 h
CO2Me
CO2Me
EtO2C
Me
CO2Et
Me
N
N
Ph
MeO
N
H
Ph
MeO
4s
50%, 2.7:1 dr
4t
HE5
50%, 2.0:1 dr
Secondary Amide Activation. Recent endeavors by
Chida and Sato, and Huang have demonstrated the utility
of [Ir(COE)2Cl]2 complex in conjunction with Et2SiH2
reductant for the nucleophilic reductive functionalization
of secondary amide building blocks, affording the
corresponding α-branched secondary amine products.4e,f
Scheme 6. Reverse polarity, photocatalytic reductive functionalization of secondary amides. (A) Optimization of
the reaction conditions. (B) Scope of the secondary amide activation protocol.
Secondary amide optimization
Secondary amide scope
A
B
2
(2 eq)
(1 mol%)
(1.5 eq)
N(Boc)
CO
(PhO)3P Ir P(OPh)3
Cl
TMDS
2 (2.0 eq)
N(Boc)2
CO2Me
[Ir]-cat.
[PC-Ir2]
HE3
O
TMDS
(3 eq)
CO2Me
Ph
(1 mol%)
(3 eq)
N(Boc)2
CO2Me
[PC-Ir1]
N
Ar
(1 mol%)
(1.5 eq)
Ph
PhMe
rt, 72 h
PhMe/DMSO
30 °C, 16 h
O
H
N
Ar
6a
HE2
H
Ar
5a
N
R
Ar
PhMe/DMSO
30 °C, 16 h
PhMe
rt, 72 h
H
N
H
R
blue LEDs
5a-f
6a-f
[Ir]-cat.a
blue LEDs
CO
CO
Cl
Cl
Ir
Ir
(PhO)3P Ir P(OPh)3
Cl
N(Boc)2
CO2Me
N(Boc)2
CO2Me
N(Boc)2
CO2Me
Ph3P Ir PPh3
Cl
N
N
N
H
b,c
1: Vaska's Complex
2: [Ir(COE)2Cl]2
3:
Vaska Derivative
H
H
d
O
6a
6a
: 0%
: 24%
6a
: 48%
F
entry
change from above
6aa
6a
95%, 1.8:1 dr
6b
70%, 1.1:1 dr
6c
51% 1:1 dr
4
[PC-Ir1] used as photocatalyst, HE4 as reductant
TMDS (2 eq) used
45
69
0
5c,e
6e
7e
N(Boc)2
CO2Me
O
O
Et2SiH2 (3 eq) used in place of TMDS
HE2 used as reductant
tBu
95f
N
CBz
N
a
Table 3:
6a
Ar = 4-fluorophenyl. Yield of
measured using 19F{1H} NMR analysis
H
N
b
of the crude reaction mixture. CH2Cl2 used as solvent and Et2SiH2 (3 eq) used
H
c HE5
as reductant in 1st step.
used as reductant. d Mass balance is unreacted
F
e
f
5a
.
[PC-Ir-tBu] used as photocatalyst. Isolated yield after silica gel column
6d
6e*
50%
14:1 dr
>20:1 dr
chromatography.
41%, 1.1:1 dr
F3C
F
(PF6)
N(Boc)2
R2
HE
R2
R3
R1
N
O
R3O2C
Me
CO2R3
Me
N
CO2Me
CF3
F
F
HE2
HE3
HE4
Me
Cy
Ph
Me
Me
Et
CF3
N
Ir
EtO
N
H
N
EtO
N
H
R1
N
H
N
N
F
HE5 4-CO2MePh Et
F3C
EPPTB
[inverse TAAR1 agonist]
6f
Hantzsch ester
R1 = tBu: [PC-Ir1]
R1 = H: [PC-Ir2]
66%, 1.4:1 dr
* benzyl (S)-2-(tert-butyl)-4-methylene-5-oxo-oxazolidine-3-carboxylate used as coupling partner
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ACS Catalysis
Accordingly, we envisioned that – drawing on their
necessary for the final reductive coupling step to take place
(see Supporting Information).
1
2
3
4
seminal work – our tandem reductive protocol could be
applied to the reverse polarity functionalization of
secondary amides (Scheme 6).
Scheme 7. (A) Control experiments with amine and/or
aldehyde starting materials (B) Proposed mechanism
and Gibbs free energy profile for the addition of α-
amino radical species to 2a.
Initial studies
demonstrated that the Vaska/TMDS system was – as
expected – ineffective in the reductive activation of
secondary amides (Table 3, entry 1). Pleasingly, the
[Ir(COE)2Cl]2 /Et2SiH2 system – when coupled with our
photocatalytic step – formed the desired α-branched
amine product (6a), albeit in low yields (entry 2).
Unfortunately this protocol suffered from reproducibility
issues attributed to the poor aerobic stability of the
[Ir(COE)2Cl]2 complex.22 Nevertheless, this challenge was
circumvented when the phosphite derivative of Vaska’s
complex enabled more efficient hydrosilylation and
subsequent formation of the C–C coupled product in
increased yields (entry 3).
5
6
7
8
Control experiments
A
N(Boc)2
[PC-Ir]
HE3
(1 mol%)
(1.5 eq)
N(Boc)2
CO2Me
9
Ph
CO2Me
+
N
Ar
Ph
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DMSO, 16 h
Me
N
Ar
Me
3ac
2
3a
4%
(4 eq)
blue LEDs
[PC-Ir]
ArCO2H (2 mol%)
HE3
(1 mol%)
N(Boc)2
CO2Me
N(Boc)2
CO2Me
Ph
O
(1.5 eq)
NH
Me
+
H
Ar
HO
Ar
3ab
100%
DMSO, 16 h
A subtle modification to the photoredox step, through
exchange of photocatalyst and Hantzsch ester, gave the
secondary amine structure (6a) in an excellent yield of
95%.23 This tandem secondary amide activation protocol
was then applied to a varied subset of secondary amide
substrates. Naphthalene (6b), furan (6c), and notably
cyclohexyl (6d) substituted amides afforded C–C coupled
products with good efficiency. Furthermore, greater
diastereocontrol was imposed with the use of a modified
2
(1 eq)
(1 eq)
3a
0%
(4 eq)
blue LEDs
Proposed Mechanism
B
HE
HE
DHA coupling partner (6e), with
a
substantial
*IrIII
TS1-anti
TS1-syn
improvement in diastereoselectivity to 14:1 at the α-
secondary amine position (blue).24 Most importantly, this
reductive amide activation protocol was showcased as a
late stage functionalization strategy in the transformation
of the drug molecule EPPTB (6f) into its α-functionalized
tertiary amine analogue in an excellent yield of 66%. This
result illustrates the advantages of using tertiary or
secondary amides as masked “iminium ion or imine”
moieties that could be feasibly accessed under mild
conditions in the presence of other sensitive functional
groups.
TS1
syn
13.7
IrII
E1°/2= 1.42 V
(DMSO)
IrIII
N(Boc)2
CO2Me
Ar
13.2
anti
SET
Ph
N
0.0
Me
3ar
-10.8
Ph
Ph
N
N(Boc)2
N
Ar
Ar
Me
Me 1ar
CO2Me
HEH
HP
iminium ion
E1°/2= 0.96 V
(DMSO)
-amino radical
E1°/2= 1.68 V
2a
(DMSO)
radical
chain
MECHANISTIC INVESTIGATIONS
3ar
HE
-56.4
Control experiments. Control studies were carried out
in order to probe the mechanistic pathway for the
formation of the α-functionalized tertiary amine. Firstly,
reactivity arising from the over-reduced amine 3ac was
investigated (Scheme 7A). Under the tandem reductive
functionalization conditions negligible quantities of the C–
C coupled product were formed, and therefore the over-
reduced amine was discounted as a source of the α-amino
radical under these reaction conditions. Secondly, a
mechanism involving direct condensation of the secondary
amine and aldehyde precursors was probed. However,
under the reaction conditions, only the alcohol adduct
(3ab) was observed, demonstrating that in this system,
such direct reactivity from the aldehyde moiety – and the
resulting α-oxy radical – outcompetes any productive
formation of an amine product (3a). It also highlights the
importance of an amide-derived iminium ion in order to
achieve .the desired reactivity. Finally, light-on and light-
off experiments confirmed that blue light irradiation was
N(Boc)2
CO2Me
R
R
HAT
Ph
N
Ar
3a
N
H
N
H
HEH
Me
HP+
HP
H+
R = Me: E° = 1.51 V
1/2
R = 4-CO2MePh: E1°/2 = 1.15 V
observation
radical centered on carbon
but delocalized through
nitrogen and the
quantum yield () = 2.0
R = Me
closed cycle
radical chain
aromatic ring
electrophilicity index
  1.11
HE= Hantzsch ester, HP= Hantzsch pyridine. Geometry optimization was completed at
SMD(DMSO)/B97X-D/6 311++G(d,p)//SMD(DMSO)/B97X-D/6-31+G(d,p). Ar = 4-
fluorophenyl. Blue colored and red colored electron density represent the alpha and beta
spin respectively.
Determining reaction pathway Quantum yield
experiments determined that a radical chain propagation
mechanism was, to a small extent, operating in the second
photocatalytic step of this dual iridium catalyzed amide
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reductive functionalisation strategy (Φ = 2.0). The iridium
Page 6 of 11
conclude that the Giese type addition of the α-amino
radical species is thermodynamically favorable.25
1
2
3
4
5
6
7
8
photocatalyst as well as the Hantzsch Ester intermediate
(HEH•) have the reducing capability to transform the
iminium ion into the α-amino radical species (1ar)
(Scheme 7B).16l Accordingly, both the closed-cycle and
radical chain pathways are likely operating under the
reaction conditions.
Additionally, similar results were produced for other
scope examples, suggesting that substituents on the
aromatic rings did not have a significant impact on the
radical’s reactivity (see Supporting Information). To
evaluate the degree to which these α-amino radicals
behave as nucleophiles the global electrophilicity scale (ω),
introduced by Parr, were employed.26 Values of ω can vary
from 0 to 4.00, with small values indicating a more
nucleophilic species.27 For the canonical radical species
1ar, ω = 1.11 was obtained, which characterises it as a
moderate nucleophile. A slightly smaller value was
observed for radical precursors with electron donating
substituents (e.g for 3k ω = 0.97), whilst extended aromatic
systems were found to be slightly more “electrophilic” (3o
(ω = 1.28) and 3p (ω = 1.25), albeit still within the acceptable
range for nucleophiles. No clear trend was observed
between these values and the activation energy calculated
for these compounds. This further supports the idea that
the variability in the electronic properties of the substrate’s
aromatic rings should not affect the favorability of final
reductive coupling.
To further investigate the closed cycle mechanism
pathway
involved
in
the
tandem
hydrosilylation/photocatalytic approach, we turned to
computational analysis. The reaction free energy profile for
the addition of α-amino radical (1ar) into the DHA
acceptor (2) was modelled at the SMD(DMSO)-ωB97X-
D/6-311++G(d,p)//SMD(DMSO)-ωB97X-D/6-31+G(d,p)
level of theory (Scheme 7B). A slight out-of-plane twist in
the geometry of the free radical species, resulted in a small
energetic discrimination between the two potential facial
orientations for the Giese-type addition.
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As a result, the labelled anti arrangement of the
transition state is favored by 0.5 kcal mol-1 (13.2 vs 13.7 kcal
mol-1 for the syn TS). However, it is acknowledged that
ultimate diastereoselective control is established in the
final HAT/protonation termination step.
A similar
behavior was observed for other representative substrates
(see Supporting Information for further details). Moreover,
the calculated reduction potential for the iminium species
Yield-determining factors. Throughout this work, the
efficiency of the tertiary amide components in the coupling
methodology was found to be reasonably substrate-
specific, with few obvious characteristics of a “good
substrate”. The interplay and balance between various
factors – including electronic and redox properties – that
favor the formation and reactivity of the two key reactive
intermediates (iminium ion and α-amino radical), as well
as their overall effect on the yield were subjected to deeper
exploration using Density Functional Theory (DFT)
methods.
(Ered = –0.96 V in DMSO) revealed that the substrate is
1/2
compatible with the photocatalytic system and is unlikely
to undergo two electron transfer events given the lower
reduction potential of the corresponding α-amino radical
(Ered1/2 = –1.68 V in DMSO). Analysis of spin density for the
free radical intermediates confirms the primary
concentration of the electron at the α-carbon position,
with
additional
stabilization
achieved
through
delocalization into the adjacent nitrogen center and
aromatic ring (Scheme 7B). The combined evidence from
activation energies, reduction potentials and spin densities
We initially turned to multilinear regression analysis,
employing several electronic and steric parameters, such
Scheme 8 (A). Identification of possible yield-determining parameters. (B) Heatmap correlating the reduction
potential of iminium ions and their hydrolytic stability with the yield of the transformation
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Possible yield-determining factors
Established yield-determining factors
A
B
1
2
3
4
5
Reduction Potential (4) vs Stability (5)
N(Boc)2
CO2Me
3p
Ar
N
R
Ar'
6
3a
C–C coupled product
7
8
9
3g
3c
radical-based
iminium-based
3d
Ar
Ar
10
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12
13
14
15
16
17
18
N
R
Ar'
N
R
Ar'
3k
(1) -amino radical

(4) iminium ion
reduction potential
philicity
(2) -amino radical

(5) iminium ion
hydrolytic stability
over-reduction
potential
(6) Sterimol
(3) NBO Charges
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as
ω
indexes, reduction potentials, NBO charges,
photocatalytic single electron transfer afforded the desired
α-amino radical in a one-pot procedure. The synthetic
utility of this open-shell intermediate was exemplified in
the coupling with DHA derivatives, resulting in the
synthesis of 18 examples of α-functionalized tertiary amine
architectures, inaccessible using conventional reductive
methodologies from tertiary amides. Furthermore, the
utility of our approach was showcased by adapting the
method to apply to intramolecular examples and
secondary amides, which we highlighted in the late stage
functionalization of an API. DFT studies established that
the energetic balance between hydrolytic stability of the
iminium ion and an accessible reduction potential were
key for the successful transition of the reactive
Sterimol28 values and hydrolytic stability an interesting
correlation was observed when comparing the iminium ion
stability and its corresponding reduction potential;
represented as a two-dimensional heat map in Scheme 8B.
These results showed that an increased stability of the
iminium ion and a lowered reduction potential enhance
reaction yield. However, optimizing both parameters
simultaneously is experimentally challenging to attain,
given their inverse relationship
For example, while electron-withdrawing groups lower
the reduction potentials, they also lead to destabilization
of the iminium ion. This can be illustrated with 3p; (Ered
1/2
= –0.88 V; ΔGhydrolysis = -4.0 kcal mol-1), which despite
having an accessible reduction potential, was isolated with
only a 24% yield. On the other hand, electron-donating
groups provide additional stability to the cationic
intermediate; however, they are challenging to reduce. In
agreement with this observation, no improvement in the
reaction output was observed for electron rich substrates
intermediate
between
the
hydrosilylation
and
photocatalytic reductive processes.
ASSOCIATED CONTENT
The Supporting Information is available free of charge at:
Experimental procedures, characterization and
computational data.
(3d/3k) (Ered = –1.07/ –1.13 V ; ΔGhydrolysis = +5.4/ -2.2 kcal
1/2
mol-1).
The model compound 3a seems to provide the best
AUTHOR INFORMATION
compromise between these two properties (Ered = –0.96
1/2
‡ These authors contributed equally to the work.
V; ΔGhydrolysis = -3.8 kcal mol-1). Interestingly, it was found
that substrates that achieve iminium stability through
geometrical constraints, without the presence of
additional electron density, such as (3g), (ΔGhydrolysis = +13.3
kcal mol-1 ; Ered1/2 = –1.00 V), have the highest experimental
and predicted yields. This predictive model indicates that
the stability and accessible redox properties of the iminium
ion were crucial for the successful tandem operation of the
two iridium catalytic cycles.
Corresponding Author
* Fernanda Duarte (for computational correspondence):
fernanda.duartegonzalez@chem.ox.ac.uk
* Darren J. Dixon (for synthetic correspondence):
darren.dixon@chem.ox.ac.uk
ACKNOWLEDGMENT
T.R. and P.G. are supported by the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine
(EP/L015838/1), generously supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis,
Pfizer, Syngenta, Takeda, UCB, and Vertex. T. R. also thanks
the Royal Commission of 1851 Industrial Fellowship and
NSERC PGS-D. J.A.L. thanks the Leverhulme Trust (RPG-2017-
CONCLUSION
In conclusion, a synthetic strategy that provides access to
α-amino radicals from robust tertiary amide building
blocks has been successfully developed. Selective tertiary
amide reductive hydrosilylation using Vaska’s complex,
revealed a reactive iminium ion intermediate which upon
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Page 8 of 11
Reductive N-Alkylation of Secondary Amides with Hydrosilanes:
069) for a research fellowship. The authors would also like to
thank Dr. Angel L. Fuentes de Arriba and Dr. Elena Lenci for
preliminary experiments.
Practical Synthesis of Secondary and Tertiary Amines by Judicious
Choice of Hydrosilanes. J. Org. Chem. 2007, 72, 7551-7559; (d)
Cheng, C.; Brookhart, M. Iridium-Catalyzed Reduction of
Secondary Amides to Secondary Amines and Imines by
Diethylsilane. J. Am. Chem. Soc. 2012, 134, 11304-11307; (e) Ou, W.;
Han, F.; Hu, X. N.; Chen, H.; Huang, P.-Q. Iridium-Catalyzed
Reductive Alkylations of Secondary Amides. Angew. Chem. Int.
Ed. 2018, 57, 5705-5708; (f) Takahashi, Y.; Yoshii, R.; Sato, T.;
Chida, N. Iridium-Catalyzed Reductive Nucleophilic Addition to
Secondary Amides. Org. Lett. 2018, 20, 5705-5708. For non-
catalytic methods see: (g) Xiao, K.-J.; Wang, A. E.; Huang, P.-Q.
Direct Transformation of Secondary Amides into Secondary
Amines: Triflic Anhydride Activated Reductive Alkylation. Angew.
Chem. Int. Ed. 2012, 51, 8314-8317; (h) Zheng, J. F.; Qian, X. -Y.;
Huang, P. -Q. Direct Transformations of Amides: a One-Pot
Reductive Ugi-Type Three-Component Reaction of Secondary
Amides. Org. Chem. Front. 2015, 2, 927-935; (i) Huang, P.-Q.;
Huang, Y. -H.; Xiao, K.-J.; Wang, Y.; Xia, X. -E. A General Method
for the One-Pot Reductive Functionalization of Secondary
Amides. J. Org. Chem. 2015, 80, 2861-2868; (j) Huang, P.-Q.; Lang,
Q.-W.; Hu, X. -N. One-Pot Reductive 1,3-Dipolar Cycloadditiion
of Secondary Amides: A Two-Step Transformation of Primary
Amides. J. Org. Chem. 2016, 81, 10227-10235; (k) Chen, H.; Ye, J. -
1
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5
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7
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REFERENCES
(1) Lemke, T. L., Review of Organic Functional Groups:
Introduction to Medicinal Organic Chemistry, 4th ed.; Lippincott
Williams & Williams: Baltimore, 2003.
(2) For select discussions of various C-H amination strategies
see: (a) Amino Group Chemistry: From Synthesis to the Life
Sciences, Ricci, A. Ed. Wiley VCH: Weinheim, 2008; (b) Bariwal,
J.; d. Eycken, E. V. C-N Bond Forming Cross-Coupling Reactions:
an Overview. Chem. Soc. Rev. 2013, 42, 9283-9303; (c) Hartwing, J.
F., Evolution of a Fourth Generation Catalyst for the Amination
and Thioetherification of Aryl Halides. Acc. Chem. Res. 2008, 41,
1534-1544; (d) Surry, D. S.; Buchwald, S. L. Biaryl Phosphane
Ligands in Palladium-Catalyzed Amination. Angew. Chem. Int. Ed.
2008, 47, 6338-6361; (e) Heinz, C.; Lutz, J. P.; Summons, E. M.;
Miller, M. M.; Ewing, W. R.; Doyle, A. G. Ni-Catalyzed Carbon-
Carbon Bond-Forming Reductive Amination. J. Am. Chem. Soc.
2018, 140, 2292-2300; (f) Ruffoni, A.; Julia, F.; Svejstrup, T. D.;
McMillan, A. J.; Douglas, J. J.; Leonori, D. Practical and
Regioselective Amination of Arenes Using Alkyl Amines. Nat.
Chem. 2019, 11, 426-433.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
L.;
Trifluoromethylation of Amides:
Huang,
P.-Q.
Chemoselective
Direct Reductive
Flexible Access to
(3) Examples include Petasis-Mannich reaction: (a) Candeias,
N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Boronic Acids
and Esters in the Petasis-Borono Mannich Multicomponent
Reaction. Chem. Rev. 2010, 110, 6169-6193. Amine
lithiation/functionalization: (b) Beak, P.; Basu, A.; Gallagher, D.
a
Functionalized α-Trifluoromethylamines. Org. Chem. Front.
2018¸5, 943-947; (l) Wang, A. E.; Yu, C.-C.; Chen, T.-T.; Liu, Y.-P.;
Huang, P.-Q. Enamines as Surrogates of Alkene Carbanions for
the Reductive Alkenylation of Secondary Amides: an Approach to
Allylamines. Org. Lett. 2018, 20, 999-1002.
J.;
Park,
Y.
S.;
Thayumanayan,
S.
Regioselective,
Diastereoselective, and Enantioselective Lithiation-Substitution
Sequences: Reaction Pathways and Synthetic Applications. Acc.
Chem. Res. 1996, 29, 552-560; (c) Hoppe, D.; Hense, T.
Enantioselective Synthesis with Lithium/(-)-Sparteine Carbanion
Pairs. Angew. Chem. Int. Ed. 1997, 36, 2282-2316; (d) Mitchell, E.
A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Direct
α-Functionalization of Saturated Cyclic Amines. Chem.-Eur. J.
2012, 18, 10092-10142. Direct α-C-H functionalisation: (e) Beatty, J.
W.; Stephenson, C. R. J. Amine Functionalization via Oxidative
Photoredox Catalysis: Methodology Development and Complex
Molecule Synthesis. Acc. Chem. Res. 2015, 48, 1474-1484; (f) Shi,
L.; Xia, W. Photoredox Functionalization of C-H Bonds Adjacent
to a Nitrogen Atom. Chem. Soc. Rev. 2012, 41, 7687-7697; (g) Le,
C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Selective
sp3 C-H Alkylation via Polarity-Match-Based Cross-Coupling.
Nature 2017, 547, 79-83; (h) Ratnikov, M. O.; Xu, X.; Doyle, M. P.
Simple and Sustainable Iron-Catalyzed Aerobic C-H
Functionalization of N,N-Dialkylanilines. J. Am. Chem. Soc. 2013,
135, 9475-9479; (i) Vasu, D.; Fuentes de Arriba, A. L.; Leitch, J. A.;
de Gombert, A.; Dixon, D. J. Primary α-Tertiary Amine Synthesis
via α-C-H Functionalization. Chem. Sci. 2019, 10, 3401-3407; (j) He,
J.; Hamann, L G.; Davies, H. M. L.; Beckwith, R. E. J. Late-Stage C-
H Functionalization of Complex Alkaloids and Drug Molecules
via Intermolecular Rhodium-Carbenoid Insertion. Nat. Commun.
2015, 6, 5943-5952; (k) Thullen, S. M.; Rovis, T. A Mild
Hydroaminoalkylation of Conjugated Dienes Using a Unified
Cobalt and Photoredox Catalytic System. J. Am. Chem. Soc. 2017,
139, 15504-15508; (l) McNally, A.; Prier, C. K.; MacMillan, D. W. C.
Discovery of an α-Amino C-H Arylation Reaction Using the
Strategy of Accelerated Serendipity. Science 2011, 334, 1114-1117.
(4) For reductive activation of secondary amides using catalytic
methods see: (a) Ohta, T.; Kamiya, M.; Nobutomo, M.; Kusui, K.;
Furukawa, I. Reduction of Carboxylic Acid Derivatives Using
Diphenylsilane in the Presence of a Rh-PPh3 Complex. Bull Chem.
Soc. Jpn. 2005, 78, 1856-1861; (b) Hanada, S.; Ishida, T.; Motoyama,
Y.; Nagashima, H. The Ruthenium-Catalyzed Reduction and
(5) For reviews on tertiary amide activation see: (a) Seebach, D.
Generation of Secondary, Tertiary and Quaternary Centers by
Geminal Disubstitution of Carbonyl Oxygens. Angew. Chem. Int.
Ed. 2011, 50, 96-101; (b) Addis, D.; Das, S.; Junge, K.; Beller, M.
Selective Reduction of Carboxylic Acid Derivatives by Catalytic
Hydrosilylation. Angew. Chem. Int. Ed. 2011, 50, 6004-6011; (c)
Pace, V.; Holzer, W. Chemoselective Activation Strategies of
Amidic Carbonyls Towards Nucleophilic Reagents. Aust. J. Chem.
2013, 66, 507-510; (d) Pace, V.; Holzer, W.; Olofsson, B. Increasing
the Reactivity of Amides Towards Organometallic Reagents: An
Overview. Adv. Synth. Catal. 2014, 356, 3697-3736; (e) Sato,T.;
Chida, N. Nucleophilic Addition to N-Alkoxyamides. Org. Biomol.
Chem. 2014, 12, 3147-3150; (f) Sato, T.; Yoritate, M.; Tajima, H.;
Chida, N. Total Synthesis of Complex Alkaloids by Nucleophilic
Addition to Amides. Org. Biomol. Chem. 2018¸16, 3864-3875; (g)
Kaiser, D.; Bauer, A.; Lemmerer, M; Maulide, N. Amide Activation:
an Emerging Tool for Chemoselective Synthesis. Chem. Soc. Rev.
2018, 47, 7899-7925.
(6) Amide activation using triflic anhydride: (a) Xiao, K. J.; Luo
J. M.; Ye, K. Y.; Wang, Y; Huang, P. -Q. Direct, One-pot Sequential
Reductive Alkylation of Lactams/Amides with Grignard and
Organolithium Reagents through Lactam/Amide Activation.
Angew. Chem. Int. Ed. 2010, 49, 3037-3040; (b) Mewald, M.;
Medley, J. W.; Movassaghi, M. Concise and Enantioselective Total
Synthesis of (-)-Mehranine, (-)-Methylenebismehranine, and
Related Aspidosperma Alkaloids. Angew. Chem. Int. Ed. 2014, 53,
11634-11639; (c) Romanens, A.; Belanger, G. Preparation of
Conformationally Restricted β2,2- and β2,3-Amino Esters and
Derivatives Containing All All-Carbon Quaternary Center. Org.
Lett. 2015, 17, 322-325; (d) White, K. L.; Mewald, M.; Movassaghi,
M. Direct Observation of Intermediates Involved in the
Interruption of the Bischler-Napieralski Reaction. J. Org. Chem.
2015, 80, 7403-7411; (e) Kaiser, D.; Maulide, N. Making the Least
Reactive Electrophile the First in Class: Domino Electrophilic
Activation of Amides. J. Org. Chem. 2016, 81, 4421-4428; (f)
Lindemann, C.; Schneider, C. Quinolizidine-Based Alkaloids: A
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General Catalytic, Highly Enantio- and Diastereoselective
Nagashima, H. Hydrosilane Reduction of Tertiary Carboxamides
by Iron Carbonyl Catalysts. Angew. Chem. Int. Ed. 2009, 48, 9511-
9514; (d) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. A
Convenient and General Iron-Catalyzed Reduction of Amides to
Amines. Angew. Chem. Int. Ed. 2009, 48, 9507-9510. Gold
nanoparticles (e) Mikami, Y.; Noujima, A.; Misudome, T.;
Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Highly Efficient Gold
Nanoparticle Catalyzed Deoxygenation of Amides, Sulfoxides,
and Pyridine N-Oxides. Chem. Eur. J. 2011, 17, 1768-1772. Platinum
(f) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H.
Practical Access to Amines by Platinum-Catalyzed Reduction of
Carboxamides with Hydrosilanes: Synergy of Dual Si-H Groups
Leads to High Efficiency and Selectivity. J. Am. Chem. Soc. 2009,
131, 15032-15040. Ruthenium/Osmium (g) Motoyama, H.; Mitsui,
K.; Ishida, T.; Nagashima, H. Self-Encapsulation of Homogenous
Catalyst Species into Polymer Gel Leading to a Facile and Efficient
Separation System of Amine Products in the Ru-Catalyzed
Reduction of Carboxamides with Polymethylhydrosiloxane
(PMHS). J. Am. Chem. Soc. 2005, 127, 13150-13151; (h) Igarashi, M.;
Fuchikami, T. Transition-Metal Complex-Catalyzed Reduction of
Amides With Hydrosilanes: a Facile Transformation of Amides to
Amines. Tetrahedron. Lett. 2001, 42, 1945-1947. Rhodium (i)
Kuwano, R.; Takahashi, M.; Ito, Y. Reduction of Amides to Amines
Synthetic Approach. Synthesis 2016, 48, 828-844; (g) Gawali, V. S.;
Simeonov, S.; Drescher, M.; Thomas, K.; Olaf, S.; Kudolo, J.;
Hanspeter, K.; Ulla, H.; Roller, A.; Todt, H.; Maulide, N. C2-
Modified Sparteine Derivatives Are a New Class of Potentially
Long-Acting Sodium Channel Blockers. ChemMedChem 2017, 12,
1819-1822.
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2
3
4
5
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(7)
Amide activation using titanium reagents: (a) Bower, S.;
Kreutzer, K. A.; Buchwald, S. L. A Mild General Procedure for the
One-Pot Conversion of Amides to Aldehydes. Angew. Chem. Int.
Ed. Engl. 1996, 35, 1515-1516; (b) Laval, S.; Dayoub, W.; Favre-
Reguillon, A.; Demonchaux, P.; Mignani, G.; Lemaire, M. A Mild
Titanium-Based System for the Reduction of Amides to
Aldehydes. Tetrahedron. Lett. 2010, 51, 2092-2094. (c) Jacubec, P.;
Hawkins, A.; Felzmann, W.; Dixon, D. J. Total Synthesis of
Manzamine A and Related Alkaloids. J. Am. Chem. Soc. 2012¸134,
17842-17485.
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57
58
59
60
(8)
Amide activation using Schwartz Reagent: (a) Oda, Y.;
Sato, T.; Chida, N. Direct Chemoselective Allylation of Inert
Amide Carbonyls. Org. Lett. 2012, 14, 950-953; (b) Shirokane, K.;
Wada, T.; Yoritate, M.; Minamikawa, R.; Takayama, N.; Sato, T.;
Chida, N. Total Synthesis of (±)-Gephrotoxin by Amide-Selective
Reductive Nucleophilic Addition. Angew. Chem. Int. Ed. 2014, 53,
512-516; (c) Yoritate, M.; Meguro, T.; Matsuo, N.; Shirokane, K.;
Sato, T.; Chida, N. Two-Step Synthesis of Multi-Substituted
Amindes by Using an N-Methoxy Group as a Reactivity Control
Element. Chem. Eur. J. 2014, 20, 8210-8216; (d) Nakajima, M.; Oda,
Y.; Wada, T.; Minamikawa, R.; Shirokane, K.; Sato, T.; Chida, N.
Chemoselective Reductive Nucleophilic Addition to Tertiary
Amides, Secondary Amides, and N-Methoxyamides. Chem. Eur. J.
2014, 20, 17565-17571; (e) Shirokane, K.; Tanaka, Y.; Yoritate, M.;
Takayama, N.; Sato, T.; Chida, N. Total Syntheses of (±)-
Gephyrotoxin and (±)-Perhydrogephyrotoxin. Bull. Chem. Soc.
Jpn. 2015, 88, 522-537.
via Catalytic Hydrosilylation by
a
Rhodium Complex.
Tetrahedron. Lett. 1998, 39, 1017-1020. Iridium (j) Park, S.;
Brookart, M. J. Development and Mechanistic Investigation of a
Highly Efficient Iridium(V) Silyl Complex for the Reduction of
Tertiary Amides to Amines. J. Am. Chem. Soc. 2012, 134, 640-653.
(12)
Nagashima, H. Highly Efficient Synthesis of Aldenamines from
Carboxamides by Iridium-Catalyzed Silane
(a) Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.;
Reduction/Dehydration Under Mild Conditions. Chem. Commun.
2009, 1574-1576; (b) Gregory, A. W.; Chambers, A.; Hawkins, A.;
Jakubec, P.; Dixon, D.J. Iridium-Catalyzed Reductive Nitro-
Mannich Cyclization. Chem. Eur. J. 2015, 21, 111-114; (c) Nakajima,
M.; Sato, T.; Chida, N. Iridium-Catalyzed Chemoselective
Reductive Nucleophilic Addition to N-Methoxyamides. Org. Lett.
2015, 17, 1696-1699; (d) Huang, P. -Q.; Ou, W.; Han, F.
Chemoselective Reductive Alkynylation of Tertiary Amides by Ir
and Cu(I) Bis-Metal Sequential Catalysis. Chem. Commun. 2016,
52, 11967-11970; (e) Katahara, S.; Kobayashi, S.; Fujita, K.;
Matsumoto, T.; Sato, T.; Chida, N. An Iridium-Catalyzed
Reductive Approach to Nitrones from N-Hydroxyamides. J. Am.
Chem. Soc. 2016, 138, 5246-5249; (f) Xie, L. G.; Dixon, D. J. Tertiary
Amine Synthesis via Reductive Coupling of Amides with Grignard
Reagents. Chem. Sci. 2017, 8, 7492-7497; (g) Fuentes de Arriba, A.
L.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. J. Iridium-
Catalyzed Reductive Strecker Reaction for Late-Stage Amide and
Lactam Cyanation. Angew. Chem. Int. Ed. 2017, 56, 3655-3659; (h)
Xie, L.G.; Dixon, D.J. Iridium-Catalyzed Reductive Ugi-Type
Reactions of Tertiary Amides. Nat. Commun. 2018, 9, 2841-2849.;
(i) Takahashi, Y.; Sato, T.; Chida, N. Iridium-Catalyzed Reductive
Nucleophilic Addition to Tertiary Amides. Chem. Lett. 2019, 48,
1138-1141; (j) Une, Y.; Tahara, A.; Miyamoto, Y.; Sunada, Y.;
Nagashima, H. Iridium-PPh3 Catalysts for Conversion of Amides
to Enamines. Organometallics, 2019, 38, 852-862; (k) Gabriel, P.;
Gregory, A. W.; Dixon, D. J. Iridium-Catalyzed Aza-
Spirocyclization of Indole-Tethered Amides: An Interrupted
Pictet-Spengler Reaction. Org. Lett. 2019, 21, 6658-6662; (l)
Gabriel, P.; Xie, L. G.; Dixon, D. J. Iridium-Catalyzed Reductive
Coupling of Grignard Reagents and Tertiary Amides. Org. Synth.
2019, 96, 511-527.
(9)
Amide activation using stoichiometric metal
reductants: (a) Shirokane, K.; Kurosai, Y.; Sato, T.; Chida, N. A
Direct Entry to Substituted N-Methoxyamines from N-
Methoxyamides via N-Oxyiminium Ions. Angew. Chem. Int. Ed.
2010, 49, 6369-6372; (b) Ong, D. Y.; Fan, D.; Dixon, D. J.; Chiba, S.
Transition-Metal Free Reductive Functionalization of Tertiary
Carboxamides and Lactams for α-Branched Amine Synthesis.
Angew. Chem. Int. Ed. 2020, 59, 1-6.
(10)
Amide activation using molybdenum catalysts: (a)
Volkov, A.; Tinnis, F.; Slagbrand, T.; Pershagen, I.; Adolfsson, H.
Mo(CO)6 Catalysed Chemoselective Hydrosilylation of α,β-
Unsaturated Amides for the Formation of Allylamines. Chem.
Commun. 2014, 50, 14508-14511; (b) Tinnis, F.; Volkov, A.;
Slagbrand, T.; Adolfsson, H. Chemoselective Reduction of
Tertiary Amide under Thermal Control: Formation of Either
Aldehydes or Amines. Angew. Chem. Int. Ed. 2016, 55, 4562-4566;
(c) Trillo, P.; Slagbrand, T.; Tinnis, F.; Adolfsson, H. Facile
Preparation of Pyrimidinediones and Thioacrylamides via
Reductive Functionalization of Amides. Chem. Commun. 2017, 53,
9159-9162; (d) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfsson,
H. An Efficient One-Pot Procedure for the Direct Preparation of
4,5-Dihydroisoxazoles from Amides. Adv. Synth. Catal. 2017, 359,
1990-1995; (e) Slagbrand, T.; Volkov, A.; Trillo, P.; Tinnis, F.;
Adolfsson, H. Transformation of Amides into Highly
Functionalized Triazolines. ACS Catal. 2017, 7, 1771-1775.
(11)
Other transition metal catalysed amide activation
methods include: Zinc (a) Das, S.; Addis, D.; Zhou, S.; Junge, K.;
Beller, M. Zinc-Cataltzed Reduction of Amides: Unprecedented
Selectivity and Functional Group Tolerance. J. Am. Chem. Soc.
2010, 132, 1770-1771; (b) Das, S.; Addis, D.; Junge, K.; Beller, M.
Zinc-Catalyzed Chemoselective Reduction of Tertiary and
Secondary Amides to Amines. Chem. Eur. J. 2011, 17, 12186-12192.
Iron (c) Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.;
(13)
Divergent Total Syntheses of Aspidosperma Alkaloids Exploiting
Iridium(I)-Catalyzed Generation of Reactive Enamine
(a) Tan, P. W.; Seayad, J.; Dixon, D. J. Expeditious and
Intermediates. Angew. Chem. Int. Ed. 2016, 55, 13436-13440; (b)
Nakayama, Y.; Maeda, Y.; Kotatsu, M.; Sekiya, R.; Ichiki, M.; Sato,
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Page 10 of 11
T.; Chida, N. Enantioselective Total Synthesis of (+)-Neostenine.
Duarte, F.; Dixon, D. J. Dearomative Photocatalytic Construction
Chem. Eur. J. 2016, 22, 3300-3303; (c) Yoritate, M.; Takahashi, Y.;
Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.;
Chida, N. Unified Total Synthesis of Stemoamide-Type Alkaloids
by Chemoselective Assembly of Five Membered Building Blocks.
J. Am. Chem. Soc. 2017, 139, 18386-18391; (d) Gammack, G. A. D.;
Dixon, D. J. Enantioselective Synthesis of the ABCDE Pentacyclic
Core of the Strychnos Alkaloids. Org. Lett. 2017, 19, 1894-1897; (e)
Yamamoto, S.; Komiya, Y.; Kobayashi, A.; Minakawa, R.; Oishi, T.;
Sato, T.; Chida, N. Asymmetric Total Synthesis of Fasicularin by
Chiral N-Alkoxyamide Strategy. Org. Lett. 2019, 21, 1868-1871; (f)
Wood, M. D.; Klosowski, D. W.; Martin, S. F. Stereoselective Total
Syntheses of (±)-Alstoscholarisine E. Org. Lett. 2020, 22, 786-790.
of Bridged 1,3-Diazepanes. Angew. Chem. Int. Ed. 2020, 59, 4121-
4130; (m) Leng, L.; Fu, Y.; Peng, L.; Ready, J. M. Regioselective,
Photocatalytic α-Functionalizatoin of Amines. J. Am. Chem. Soc.
2020, 142, 11972-11977.
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4
5
6
7
8
(17)
(a) Aycock, R. A.; Vogt, D. B.; Jui, N. T. A Pratical and
Scalable System for Heteroaryl Amino Acid Synthesis. Chem. Sci.
2017, 8, 7998-8003; (b) Aycock, R. A.; Pratt, C. J.; Jui, N. T.
Aminoalkyl Radicals as Powerful Intermediates for the Synthesis
of Unnatural Amino Acids and Peptides. ACS. Catal. 2018, 8, 9115-
9119; (c) Seath, C. P.; Jui, N. T. Intermolecular Reactions of Pyridyl
Radicals with Olefins via Photoredox Catalysis. Synlett 2019, 30,
1607-1614.
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(14)
hemi-aminal-derived enamine, see ref 13a.
(15) For reviews see: (a) Leitch, J. A.; Rossolini, T.; Rogova,
For nucleophilic reactivity at the β-position from a
(18)
Anhydrous conditions were essential to prevent
iminium ion hydrolysis. Toluene was degassed and stored over 4
Å molecular sieves in an AcrosSeal® bottle.
(19)
incompatible with these reaction conditions (see supporting
information).
(20) The propensity for over-reduction is unclear, but a
potential intramolecular [1,4]-HAT event from the α-amino
radical instead of Giese addition could be responsible.
T.; Maitland, J. A. P.; Dixon, D. J. α-Amino Radicals via
Photocatalytic Single-Electron Reduction of Imine Derivatives.
ACS Catal. 2020, 10, 2009-2025; (b) Garrido-Castro, A. F.; Maesto,
M. C.; Alemán, J. α-Functionalization of Imines via Visible Light
Photoredox Catalysis. Catalysts, 2020, 10, 562; (c) Lee, K. N.; Ngai,
M.-Y. Recent Development in Transition-Metal Photoredox-
Catalyzed Reactions of Carbonyl Derivatives. Chem. Commun.
2017, 53, 13093-13112.
Dialkyl and benzyl-substituted amides were found to be
(21)
Tahara, A.; Miyamoto, Y.; Aoto, R.; Shigeta, K.; Une, Y.;
Sunada, Y.; Motoyama, Y.; Nagashima, H. Catalyst Design of
Vaska-Type Iridium Complexes for Highly Efficient Synthesis of
π-Conjugated Enamines. Organometallics 2015, 34, 4895-4907.
(22) Herde, J. L.; Lambert, J. C.; Senoff, C. V. Inorganic
Syntheses; Parshall, G. W. Ed. McGraw-Hill, 1974; Vol. 15, 18-20.
(23) The relative stereochemical configuration of the major
diastereoisomer of 6a was assigned as anti by comparison of its
spectroscopic data with that of a literature compound (see
reference 16f and the Supporting Information).
(24) Despite the high levels of selectivity, due to the lack of
crystallinity of 6e, it was not possible to assign stereochemical
configurations to either of the newly formed α- or γ- stereogenic
centers.
(25) Direct and indirect terminations in the final step by a
Hantzsch ester intermediate may be possible. See deuterium
labelling studies in the supporting information.
(26) Parr, R. G.; v. Szentpaly, L.; Liu, S. Electrophilicity Index.
J. Am. Chem. Soc. 1999, 121, 1922-1924.
(27) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier,
M.; Geerlings, P.; De Proft, F. Electrophilicity and Nucleophilicity
Index for Radicals. Org. Lett. 2007, 9, 2721-2724.
(28) Brethome, A. V.; Fletcher, S. P.; Paton, R. S.
Conformational Effects on Physical-Organic Descriptors: The
Case of Sterimol Steric Parameters. ACS Catal. 2019, 9, 2313-2323.
(16)
For select examples refer to: (a) Qi, L.; Chen, Y. Polarity-
Reversed Allylations of Aldehydes, Ketones, and Imines Enables
by Hantzsch Ester in Photoredox Catalysis. Angew. Chem. Int. Ed.
2016, 55, 13312-13315; (b) Fuentes de Arriba, A. L.; Urbitsch, F.;
Dixon, D. J. Umpolung Synthesis of Branched α-Functionalized
Amines From Imines via Photocatalytic Three-Component
Reductive Coupling Reactions. Chem. Commun. 2016, 52, 14434-
14437; (c) Lee, K.N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive
Coupling of Alkenylpyridines with Aldehydes and Imines via
Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem. Soc.
2017, 139, 5003-5006; (d) Leitch, J. A.; Fuentes de Arriba, A. L.; Tan,
J.; Hoff, O.; Martinez, C. M.; Dixon, D. J. Photocatalytic Reverse
Polarity Povarov Reaction. Chem. Sci., 2018, 9, 6653-6658; (e)
Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent Synthesis
of
Tertiary
Alkylamines
by
Photocatalytic
Olefin-
Hydroaminoalkylation. Nature 2018, 561, 522-527; (f) Rossolini, T.;
Leitch, J. A.; Grainger, R.; Dixon, D. J. Photocatalytic Three-
Component Umpolung Synthesis of 1,3-Diamines. Org. Lett. 2018,
20, 6794-6798; (g) Floden, N. J.; Trowbridge, A.; Willcox, D.;
Walton, S. M.; Kim, Y.; Gaunt M. J. Streamlines Synthesis of
C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-
Mediated Photocatalysis. J. Am. Chem. Soc. 2019, 141, 8426-8430;
(h) Cao, K.; Tan, S. M.; Lee, R.; Yang, S.; Jia, H.; Zhao, X.; Qiao, B.;
Jiang, Z. Catalytic Enantioselective Addition of Prochiral Radicals
to Vinylpyridines. J. Am. Chem. Soc. 2019, 141, 5437-5443; (i) Wang,
R.; Ma, M.; Gong, X.; Fan, X.; Walsh, P. J. Reductive Cross-
Coupling of Aldehydes and Imines Mediated by Visible Light
Photoredox Catalysis. Org. Lett. 2019, 21, 27-31; (j) Reich, D.;
Trowbridge, A.; Gaunt, M. J. Rapid Syntheses of (-)-FR901483 and
(+)-TAN1251C Enables by Complexity-Generating Photocatalytic
Hydroaminoalkylation. Angew. Chem. Int. Ed. 2020, 59, 2256-2261;
(k) Kumar, R.; Floden, N.; Whitehurst, W. G.; Gaunt, M. J. A
General Carbonyl Alkylative Amination for Tertiary Amine
Synthesis. Nature 2020, 581, 415-420; (l) Leitch, J. A.; Rogova, T.;
hydrosilylation
photoredox
O
H
O[Si]
N
Ir
Ir
N
N
N
e, H+
[Si]
H
tertiary amide
silyl
hemiaminal
-functionalized
tertiary amine
-amino
radical
one-pot streamlined protocol
applied to secondary amides
DFT studies
reverse polarity tertiary amide activation
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