Photoinduced Remote Functionalization of Amides and Amines Using Electrophilic Nitrogen Radicals

Article abstract of DOI:10.1002/anie.201807941

The selective functionalization of C(sp³)?H bonds at distal positions to functional groups is a challenging task in synthetic chemistry. Reported here is a photoinduced radical cascade strategy for the divergent functionalization of amides and protected amines. The process is based on the oxidative generation of electrophilic amidyl radicals and their subsequent transposition by 1,5-H-atom transfer, resulting in remote fluorination, chlorination and, for the first time, thioetherification, cyanation, and alkynylation. The process is tolerant of most common functional groups and delivers useful building blocks that can be further elaborated. The utility of this strategy is demonstrated through the late-stage functionalization of amino acids and a dipeptide.

Full text of DOI:10.1002/anie.201807941

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Photoinduced Remote Functionalization of Amides and Amines
Using Electrophilic Nitrogen-Radicals
Authors: Sara P. Morcillo, Elizabeth M. Dauncey, Ji Hye Kim, James J.
Douglas, Nadeem S. Sheikh, and Daniele Leonori
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807941
Angew. Chem. 10.1002/ange.201807941
Link to VoR: http://dx.doi.org/10.1002/anie.201807941
http://dx.doi.org/10.1002/ange.201807941

10.1002/anie.201807941
Angewandte Chemie International Edition
COMMUNICATION
Photoinduced Remote Functionalization of Amides and Amines
Using Electrophilic Nitrogen-Radicals
Sara P. Morcillo,[a]# Elizabeth M. Dauncey,[a]# Ji Hye Kim,[a] James J. Douglas,[b] Nadeem S. Sheikh[c]
and Daniele Leonori*[a]
Abstract: The selective functionalization of sp3 C–H bonds at distal
positions to functional groups is a challenging task in synthetic
chemistry. Here we report a photoinduced radical cascade strategy
for the divergent functionalization of amides and protected amines.
The process is based on the oxidative generation of electrophilic
amidyl radicals and their following transposition via 1,5-HAT
resulting in remote fluorination, chlorination and, for the first time,
thioetherification, cyanation and alkynylation. The process is tolerant
of most common functional groups, and delivers useful building
blocks that can be further elaborated. The utility of this strategy is
demonstrated through the late-stage functionalization of aminoacids
and a dipeptide.
We and the group of Studer have recently developed a reaction
for the oxidative generation of iminyl radicals and the following
1,5-HAT–functionalization (Scheme 1B).[15] In our hand this
process enabled γ-chlorination and γ-fluorination but was only
feasible on tertiary centres, thus limiting the synthetic
applicability to a narrow range of substrates. In this paper we
demonstrate how changing the nature of the nitrogen radical to
amidyl and N-protected aminyl radicals unlocks distal
functionalizations of amides, carbamates and amines (Scheme
1C). This methodology targets tertiary, secondary and even
primary centres and has been applied to five different
functionalizations spanning distal C–X (X = heteroatom) and C–
C bond formation.
The selective functionalization of sp3 C–H bonds is a long
sought-after goal in synthetic chemistry.[1] In general, when a
directing group is present, products of α- and β-functionalization
are easy to access through ionic (e.g. enolate chemistry, 1,4-
addition) and transition metal-mediated reactivity (e.g. directed
metallation) (Scheme 1A). Targeting more distal positions, such
as the γ and δ, is more difficult.[2] One way of achieving this is to
use nitrogen radicals harnessing their ability to undergo
transposition processes by 1,5-H atom transfer (1,5-HAT).[3] This
reactivity constitutes the key step of the name reaction
developed by Hoffman and Löffler[4] and has been pioneered in
classical radical processes by Forrester,[5] Minisci,[6] Suarez[7]
and others.[8] More recently, the advent of visible-light
photocatalysis[9] has propelled the development of milder ways
for exploring this reactivity. For example, Muñiz[10] has identified
an array of protocols for the preparation of nitrogen heterocycles
using catalytically generated N–I and N–Br amides. Nagib[11] has
used N–I imine-type derivatives to access 1,2-amino-alcohols
and Nevado[12] has employed electron poor O-acyl oximes in the
assembly of tetralones. Most relevant here is the work of
Knowles[13] and Rovis[14] which, through proton-coupled electron
transfer, have generated amidyl radical from amides and
developed cascades based on 1,5-HAT and following radical
addition to Michael acceptors.
A) Functionalization of sp3 C–H bonds (DG = directing group)
DG
DG
β
DG
DG
X
FG
δ
R
R
R
R
R
X
α
γ
X
X
ionic and transition metal reactivity
radical reactivity
B) Previous work: γ-chlorination and γ-fluorination of tertiaty centres via iminyl radicals
Me
Me
CO2H
selectfluor or NCS
O
Cs2CO3
N
O
NCl
Mes-acridinium
γ
γ
γ
R1
R1
R2
R1
and
R
R
R
blue LEDs
F
Cl R2
R2
C) This work: remote functionalizations of amides and amines
R
OR
R
R
N
NH
NH
δ
γ
R1
R1
R2
R1
and
O
X
O
X
R2
X
X
R2
δ-functionalization
• 5 different functionalizations • amenable to tertiary, secondary and primary centres
γ-functionalization
Scheme 1. A) Ionic versus radical reactivity for the functionalization of sp3-C–
H bonds. B) γ-Fluorination and chlorination of tertiary centres via 1,5-HAT of
iminyl radicals. C) γ- and δ-Functionalizations via 1,5-HAT of amidyl radicals.
At the outset of our work, we surmised that to achieve efficient
1,5-HAT–functionalization cascades at room temperature, both
enthalpic and polar effects had to be maximized.[16] We therefore
turned our interest towards the use of amidyl radicals because of
their high electrophilic character[17] and the strong N–H bonds of
the corresponding amides. These properties were expected to
[a]
Dr. Sara P. Morcillo, Elizabeth M. Dauncey, Dr. Ji Hye Kim and Dr.
D. Leonori
synergistically render the reaction exothermic (ΔGº
< 0;
School of Chemistry, University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: daniele.leonori@manchester.ac.uk
Homepage: http://leonoriresearchgroup.weebly.com
Dr. J. J. Douglas
Early Chemical Development, Pharmaceutical Sciences
IMED Biotech Unit, AstraZeneca
Macclesfield SK10 2NA (UK)
Prof. N. S. Sheikh
Department of Chemistry, Faculty of Science
King Faisal University
P.O. Box 380, Al-Ahsa 31982 (Saudi Arabia)
These authors contributed equally to the work.
enthalpic contribution) and lower the activation barrier (ΔG‡;
polar effects contribution). To obtain more information on these
aspects, we have conducted computational studies on a range
of model 1,5-HAT processes spanning amidyl, carbamoyl, N-Ts-
aminyl and iminyl radicals (Scheme 2A).[18] For example, while
1,5-HAT of iminyl radical A is endothermic, amidyls (B, C and E)
and N-Ts-aminyl radical D are ought to undergo exothermic
abstraction of H-atoms on tertiary, secondary and even primary
positions. Indeed, a good correlation was found between the
variation of bond dissociation energies (BDEs)[19] between the
[b]
[b]
#
incipient N–H bond and the γ-sp3 C–H bond (δBDE = BDEN–H
BDEC–H) and the ΔGº of the processes. Correlation between the
–
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807941
Angewandte Chemie International Edition
COMMUNICATION
δBDE and the activation barrier for 1,5-HAT (ΔG‡) was less
obvious but a clear trend was observed within the amidyl series
(γ-abstractions, light blue squares). The high exothermicity
characterizing these reactions means that early transition states
are likely operating[20] which makes the reaction parameters
sensitive to polar effects. Indeed, a good correlation between
the nitrogen-radical electrophilicity indeces (ω+rc) and both ΔGº
and ΔG‡ was observed. These results make the evaluation of
this parameter of relevance when planning similar reactions.
Our mechanistic proposal was centered on a photoredox cycle
generating an amidyl (or an N-protected aminyl) radical (G) via
SET oxidation and fragmentation of the precursor F (Scheme
2B). At this point, enthalpy-favorable 1,5-HAT would deliver the
distal radical H, which should display nucleophilic character.
Homolytic atom/group-transfer (e.g. SH2 reaction) with
a
polarized SOMOphile (X–Y) would furnish the targeted amides
and protected amines I as well as the electron poor radical Y•
that ought to close the photoredox cycle by SET with the PC•–.[21]
A) DFT studies
ω+rc : nitrogen radical electrophilicity scale (eV)
0.7
Me
0.8
0.9
1.0
1.1
1.2
1.3
1.4
Me
Me
Ts
H
O
N
N
N
N
N
H
H
H
H
H
Me
Me
H
Me
Me
O
O
Me
Me
Me
Me
Me
A
B
C
D
E
BDEC–H 95.6
BDEN–H 93.2
95.4
107.1
–10.9
8.8
98.0
93.8
98.8
–6.1
9.3
95.3
107.7
–8.3
11.1
113.9
–16.6
5.7
ΔGº
ΔG‡
4.2
13.7
B) Proposed mechanism
hν
R
O
I
Y
NH
PC
γ
R2
R1
X
SET
X
SH2
Y•
amides
*PC
PC•–
X
Y
R
NH
δ
R2
R1
R
O
NH
SET
R2
X
X
Me
Me
– CO2
– acetone
amines
CO2H
H
R1
R
O
R
O
N
N
H
R2
R2
1,5-HAT
O
X
X
G
R1
R1
F
Scheme 2. A) DFT studies on the 1,5-HAT of nitrogen-radicals and correlations with the reaction parameters (ΔGº and ΔG‡). B) Proposed mechanism for the
divergent remote functionalization of amides and amines.
Initial efforts focused on the development of γ-fluorinations using
amide 1a, which was prepared on gram scale (Scheme 3).[18]
Pleasingly, blue LEDs irradiation of 1a, Fuzukumi’s acridinium
(2a) as the photocatalyst (*Eox = +2.1 V vs SCE),[22] selectfluor[23]
(3a) as the SOMOphile, Cs2CO3 as the base in CH3CN–H2O
gave the desired product 4 in 36% yield (entry 1). By changing
the photocatalyst to the more chemically robust Ir(III) complex
2b the yield was improved to 87% (entry 2). Using NCS (3b) as
the SOMOphile, we developed a γ-chlorinating process (5). Also
in this case, the use of photocatalyst 2b led to better results than
2a (entries 3 and 4), and the organic dye 2c was identified as
optimum for this transformation (entry 5). A similar trend in
photocatalyst-based efficiency was observed for the γ-
thioetherification using the S-donor 3c, which lead to the
formation of 6 in high yield (entries 6–8). Finally, by employing
the IBX-reagents 3d[24] and 3e,[25] in the presence of 2c as the
photocatalyst, we developed cascade reactions resulting in sp3
γ-cyanation (7) and γ-alkynylation (8). It is worth mentioning that
while the γ-fluorination of amides has been developed using Fe-
catalysts,[26] and γ-chlorinations have been reported using N-Cl-
amides via radical chain propagations,[27] γ-thioetherification, γ-
cyanation and γ-alkynylation are, to the best of our knowledge,
unprecedented.
In order to obtain mechanistic insights we conducted
luminescence-quenching studies (Stern-Volmer analysis) which
showed that 1 (as its Cs salt) quenches all three photocatalysts
2a–c at significant higher rates than all the other SOMOphiles
3a–e.[18] Quantum yields (Φ) were determined for all optimized
reactions (Scheme 3). The very low values obtained in these
studies suggest that mechanisms based on radical chain
propagations (dark reactivity) should not account for the full
reaction productivity thus corroborating our proposed
mechanism.[18]
We then evaluated the scope for this divergent functionalization
strategy using a host of functionalized amides and N-protected-
amines (1a–z and 1aa–ae) (Scheme 4). In accordance with our
computational studies, we were able to perform γ-fluorination at
tertiary (4) and both secondary alkyl (9) and benzylic (10)
positions. The process could also be expanded to γ-terminal
centres via the generation of a primary radical albeit in lower
yield (11). The N-substitution was also evaluated and we
successfully engaged amide precursors with a removable N-Bn
This article is protected by copyright. All rights reserved.

10.1002/anie.201807941
Angewandte Chemie International Edition
COMMUNICATION
group (12) as well as an unprotected substrate, which gave the
corresponding fluorinated primary amide 13 in good yield.
successful on secondary alkyl centres. The functionalization of γ-
secondary benzylic and primary positions was in general less
efficient.
X–Y (2–3 equiv.)
PC (5 mol%), Cs2CO3 (1.0 equiv.)
The possibility of using SOMOphile 3b–e to obtain δ-
functionalized amines was evaluated next and found feasible in
good to moderate yields (38, 39 and 41) with the exception of
the cyanation process (40) that consistently resulted in complex
mixtures.
Me
OR
Me
N
NH
Me
R = Me
CO2H
Me
Me
X
O
O
solvent, r.t., o/n
blue LEDs
Me Me
1a
4–8
Φ
Entry
X–Y
Cl
PC
Solvent
Yield (%)
Product
Me
More structurally diverse starting materials were then evaluated
with the intention of accessing complex building blocks and
obtain information on the functional groups compatible with the
process. We were able to selective functionalise unsymmetrical
tertiary centres (42–44), as well as γ-carbons embedded into
cyclic motifs like the rigid norbornene (45–49) and the
cyclopentyl-ring (50–53). This procedure also streamlined
access to several C–4 functionalized N-Boc-piperidines (54–57)
that are valuable building blocks with frequent applications in
medicinal chemistry.[30] The successful formation of 58–61
showed that alkyl halides as well as protected alcohols are
tolerated, thus giving access to products with handles for further
functionalization.
Strategies for the selective modification of natural aminoacid
side chains are a valuable tool to access novel and high value
chemotypes.[31] In general, this is achieved by oxidation followed
by stepwise functionalization and several strategies based on
selective H-atom abstraction have been reported.[16, 32] Using a
range of differentially protected leucine derivatives we were able
to perform γ-fluorination (62–64) and γ-alkynylation (65). The γ-
fluorination could also be achieved on an unprotected substrate
(66) albeit in low yield. The successful γ-alkynylation might have
applications given the importance of preparing side chain-
modified aminoacids with functional groups that undergo click
type reactions like azide-alkyne cycloaddition and thiol-yne
reaction.[33] Pleasingly, this strategy could be extended to the
selective late-stage modification of L-isoleucine (67, 68) and L-
lysine (69), which normally give isomeric-mixture under other
protocols. Finally, the L-leucine γ-functionalizations was also
expanded to a dipeptide building block (70, 71) in good yield.
In conclusion, we have developed a divergent strategy for the
selective functionalization of amides, carbamates and amines at
distal positions. The methodology involves the photoinduced
SET oxidation of α-oxiamido acids to generate electrophilic
amidyl radicals. Through a cascade of 1,5-HAT and SH2-
functionalization, fluorine, chlorine, SPh, cyano and alkyne
functionalities can easily be installed. Applications to the
selective modification of aminoacids and a dipeptide highlight
the compatibility of this approach to medicinal chemistry-relevant
motifs.
NH
NH
N
1
2
2a CH3CN–H2O
36
F
N
O
2b CH3CN–H2O
87
0.08
(BF4)2
3a
F
Me Me
4
O
Me
3
4
5
2a
2b
2c
CH3CN
CH3CN
CH3CN
39
55
76
N
Cl
Cl
O
Me Me
0.06
0.02
O
3b
5
O
Me
NH
NH
NH
6
7
8
2a
2b
2c
CH2Cl2
CH2Cl2
CH2Cl2
32
69
71
N
SPh
SPh
O
Me Me
O
3c
6
O
Me
O
I
CN
9
2a
2b
2c
CH2Cl2
CH2Cl2
CH2Cl2
42
21
97
CN
Me Me
10
11
O
0.02
0.06
7
3d
O
Me
O
Ph
I
Ph
12
2c
CH2Cl2
80
O
Me Me
8
3e
2a: Mesityl acridinium (ClO4); 2b: Ir[dF(CF3)ppy]2(dtbpy)(PF6); 2c: 4CzIPN
Scheme 3. Optimization of the divergent radical functionalization strategy
using 1a.
The possibility to engage carbamoyl radicals was investigated
next but in this case, the reaction was found feasible only on a
tertiary centre (14 vs 15).
As further element of substrate scope investigation, we
evaluated the development of δ-fluorination of N-protected
amines. We quickly discovered that commonly used N-
protecting groups like Cbz (16), Boc (17) and Ts (18) were
compatible and provided the desired δ-fluoro amines in good
yields.[28] The process was also extended to the functionalization
of δ-secondary alkylic (19), benzylic (20) as well as primary
centres (21).
In general, 1,5-HAT processes are favoured over 1,6-HATs due
to their optimum chair-like six-membered cyclic transition state.
Nevertheless, 1,6-translocations could be efficiently achieved by
providing an enthalpic bias to the system.[20, 29] As demonstrated
by the formation of 22 and 23, there is a preference for 1,6-HAT
when this position is a tertiary centre. This is in line with an
energetically more favourable reaction profile: ΔΔGº(1,6tert
–
Acknowledgements
1,5sec) = –4.7 kcal mol–1 and ΔΔG‡(1,6tert – 1,5sec) = –2.4 kcal
mol–1.[18] The increased chain flexibility of N-Boc-amine however,
resulted in mixtures of 1,5- (δ) and 1,6-(ε)-fluorination (24).
The γ-chlorination (5, 25–28), γ-thioetherification (6, 29–31), γ-
cyanation (7, 32, 33) and γ-alkynylation (8, 34–37) were also
attempted on the same precursors and, much to our liking, were
D. L. thanks the Leverhulme Trust for a research grant (RPG-
2016-131), EPSRC for a Fellowship (EP/P004997/1) and the
European Research Council for a research grant (758427). E. D.
thanks AstraZeneca for a PhD CASE Award. N. S. S. thanks the
support from the Deanship of Scientific Research, King Faisal
University.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807941
Angewandte Chemie International Edition
COMMUNICATION
Me
Me
Starting Materials
CO2H
F
Cl
SPh
CN
R1
1a: Me CH2 Me Me 1g:
X
R2 R3
R1
H
X
R2
CH2 Me
R3
Me
Me
H
i-Pr
i-Pr
photocatalyst (5 mol%)
K2CO3 or Cs2CO3 (1.0 equiv.)
R
O
NH
R1 OR
N
R
O
R1
R2
N
+
X
Y
1b: Me CH2 Me
1c: Me CH2 Ph
H
H
H
1h: Me
1i: Me
1j: Me CH2
O
O
Me
Me
H
X
R1
r.t.
R2
O
X
X
blue LEDs
O
X
Ph
1d: Me CH2
H
R2
R3
1e: Me CH2 n-Bu Me 1k: Me
1f: Bn CH2 Me Me 1l: Me CH2 Me CH2CH2Br
O
n-Bu
1a–z, 1aa–ae
4–71
R1
R2 R3
Me Me
Me Me
Me Me
R1
OAc
NPhth
1z: N(Boc)Me
1aa: NHCbz
R2
R1
X
O
O
R2
1m: Cbz
1n: Boc
1o: Ts
1p: Boc
1q: Boc
1r: Boc
1s: Boc
R1
1x:
1y:
R2
Me
R1 OR
N
Me
OR
R1 OR
N
N
Me
Me
1u: Me
R2
R2
NHCbz
NHCbz
Me
Me
Ph
H
H
H
H
1ad:
1ae:
O
OR
X
R2 1v: Me
1w: Boc CH2
O
N
1ab:
NH2
1ac: NHGly
R1
R3
N
Boc
( )4
NHCbz
1t
Me
H
i-Pr
Substrate Scope
R1 R2 Yield (%)
R
X
R1 R2 Yield (%)
R
4: Me CH2 Me Me
87
67
72
16
72
63
66
–
R
O
R
Me
Me
Boc
NH
NH
NH
NH
NH
F
Me
Me
F
Me
Me
F Me
Cbz Me Me
Boc Me Me
Ts Me Me
72
68
61
85
68
30
9: Me CH2 Me
10: Me CH2 Ph
H
H
H
16:
17:
18:
19:
20:
21:
R1
R1
R2
X
O
O
O
Me
ε
δ
δ
11: Me CH2
H
F
R2
F
Boc Me
Boc Ph
H
H
H
12: Bn CH2 Me Me
13: CH2 Me Me
22
71%
23
59%
24
86%
16–21
4, 9–15
H
Boc
H
14: Me
15: Me
O
O
Me Me
Me
1,5:1,6 = 1:1
H
R
R1 R2 Yield (%)
R
R1 R2 Yield (%)
R
O
R
R
O
R
R1 R2 Yield (%)
NH
NH
NH
R1
R1
R1
NC R2
7, 32, 33
5: Me Me Me
25: Me Me
26: Me Ph
27: Me
28: Bn Me Me
75
42
–
11
52
6: Me Me Me
29: Me Me
30: Me Ph
71
55
38
10
O
H
H
H
7: Me Me Me
32: Me Me
33: Me Ph
97
37
–
H
H
H
Cl R2
5, 25–28
PhS R2
6, 29–31
H
H
H
31: Me
H
R
R1 R2 Yield (%)
X
R
Yield (%)
R
R
Me
X
Yield (%)
NH
NH
NH
R1
Me
Me
8: Me Me Me
80
65
–
30
28
38: Cbz
39: Boc
40: Cbz
41: Cbz
Cl
SPh
CN
73
44
–
O
O
Me
34: Me Me
35: Me Ph
H
H
42:
43:
44:
F
Cl
SPh
68
51
39
R2
8, 34–37
X
X
Me
36: Bn Me Me
38–41
NH
42–44
Ph 52
Ph
37:
H
Me Me
Yield (%)
X
dr
X
Yield (%)
Me
Me
O
NH
X
Yield (%)
X
45:
46:
47:
48:
49:
F
Cl
SPh
CN
71
45
49
41
44
10:1
10:1
20:1
20:1
3:1
50:
51:
52:
53:
F
Cl
67
50
73
O
N
Boc
Me
X
X
54:
55:
F
59
Ph 79
O
N
H
SPh
50–53
54, 55
Ph 76
45–49
Ph
Me
Me
F
Me
F
Me F
Boc
Me
X
Yield (%)
NH
NH
Me
Me
X
F
Yield (%)
H
H
N
H
Br
N
Boc
N
N
Boc
O
AcO
Me
NPhth
Me
N
Me
58:
59:
60:
F
Cl
37
58
Ph 58
X
56:
57:
58
44
X
O
O
Me
O
Cl
56, 57
58–60
61
89%
62
63
40%
37%
Me
Me
F
Me Me
Me
Me
F
Me
F
Me Me
Me
Me
F
Me
Me Cbz
H
N
H
N
Me
F
N
H
N
H
H
H
H
H
Ph
H
Cbz
Ph
N
N
Cbz
N
Ph
N
Cbz
N
HN
Me
HN
Me
H
H
N
H
Me
Cbz
N
Me H2N
Me
N
Me
Cbz
N
H
Me
N
H
Me
Cbz
N
O
N
O
H
H
O
O
O
O
O
O
O
Cbz
O
64
56%
65
47%
66
13%
67
39%, 3:2 dr
68
54%, 2:1 dr
69
70
52%
71
65%
25%, 1:1 dr
Scheme 4. Substrate scope for the divergent remote functionalization of amides and amines.
Keywords: remote functionalization • photoinduced • nitrogen
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