Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition-Metal-Free Hydroamination and N-Arylation Reactions

Article abstract of DOI:10.1021/jacs.6b04920

The development of photoredox reactions of aryloxy-amides for the generation of amidyl radicals and their use in hydroamination-cyclization and N-arylation reactions is reported. Owing to the ease of single-electron-transfer reduction of the aryloxy-amides, the organic dye eosin Y was used as the photoredox catalyst, which results in fully transition-metal-free processes. These transformations exhibit a broad scope, are tolerant to several important functionalities, and have been used in the late-stage modification of complex and high-value N-containing molecules.

Full text of DOI:10.1021/jacs.6b04920

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Communication
Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition
Metal-Free Hydroamination and N-Arylation Reactions.
Jacob Davies, Thomas D. Svejstrup, Daniel Fernandez Reina, Nadeem S. Sheikh, and Daniele Leonori
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Jun 2016
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Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition
Metal-Free Hydroamination and N-Arylation Reactions.
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Jacob Davies,a‡ Thomas D. Svejstrup,a‡ Daniel Fernandez Reina,a Nadeem S. Sheikhb and Danie-
le Leonori a*
a School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. b Department of Chemis-
try, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
Supporting Information Placeholder
tions are very favorable and this frequently thwarts
the development of C–N bond-forming processes.5
ABSTRACT: The development of photoredox reac-
tions of aryloxy amides for the generation of amidyl
radicals and their use in hydroamination–cyclization
and N-arylation reactions is reported. Owing to the
ease of SET reduction of the aryloxy amides, the or-
ganic dye eosin Y was used as the photocatalyst,
which results in fully transition metal-free processes.
These transformations exhibit a broad scope, toler-
ant to several important functionalities and have
been used in the late-stage modification of complex
and high-value N-containing molecules.
Recent progress towards the generation and use of
N-radicals has involved the use of photoredox cataly-
sis6 as an enabling tool for mild and selective single-
electron transfer (SET)7 processes.8 Of relevance to
this work are the reports of Sanford,9a Studer,9b Lee,9c
Luo,9d and Yu,9e which developed the photoredox
generation of N-radicals and used them in N-
arylation reactions. These methodologies involve the
use and introduction of substrate-specific and diffi-
cult-to-modify N-groups. More recently Knowles10a
and Xu10b reported two elegant hydroamination reac-
tions of amidyl radicals by using oxidative photore-
dox and electrochemical approaches respectively
(Scheme 1A). These processes require the use of N-
aryl-amides and therefore cannot be used in a gen-
eral sense for the synthesis of N-containing mole-
cules.
Nitrogen-containing compounds form the structural
basis of almost all pharmaceuticals, agrochemicals
and materials.1 As a result, the development of new
methodologies that allow the selective formation of
C–N bonds under mild conditions and in complex
molecular settings are of great relevance. Amidyl rad-
icals represent a very useful class of reactive inter-
mediates with potentially broad applications in the
preparation of amides and carbamates.2 However,
their implementation in synthesis is somewhat lim-
ited by (i) their available precursors, which are often
difficult-to-make and highly reactive, and (ii) the
reaction conditions required for their generation,
which often preclude the presence of many function-
al groups.2a Pioneering studies from Ingold revealed
that amidyl radicals display remarkably high electro-
philic character and this offers the advantage of an
umpolung reactivity complementing the nucleo-
philic character of N-species in classical polar reac-
tion modes.3,4 However, as detailed by Newcomb, the
amidyl radical electrophilicity also means that both
inter and intra-molecular H-atom abstraction reac-
SCHEME 1. Amidyl radicals.
A) Nitrogenꢀradical precursors for photoredox transformations
O
O
Me
Ar
Me
Ts
Me
R
Bs
NH
N
X
N
N
Me
N
O
N Br
S
O
O
Me
O
O
• Sanford [ref. 9a]
X = OC(O)CF3
• Lee [ref. 9c]
X = Cl
Studer [ref. 9b] • MacMillan [ref. 8d]
Luo [ref. 9d]
Knowles [ref. 10a]
R = CO2Me
• Yu [ref. 9e]
R = Bs
B) This work:
Ar
(π*+σ*)
R2
Ar
R1
R1
R1
O
electrophore
O
hydroamination
Nꢀarylation
N
N
N
weak bond
transition metal
free
X
transition metal
free
O
R
R
O
We have recently developed a transition metal-free
photoredox cyclization of iminyl radicals derived
from aryloximes.11 We decided to evaluate whether
this activation mode could be applied to the genera-
tion of amidyl radicals and use it as a general plat-
form for the synthesis of N-containing molecules.
We reasoned that electron poor aryloxy-amides
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would be ideal amidyl radical precursors owing to
the aryloxy motif serving as a (π*+σ*)-electrophore7b
that should facilitate a photoredox SET reduction–
fragmentation cascade en route to the amidyl radical.
We were particularly keen to explore whether this
methodology had the potential to solve the challenge
of generating any amidyl radical independently from
the nature of its N-substituents and therefore decid-
ed to focus our attention on (i) substrates and substi-
tution patterns that go far beyond the limits of cur-
rent methodologies and (ii) on providing access to
highly functionalized, high-value N-containing
compounds. In this paper we report the development
of transition metal-free photoredox hydroamination-
cyclization and N-arylation reactions of amidyl radi-
cals and their use in the late stage functionalization
of compounds with therapeutic applications.
irreversible reduction profiles and the nitro-
containing compounds (1a–c) fell well inside the
1
2
3
4
5
6
7
8
range for SET reduction by the excited state of the
red
organic dye eosin Y [E1/2 = –1.11 V (vs SCE)].13 DFT
calculations aimed at evaluating the N–O bond dis-
sociation energies (BDEs) revealed that all substrates
1a–e have N–O BDEs ≈ 40 kcal/mol. However, upon
SET reduction a dramatic weakening of the N–O
bond takes place, which makes the fragmentation
process thermodynamically driven and essentially
immediate in the case of the nitro-substituted deriv-
atives 1a–c.14 Since a major element of concern in the
development of our approach is the tendency of
amidyl radicals to undergo H-atom abstraction, we
were surprised by the high reactivity displayed by the
N-Ar-amidyl radicals reported by Knowles10a and
Xu.10b We performed further DFT studies to evaluate
how the N-substitution pattern would impact the
radical electrophilicity and, as a result, its ability to
undergo H-atom abstraction. As described in
Scheme 3B, local electrophilicity index-values
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Our proposed catalytic cycle for the photoredox cy-
clization of aryloxyamides A is described in Scheme
2. We reasoned that upon photocatalyst (PC) excita-
tion by visible light irradiation, SET reduction of the
aryl unit of A would occur delivering the radical ani-
on B and PC•+. At this point, N–O bond fragmenta-
tion would form the amidyl radical C, which would
produce D after 5-exo-trig cyclization. H-atom ab-
straction from 1,4-cyclohexadiene (1,4-CHD) would
form the product E and generate the radical F, which
would close the photoredox cycle by SET with PC•+.
As aforementioned, a major element of concern was
the high tendency of C to undergo preferential H-
atom abstraction from 1,4-CHD over the desired 5-
exo-trig cyclization.12 This situation would be partic-
ularly problematic in our case as (i) 1,4-CHD has a
dual role as both a H-atom donor and SET reductant
in two distinct but sequential event of the catalytic
cycle and (ii) direct H-atom abstraction would form
F, which would close the catalytic cycle and eventu-
ally consume A.
(ω+ )15a and Hirshfeld charges15b for various radicals
rc
were calculated. This study revealed a remarkable
modulation of the radical electrophilicity that is of-
fered by the N-Ar substituent. According to our
scale, Ar-amidyl radicals (2a–c) are significantly less
electrophilic than alkyl-amidyl radicals (2d–e). They
are even less electrophilic than iminyl radicals (e.g.
3) and this might be the reason for their low tenden-
cy to abstracting H-atoms.14 To further corroborate
this scenario, we have calculated the barrier for H-
atom abstraction (ꢀG‡) for the reaction between rad-
icals 2a–f and 1,4-CHD. As described in Scheme 3B,
N-Ph substituted radicals 2a–c displayed higher bar-
riers for H-abstraction compared with the more elec-
trophilic N-alkyl radicals 2d–f.14 These results clearly
show the relevance and challenges that are associat-
ed with the development of photoredox reactions of
amidyl radicals with alkyl and carbonyl-containing
substitution patterns.
SCHEME 2. Proposed photoredox cycle for the
hydroamination-cyclization reaction.
SCHEME 3. Electrochemical and DFT studies.
– H+
Side reaction:
direct H-abstraction
H
PC
R
N
SET
O
E
H
H
PC•+
*PC
F
R
O
R
O
N
N
SET
EWG
EWG
H
H
D
F
O
O
R
O
R
R
O
N
R
H
N
N
N
O
Ar
O
O
A
B
C
We started our investigation by performing cyclic
voltammetry studies on model precursors 1a–e
(Scheme 3A). All of the substrates tested displayed
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A) Electrochemical scale (vs SCE) and calculated N–O bond BDEs [UB3LYP/6ꢀ311+G(d,p)]
tone was found to be the best reaction medium and
in terms of the light source, we found that green
LEDs (λ = 530 nm) gave the best results. Under these
reaction conditions 7a was obtained in 78% yield.14
With these optimized reaction conditions in hand,
we evaluated the scope of this photoredox cyclization
reaction. Pleasingly, our protocol enabled the genera-
tion and the use of amidyl radicals with broad N-
substitution patterns, as shown by the use of a pri-
mary alkyl group (7b–c) as well as the hindered cy-
clohexyl (7d) and a redox-active sulfone16-containing
heterocycle (7e). More remarkably, we were able to
generate and implement N-Boc and N-Cbz-protected
amidyl radicals (7f and 7g). The success of these cy-
clizations is noteworthy owing to the high electro-
–0.2 V
–0.6 V
–1.0 V
–1.4 V
–1.8 V
–2.2 V
1
2
3
4
5
6
7
8
9
NO2
NO2
NO2
CN
NO2
NO2
NO2
Me
O
Me
O
Me
O
Me
O
Me
O
N
N
N
N
N
O
Me
O
NMe2
O
OMe
O
Me
O
Me
1a
1b
1c
1d
1e
–0.26 V
–0.37 V
N–O Bond BDEs: Ground state
36.5 –19.3 42.3
B) Electrophilicity scale – Hirshfeld charges on N in brackets [UB3LYP/6ꢀ311+G(d,p)]
–0.57 V
Radical anion (kcal/mol)
–13.9 41.0 11.8
–1.43 V
–2.10 V
ꢀ
44.2
ꢀ
–10.3
ꢀ
ꢀ
ꢀ
39.7
ꢀ
17.3
0.6
0.7
0.8
0.9
1.0
1.1
1.2
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Ph
Ph
Ph
Me
Me
Me
N
N
N
N
N
N
N
O
NMe2
O
Me
O
OMe Ph
Me
O
NMe2
O
Me
O
OMe
2a
2b
2c
3
2d
2e
2f
0.66 (–0.15)
0.68 (–0.16) 0.68 (–0.15) 0.77 (–0.18) 1.00 (–0.12)
1.09 (–0.11) 1.11 (–0.10)
ꢀ
G‡ for Hꢀatom abstraction from 1,4ꢀCHD (kcal/mol) [UB3LYP/6ꢀ311+G(d,p)]
15.3
9.4 8.5 6.9 2.6
2.3
We started the optimization of our proposed process
using the di-nitro-substituted amide 4a due to its
synergistic (i) ease of synthesis, (ii) ease of SET re-
duction and (iii) very favorable N–O bond fragmen-
tation (Scheme 4).11 Our optimized reaction condi-
tions required the use of eosin Y as the PC, 1,4-CHD
as the H-atom source, and K2CO3 as the base. Ace-
philicity of these radicals (ω+ = 1.3).14 To the best of
rc
our knowledge, the generation and the use of these
amidyl radicals have never been reported in the liter-
ature.
SCHEME 4. Scope of the photoredox hydroamination-cyclization reaction.
Me Me
EY (2 mol%)
CHD (2.0 equiv.)
K2CO3 (2.0 equiv.)
Me
7a: R = Me
7b: R = PhCH2CH2 : 67%
7c: R = Bn
7d: R = Cy
7f: R = Boc
7g: R = Cbz
7h: R = Ph
: 78%
Me
R
O
OAr
Me
Me
O
R2
O
O
Me
O
O
O
N
Me
Me
N
S
Me
O
R1
N
R
O
: 68%
: 65%
: 65%
: 54%
: 63%
R
N
Me
N
H
Boc
N
N
X
R1
N
acetone (0.1–0.05M), rt
green LEDs
[4a–s: 01 M]
[5a–i,6: 0.05 M}
O
N
X
Me
O
R2
Me
7k
75%
O
7e
O
O
Ar = 2,4ꢀ(NO2)2ꢀC6H3
X = C: 4a–s; O: 5a–i; S: 6
X = C: 7a–s
O: 8a–i; S: 9
Me
7i
7j
7l
79% (dr 2:1)
O
Me
77% (dr 1:5:1)
29% (dr 1.2:1)
73%
F
Me
H
Me
Me
Me
Me
Me
O
F
Me
H
O
Me
O
Me
Me
Me
F
N
Me
Me
O
8a: R = Me
8b: R = Cy
: 59%
: 72%
N
O
N
Me
N
N
N
Me
Me
N
Me
N
N
Boc
R
N
Me
H
N
O
O
H
O
O
O
O
O
Me
Me
O
Me
O
S
8c: R =
: 48% (dr 1.5:1)
O
O
7m
64%
O
7n
61%
7o
75%
7p
67%
7q
64%
O
8d
59%
8e
40%
8f
35%
8g
38%
Me
Modification of pharmaceuticals
Me Me
Me
N
Me
O
Me
O
Me
Me
Me
Me
Me
Me
Me
N
2 Step
see SI
2 Step
N
O
R
OAr
4r
O
R
OAr
4s
NH2
N
N
N
N
NH2
O
S
see SI
O
Me Me
8h
Me
O
Me
O
O
O
7s
67% (dr 3:1)
8i
59%
9
50%
mexiletine
7r
rimantadine
41% (dr 1.8:1)
anti-arrhythmic
70% (dr 1.7:1)
antiviral
We then showcased our method by preparing more
complex products, including 7i which contained a
sugar-like moiety as N-substituent, and bicyclic
(7j,k,n), tricyclic (7o) and spirocyclic (7l) molecules.
Cyclization to form a fully substituted carbon centre
was possible (7p), and we succeeded in using a tri-
fluoro substituted olefin substrate (7q). We then ex-
tended this chemistry to the synthesis of cyclic car-
bamates. However, in this case the reaction condi-
tions had to be adjusted because the competing H-
atom abstraction became significantly more prob-
lematic owing to the increased radical electrophilici-
ty (see Scheme 3B). Nevertheless, we were able to use
a range of differentially substituted substrates with-
out the need for a stabilizing N-aromatic group (8a–
f). We then used our methodology for the modifica-
tion of the terpenes (–)-linalool (8g) and (–)-
myrtenol (8h) as well as performing a cyclization
that produced a cyclic thiocarbamate (9). Finally, as
many therapeutic molecules contain alkyl-
substituted amino groups, we showcased the ap-
plicability of our methodology with the late-stage
modification of the blockbuster drugs mexiletine
and rimantadine, which gave 7r and 7s in high yields.
Having developed a photoredox transition-metal free
hydroamination process, we decided to evaluate
whether our method could be used to achieve inter-
molecular N-arylation reactions (Scheme 5A).17
Mechanistically, we envisaged that upon photoredox
amidyl radical generation (AꢀC) and in the presence
of an electron rich aromatic partner, an intermolecu-
lar reaction18 would take place to forge the C–N bond
in G. This species would then close the photoredox
cycle and provide the product H. Related reactions
have been reported in the literature (Scheme 2A),9
however they do not allow structural modification of
the N-radical and they require a large excess of the
aromatic partner (normally 5/10-fold excess). We
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hoped that our substrates and activation mode
pharmaceutical agents1 we decided to evaluate
1
would address these two major limitations and pro-
vide a general platform for the arylation of N-
molecules. As described in Scheme 5B, by simply
exposing 1a to N-Me-indole (2.0 equiv.), EY and
K2CO3 in acetone under green LEDs irradiation, the
coupled product 11a was obtained in high yield.14
Gratifingly, our approach enabled us to easily modify
the N-substitution pattern as shown by the imple-
mentation of substrates that contain a N-alkyl chain
(11b), a N-Bz (11c), the most commonly used N-
protecting groups: N-Boc (11d), N-Cbz (11e) and N-
dimethyl-Troc (11f), and a thiocarbamate (11g). The
compatibility of the N-dimethyl-Troc group is note-
worthy as the X–CCl3 motif is frequently used as pho-
toredox SET acceptor.
whether our method could be used as a late-stage
amination protocol. We were intrigued by the idea of
modifying the core structure of lysergic acid, a mole-
cule that has been a source of interest and imagina-
tion in both chemistry and pop-culture.19 We were
delighted to see that, upon exposure of the therapeu-
tically active ergot derivatives nicergoline and meter-
goline to our reaction conditions the C-2 amino-
functionalised products 11u and 11v were obtained in
good yields. We believe that these examples show-
case the power of our arylation manifold owing to
the high structural complexity and the number of
functional groups that are tolerated, which includes
an unprotected carbamate. In fact, the excited state
of a photoredox catalyst could potentially oxidize the
piperidine ring N-atom and reduce the electron poor
pyridine ring. As an example, when the reaction on
nicergoline was repeated by using Ir(ppy)3 as the PC,
we obtained a complex mixture, which was possibly
due to the stronger redox properties of its excited
state.
In conclusion, we have identified a class of easy-to-
make and highly reactive aryloxyamides that were
used in the first photoredox transition metal-free
generation of amidyl radicals. This activation mode
represents a general strategy for the implementation
of intramolecular hydroamination reactions as well
as intermolecular N-arylation processes. The meth-
odology reported here displays high functional group
tolerance, which is illustrated by the late-stage modi-
fication of terpenes, blockbuster drugs and complex
ergot derivatives.
2
3
4
5
6
7
8
9
10
11
12
13
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SCHEME 5. Photoredox N-arylation reaction.
A) Proposed photoredox Nꢀarylation reaction
Ar
– H+
R
O
R
O
N
N
R1
R
R1
EY
H
SET
N
O
R1
EY•+
*EY
G
R
O
SET
N
C
Ar
R1
A
B
Ar
O
B) Scope of the photoredox Nꢀarylation reaction
Ar
R
O
OAr
H
R
O
EY (2 mol%), K2CO3 (2.0 equiv.)
N
N
+
Ar
R1
acetone (0.1 M), rt
green LEDs
R1
11a–v
1a, 10a–e
11a: R = Me
R1 = Ac
: 80%
: 79%
: 68%
: 64%
: 56%
R1
Me
N
Ac
11b: R = PhCH2CH2 R1 = Ac
R
N
11c: R = Me
11d: R = Me
11e: R = Me
11f: R = Me
11g: R = Me
R1 = Bz
N
R1 = Boc
R1 = Cbz
R1
R
N
11h: R = Bn, R1 = H : 61%
11i: R = Me, R1 = Br: 90%
R1 = dmTroc : 51%
R1 = C(O)SEt : 71%
Me
OMe
Me
Me
N
Ac
Me
Me
Me
Me
N
N
N
O
N
N
N
N
N
S
Ac
Ac
MeO2C
Boc
Ph
Me
11l
64%
Ac
Me
11j
72%
ASSOCIATED CONTENT
Supporting Information
11k
61%
11m
51%
11n
38%
R
Me
Me
Ac
R
R
Me
N
N
N
Ac
Me
Ac
The Supporting Information is available free of charge on the
ACS Publications website.
N
R1
R1
R
11o: R = OMe, R1 = H : 47%
11p: R = H, R1 = OMe : 38%
11q
11r: R = Me, R1 = CO2Me : 21%
11s: R = OMe, R1 = Ac : 50%
11t
63%
1
Experimental procedures, H and 13C NMR spectra, DFT cal-
79%
Modification of ergot derivatives
Br
Br
culations (PDF).
N
O
N
O
Ph
Ph
O
O
AUTHOR INFORMATION
O
O
HN
O
HN
O
Me
H
Me
H
Me
H
Me
H
N
N
N
N
Corresponding Author
MeO
MeO
H
H
* daniele.leonori@manchester.ac.uk
Me
Me
N
Ac
N
Ac
N
N
N
N
Author Contributions
Me
nicergoline
Me
11u
77%
Me
metergoline
Me
11v
57%
‡These authors contributed equally.
We then looked at the aromatic unit and extended
the scope of this reaction to N-Bn and 5-Br-N-Me-
indole (11h–i) azaindole (11j), pyrroles (11k–l), furan
(11m), thiophene (11n), naphthalenes (11o–p), an-
thracene (11q), mesitylene (1r), trimethoxybenzene
(1s) and azulene (11t). As electron rich heteroaromat-
ics constitute the core of many natural products and
ACKNOWLEDGMENT
We thank Dr. J. Douglas, S. G. Booth, Dr. M. Simonetti, Prof.
M. Bickelhaupt and Prof. T. Poisson for useful discussions.
D.L. thanks the European Union for a Career Integration
Grant (PCIG13-GA-2013-631556), Unesco-IUPAC-PhosAgro
for a research grant (4500284613), AstraZeneca for a PhD
Case Award to D.F.R. and the School of Chemistry at the
University of Manchester for generous support.
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R2
R1
O
R3
hydroamination
N
Ar
X
(π*+σ*)
R1
O
electrophore
29 examples
N
weak bond
O
R
transition
metalꢀfree
aryloxyamides
ꢀ easyꢀtoꢀmake
R1 = alkyl, Boc, Cbz
ꢀ
Ar
Nꢀarylation
R1
N
O
R
22 examples
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