A case of chain propagation: α-aminoalkyl radicals as initiators for aryl radical chemistry

Article abstract of DOI:10.1039/d0sc04387g

The generation of aryl radicals from the corresponding halides by redox chemistry is generally considered a difficult task due to their highly negative reduction potentials. Here we demonstrate that α-aminoalkyl radicals can be used as both initiators and chain-carriers for the radical coupling of aryl halides with pyrrole derivatives, a transformation often employed to evaluate new highly reducing photocatalysts. This mode of reactivity obviates for the use of strong reducing species and was also competent in the formation of sp2 C-P bonds. Mechanistic studies have delineated some of the key features operating that trigger aryl radical generation and also propagate the chain process.

Full text of DOI:10.1039/d0sc04387g

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DOI: 10.1039/D0SC04387G
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A Case of Chain Propagation: -Aminoalkyl Radicals as Initiators
for Aryl Radical Chemistry
Timothée Constantina, Fabio Juliáa, Nadeem S. Sheikhb, and Daniele Leonori*a
Received 00th January 20xx,
Accepted 00th January 20xx
The generation of aryl radicals from the corresponding halides by redox chemistry is generally considered a difficult task due
to their highly negative reduction potentials. Here we demonstrate that -aminoalkyl radicals can be used as both initiators
and chain-carriers for the radical coupling of aryl halides with pyrrole derivatives, a transformation often employed to
evaluate new highly reducing photocatalyst. This mode of reactivity obviates for the use of strong reducing species and was
also competent in the formation of sp2 C–P bonds. Mechanistic studies have delineated some of the key features operating
that trigger aryl radical generation and also propagate the chain process.
DOI: 10.1039/x0xx00000x
of sequentially absorbing two photons,17 both in combination
with excess of amines as sacrificial electron donors.
An alternative approach for aryl radical generation involves the
homolytic sp2 C–X bond cleavage via halogen-atom transfer
(XAT) which has historically been achieved using tin radicals.18
Strategies based on silicon radicals19 have circumvented the use
of toxic tin hydrides and more recently have been successfully
exploited in metallaphotoredox manifolds, retrieving an
increasingly renewed interest.20
Introduction
Aryl radicals are versatile synthetic intermediates for the
assembly of sp2 C–C and C–Y (Y = heteroatom) bonds.1 Reactions
like the Meerwein cyclization and arylation,2 the Pschorr
cyclization3 and the Gomber-Bachmann biphenyl synthesis4 are
text-book examples of aryl radical reactivity and are still used in
the assembly of high-value materials.5
Historically, aryl radicals have been generated by SET (single-
electron transfer) reduction of aryl diazonium,6 iodonium7 and
sulfonium salts8 or oxidation of benzoates9 (Scheme 1A).
Despite their synthetic versatility, these substrates can
sometimes be difficult to prepare or unstable or they might
require forcing reaction conditions which has somewhat limited
their application especially on large-scale settings.10
Aryl halides are a large class of stable and commercial building
blocks, which are routinely used in synthetic chemistry through
transition-metal-catalysed cross-coupling reactions. Aryl radical
generation by SET reduction followed by heterolytic sp2 C–X (X
= halogen) bond fragmentation is feasible for substrates
containing electron withdrawing groups (e.g. CN, NO2…) but
challenging for electron neutral/rich ones owing to their highly
negative reduction potentials (Ered < –2 V vs SCE). Nevertheless,
recent work based on electrochemistry,11 sulfoxylate radical
anion chemistry,12 organic super electron donors13 and photo-
electro-chemistry14 has successfully addressed some of these
issues. Within the field of visible-light photoredox catalysis,15
targeting such negative reduction potentials has been tackled
using homoleptic Ir(III)-photocatalysts16 and organic dyes able
a. Department of Chemistry, University of Manchester, Manchester M13 9PL, UK. E-
mail: daniele.leonori@manchester.ac.uk. Homepage:
Scheme 1. Most common approaches for aryl radical generation
and this work.
https://leonoriresearchgroup.com
b. Department of Chemistry, College of Science, King Faisal University, P. O. Box 400,
Al-Ahsa 31982, Saudi Arabia.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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We have recently demonstrated that generating -aminoalkyl photocatalyst (either in the photoexcited or the reduced state)
View Article Online
radicals from alkylamines (A  B) under photoredox catalysis triggers the SET reduction of the DOIa:r1y0l.10h39a/lDid0eS,C04w3h87ilGe
represents an effective gateway to access alkyl and aryl radicals stoichiometric amounts of amines are employed as sacrificial
from the corresponding halides (Scheme 1B).21 In this reactivity, reductants. In general, the absence of the amine completely
the highly nucleophilic -aminoalkyl radical B homolytically switches off the reactivity and other types of electron donors
activates the sp3 or sp2 C–X bond by XAT (B + C  E) through a are either not discussed or not feasible. We were therefore
polarised transition state (D) stabilised by extensive charge intrigued by the possibility of establishing a mechanistically
transfer character.
alternative approach where -aminoalkyl radicals and XAT
As part of our ongoing interest in exploring this activation mode, deliver the key aryl radicals thus bypassing the need for strongly
we recently questioned if -aminoalkyl radical-mediated XAT reducing photocatalysts. Herein we report the successful
could be leveraged to enable divergent arene functionalization implementation of this proposal which demonstrates how
under photoredox conditions. Our interest was mainly focused photoredox catalysis and -aminoalkyl radical chemistry can be
on the radical coupling of aryl halides with pyrrole derivatives, used to generate and explore the reactivity of aryl radicals in
a benchmark transformation often used to assess the reductive chain propagating manifolds (Scheme 1C).
ability of new photoredox catalysts.22 In these examples, the
B) A photoredox manifold is non-redox neutral
A) Initial results demonstrating a photoredox C–H arylation via XAT
h
N
4CzIPN (5 mol%)
n-Bu3N (2.0 equiv.)
K2HPO4 (2.0 equiv.)
4CzIPN
Me
Ac
3
I
N
+
N
DMSO–H2O (10:1, 0.1 M)
r.t., 16 h, blue LEDs
Me
Me
2
(50 equiv.)
Ac
(1.0 equiv.)
Ac
reductive-quenching
photoredox cycle
*4CzIPN
both steps
require SET oxidation
– non-redox neutral –
1
3
xx%
– H+
SET
SET
C) -Aminoalkyl radicals initiated C–H arylation based on a radical-chain
n-Bu3N
2
4CzIPN•–
SET
– H+
N
Me
Ac
E2
n-Bu
n-Bu
radical chain
propagation
n-Pr
N
n-Pr
N
N
1
N
n-Bu
B1
n-Bu
Me
2
Ac
Ac
Me
E1
Ac
E1
B1
initiation by XAT
E2
XAT
extended
aminoalkyl radical
I
XAT
or
I–
N(n-Bu)2
I
n-Pr
N(n-Bu)2
n-Pr
SET
Ac
1
F1
G1
3
1
D) Experimental results supporting -aminoalkyl radical-mediated XAT as initiation mechanism
photocatalyst (5 mol%)
electron donor (2.0 equiv.)
OH
I
O
HO
N
+
O
N
Me
Me
Me
Me
N
N
Me
Me
Me
Me
N
K2HPO4 (2.0 equiv.)
DMSO–H2O (10:1, 0.1 M)
r.t., 16 h, blue LEDs
Me
N
H
Me
2
(50 equiv.)
R
R
H
Me
R = Ac: 1
R = Ac: 3
R = OMe: 5
NaO
Na-ascorbate
OH
R = OMe: 4
(1.0 equiv.)
TMP
PMP
DABCO
electron donor = n-Bu3N
E(PC•+/*PC) E(PC/PC•–
photocatalyst = 4CzIPN
Eox
)
Yield for Yield for
Electron
Donor
kq (*4CzIPN) Yield for Yield for
(107 M–1 s–1
)
(V vs SCE)
3 (%)
5 (%)
3 (%)
5 (%)
Entry
Photocatalyst
(V vs SCE)
(V vs SCE)
Entry
+0.71
–0.19
+1.01
+0.98
+0.78
+0.69
60
66
61
73
52
37
56
56
n-Bu3N
Na-ascorbate
(i-Pr)2NH
TMP
60
traces
64
58
–
1
2
3
4
5
6
4CzIPN
Ir[dF(ppy)]3
–1.04
–1.46
–0.89
–0.81
–1.58
–1.55
–1.21
–2.11
–1.37
–1.33
–1.08
–1.22
7
8
8
26
6
[Ir(dF(CF3)ppy2)(dtbbpy)]PF6
[Ru(bpy)3](PF6)2
eosin Y
39
9
45
30
18
–
10
11
12
7
traces
6
PMP
38
50
106
214
fluorescein Na salt
DABCO
traces
traces
Scheme 2. (A) Initial results on the radical addition of iodide 1 to pyrrole 2. (B) Mechanistic analysis of a photoredox manifold reveals a redox
imbalance. (C) Mechanism based on a radical-chain propagation. (D) Control experiments supporting initiation by -aminoalkyl radicals.
demonstrating that coupling between 4-acetyl-iodobenzene
with N-Me-pyrrole (1 + 2  3) was efficiently achieved using
4CzIPN as the photocatalyst, n-Bu3N as the amine and KH2PO4
Results and Discussion
Mechanistic Considerations.
as the base in DMSO–H2O under blue light irradiation (Scheme
2A). We were initially puzzled by this experimental outcome as
we recognized an inherent chemical reactivity issue that should
have thwarted product formation. As shown in Scheme 2B, the
reductive-quenching photoredox cycle required for -
We initially questioned whether photoredox catalysis could be
used to generate -aminoalkyl radicals to enable C–H arylation
of electron rich heteroaromatics with aryl halides. Our interest
in exploring this reactivity stem from preliminary results
2 | J. Name., 2012, 00, 1-3
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aminoalkyl radical generation (n-Bu3N  B1) followed by XAT donors. Sodium ascorbate is a commonly used sacrificial
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(B1 + 1  E1 + F1) and radical addition to pyrrole (E1 + 2  E2) reductants in photoredox catalysis,25 but failed to provide
DOI: 10.1039/D0SC04387G
generates a redox imbalance as it requires the simultaneous products formation (Scheme 2D, entry 8). Other amines were
oxidation of 4CzIPN•– and the intermediate E2. This should evaluated and, while all efficiently quench *4CzIPN, they were
disfavour a mechanism based on a closed photoredox system successful as long as they contained -sp3 C–H bonds required
and, as a result, hamper catalysis.
for -aminoalkyl radical generation (Scheme 2D, compare
We therefore considered a different mechanistic scenario entries 9 and 11 with 10 and 12). Overall, these experimental
where photoredox catalysis would serve, through the results support the formation and the involvement of -
generation of B1, as initiation step for a radical-chain aminoalkyl radicals as the key element for the activation of the
propagating system (Scheme 2C).23 This proposed reactivity sp2 C–I bonds and the initiation of the radical-chain
hinged however on the ability of the electron rich 5-radical E2 propagation.
to regenerate the aryl radical E1 by reaction with 1. While this The Radical-Chain Propagation. In order to obtain more
mechanistic possibility has not been considered in the analysis information on the feasibility of the chain process two more
of previous radical arylation processes, we were intrigued by experiments were performed using iodide 1 and pyrrole 2
the fact that E2 is electron rich and, crucially, also an extended (Scheme 3A). Firstly, we evaluated the use of sub-stoichiometric
aminoalkyl radical. Hence, we postulated that it might be able amounts of amine and obtained efficient reactivity with as little
to participate in XAT (or SET) events with 1. Two major as 5 mol% n-Bu3N, while no reaction was observed when the
mechanistic aspects became a focal point: (1) which is the amine was omitted (Scheme 3A).24 Second, we decided to
species involved in the key C–X activation step and (2) whether identify photocatalyst-free conditions for aryl radical
a radical propagation pathway could be operative.
generation in order to exclude the presence of any potential
The Initiation Process. In order to confirm the key involvement reductant. We started evaluating several electron rich species
of -aminoalkyl radical-mediated XAT as initiation step we with the hope of forming an EDA (electron donor-acceptor)
conducted a series of control experiments using electron poor complex26 with 1 and identified Ph2NPMP (PMP = p-MeO-Ph),
4-acetyl-iodobenzene
1
and electron rich 4-methoxy- as optimum due to the appearance of an absorbance tail in the
iodobenzene 4 as model for electron poor and electron rich aryl visible range (max ~ 450 nm) in 6.24 In order to exclude a purely
iodides, respectively (Scheme 2D). (1) First of all, 4CzIPN was EDA-based photochemical reactivity, we performed this
chosen as photocatalyst because, in contrast to strongly reaction using 20 mol% of amine. In line with our mechanistic
reducing systems, it should not be able to promote direct SET hypothesis, blue light irradiation triggered a photoinduced SET
reduction of 1 and 4 (1: Ered = –1.64 V vs SCE and 4: Ered = –2.17 leading to the formation of the corresponding aryl radical E1.
V vs SCE)24 according to its reduced and excited-state oxidation This provided, through a chain-process, 3 in high yield. It is
potentials (Scheme 2D, entry 1). (2) In agreement with our important to note that this EDA-initiated radical coupling is
mechanistic hypothesis, any visible light-excited photocatalyst restricted to electron poor aryl iodides as demonstrated when
able to oxidise n-Bu3N (Eox = +0.71 V vs SCE) should enable attempting the coupling using electron rich iodide 4. In this
reactivity and indeed useful formation of 3 and 5 was obtained case, EDA complexation was not observed (even increasing the
with a broad range of systems (Scheme 2D, entries 2–6). (3) amounts of Ph2NPMP to 2.0 equiv.) which resulted in no
Further evidence for the key role of -aminoalkyl radicals as product formation.
initiators was obtained by replacing n-Bu3N with other electron
Scheme 3. (A) Impact of the n-Bu3N stoichiometry on the radical coupling between 1 and 2. (B) Radical couplings via EDA. (C) Computational
studies on key properties of -aminoalkyl radical (B1) and extended aminoalkyl radical (E2) and the thermodynamic feasibility of the chain
propagation step. PMP = p-OMe-C6H4.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0SC04387G
ARTICLE
The stabilised 5-radical E2 is the key intermediate enabling aryl functional groups such as free anilines (14) thus showcasing
radical regeneration in the proposed chain-propagating high chemoselectivity. The effect of the substituent position
process. As mentioned earlier, the reaction between E2 and an was also evaluated using meta- or ortho-substituted rings. Little
aryl iodide can be considered to go via XAT (or SET). To further difference in yields were observed for both meta- (15–18) and
support this hypothesis, we have conducted preliminary ortho-substituted (18, 19, 29 and 32) aryl halides in comparison
computational studies (Scheme 3C). Our results support the with their para-functionalised counterparts. Other aryl iodides
hypothesis that -aminoalkyl radical B1 and 5-radical E2 like 1- and 2-iodo-napthalenes, 2-iodo-pyrazine, 4-iodo-
should display similar reactivity by virtue of their very similar pyridine and 2-iodothiophenes were also suitable substrates for
electronic features. In particular, the close values obtained for the transformation giving 21–26 in moderate to good yields.
their ionization potential (IP), global electrophilicity (+rc) and Furthermore, the weaker nature of sp2 C–I bonds compared to
Hirshfeld charge (HC) demonstrate E2 is a highly nucleophilic sp2 C–Br/Cl bonds meant that aryl iodides could be selectively
radical that could therefore participate in XAT processes and functionalised in the presence of sp2 C–Br and C–Cl bonds (28
benefit from related polar effects in the transition state. It is and 29).
however important to note that due to the high-degree of This strategy was also extended to (hetero-)aryl bromides (8, 9,
charge transfer in XAT processes, a SET between E2 and the aryl 30 and 31) and even electron-rich aryl bromides (17) which are
iodide might be operative in the case of highly electron poor often challenging substrates. Consistently with the trend
systems (e.g. 4-NO2-iodobenzene). Moreover, the overall observed in the aryl iodide scope, electron-poor systems gave
reaction leading to the aryl radical regeneration (E2 + 1 + n-Bu3N higher yields than the electron-rich ones. Electron-deficient aryl
 3 + E1 + n-Bu3N•HI) was found to be feasible according to the chlorides were also tested and they could be engaged in this
exothermic Gº energy of this step.24
reactivity albeit in moderate conversions (8, 9 and 24).
Taken together, these experimental and computational results Having evaluated the scope around the aryl halide partner we
support the feasibility of a radical chain propagation as the decided to investigate other electron rich aromatics (Scheme
operating mechanism in these radical coupling reactions. 4B). o-CN-Iodobenzene displayed good reactivity with 2 (to give
Furthermore, we believe the ability of this -aminoalkyl 32) and could also be used for the C-2 arylation of unprotected
radicals-mediated strategy to activate both electron rich and pyrrole (33) as well as poly-substituted derivatives (34 and 35)
electron poor aryl iodides exemplifies its versatility as initiation including the highly-hindered cryptopyrrole. Furthermore, we
mode for aryl radical-based chain propagations.
also evaluated the possibility to render these reactions
In order to have more insights on the extent of the radical chain intramolecular, which was successfully achieved by preparing
propagation we determined the quantum yield for the reaction 36 that provided the tricyclic heterocycle 37.
between 1 and 2 to give 3 under standard conditions. This analysis While this approach enables the efficient C-2 arylation of
provided  = 0.37. Such a moderate value can be rationalised with pyrrole and its derivatives, we did not succeed in extending it to
the process being supported by either short-lived radical chain other electron rich heteroaromatics like furan (38) and
propagations or, as demonstrated by Scaiano,27 an inefficient thiophene (39). We were initially surprised by this lack of
initiation process.28
reactivity especially considering (1) the lower degree of
aromaticity of these systems29 and (2) their successful
engagement in radical arylations based on diazonium
precursors.30 We propose that these failed reactions are a clear
manifestation of the intrinsic reactivity difference between -N
vs -O/S-5-radical intermediates E vs H–J. The latter species
should be less nucleophilic and therefore radical-chain
propagation might now be hampered by their lower ability to
regenerate the key aryl radical by XAT/SET. Indeed,
computational analysis of H1,2 and J1,2 demonstrated their
attenuated nucleophilic character which is in line with our
working hypothesis (Scheme 4C).24, 31
Substrate Scope.
After identifying optimal reaction conditions, we explored the
scope of the transformation by evaluating different aryl halides
(Scheme 4A). Aryl iodides substituted with electron
withdrawing groups at the para-position reacted in good to high
yields (3, 7–11). More challenging electron-neutral substrates
as well as the ones equipped with electron-donating groups,
which are elusive in some redox-based approaches, reacted
well delivering the desired 2-aryl-pyrroles in good yields (11, 13
and 5). Pleasingly, the reaction was also tolerant of polar
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DOI: 10.1039/D0SC04387G
ARTICLE
A) Scope of the aryl halides
4CzIPN (5 mol%)
n-Bu3N (2.0 equiv.), TMG (2.0 eq.)
X
+
N
N
Me
Ar
Ar
DMSO–H2O (10:1, 0.1 M), r.t., 16 h
Me
blue LEDs
(1.0 equiv.)
(50 equiv.)
3, 5, 7–35, 37
examples using aryl iodides
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Ac
MeO2C
NC
OHC
O2N
Me
F
Me
3
73%
7
63%
8
71%
9
67%
10
70%
11
54%
12
55%
13
48%
Me
F
NC
F3C
MeO
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
MeO
H2N
5
58%
14
42%
15
77%
16
67%
17
48%
18
49%
19
38%
20
80%
CF3
Cl
S
S
N
N
Br
Ac
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
21
40%
22
57%
23
64%
24
73%
25
67%
26
64%
27
75%
28
65%
29
70%
examples using aryl bromides
examples using aryl chlorides
MeO
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
NC
OHC
N
NC
OHC
8
54%
9
42%
17
34%
30
44%
31
38%
8
33%
9
42%
24
37%
Cl
B) Examples using other electron rich aromatics
C) Radical properties
Et
Me
CN
Me
CN
R
R
R
CN
CN
N
S
Me
Me
O
N
N
N
H
N
H
H
Me
Me
32
65%
33
71%
34
75%
35
76%
E3
E4
H1
H2
J1
J2
R = H
R = CN
R = H
R = CN
R = H
R = CN
CN
CN
I
IP (eV)
+rc (eV)
HC
5.73
0.16
5.99
0.17
6.51
0.26
6.81
0.26
6.55
0.30
6.65
0.32
O
S
N
N
–0.039
–0.030
–0.021
–0.012
–0.012
–0.012
36
37
36%
38
traces
39
7%
Scheme 4. (A) Scope of the radical coupling between pyrrole 2 and aryl iodides, bromides and chlorides. (B) Scope of the heteroaromatics.
(C) Computational studies of different 5-radicals.
Expanding -Aminoalkyl Radicals Initiation to Phosphonylation.
initiate the sp2 phosphonylation of aryl halides with trialkyl
phosphites.17b, 22a, 33 We were hopeful that upon XAT-initiated
aryl radical generation and addition to the phosphite, the
Our current mechanistic understanding of these radical
arylations suggests that -aminoalkyl radical-mediated XAT can
serve as initiation step to access chain propagations where “in
cycle” aryl radical re-generation is possible. To test the validity
of this hypothesis, we decided to extend this concept to other
arene-functionalization processes. We were particularly
interested by recent reports demonstrating the ability of the
ethyl radical to act as chain carrier species.32 We therefore
decided to evaluate the ability of -aminoalkyl radicals to
resulting P-radical intermediate would undergo
a
thermodynamically driven -scission resulting in the formation
of a strong P=O bond and an ethyl radical that could continue
the chain propagation by reacting with the aryl halide.
Pleasingly, exposure of aryl iodides and several phosphites
[P(OEt)3, P(OMe)3 and P(Oi-Pr)3] to conditions identical to the
ones developed for pyrrole arylation provided the desired
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phosphonates 40–45 in good to moderate yield (Scheme 5). It is
worth mentioning that this reactivity enabled engagement of
both electron poor and electron rich substrates and could be
extended, albeit with lower chemical yields, to aryl bromides
and, in the case of substrates with electron withdrawing groups,
also to aryl chlorides.
Notes and references
View Article Online
DOI: 10.1039/D0SC04387G
1. G. Pratsch and M. R. Heinrich, Top. Curr. Chem., 2012, 320, 33-59.
2. (a) D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734-
4743; (b) A. L. J. Beckwith and G. F. Meijs, J. Org. Chem., 1987, 52,
1922-1930.
3. D. F. DeTar, in Organic Reactions, 2011, DOI:
10.1002/0471264180.or009.07, pp. 409-462.
4. Name Reactions: A Collection of Detailed Reaction Mechanisms,
Springer Berlin Heidelberg, Berlin, Heidelberg, 2006, DOI: 10.1007/3-
540-30031-7_118, pp. 267-268.
5. F.-X. Felpin and S. Sengupta, Chemical Society Reviews, 2019, 48,
1150-1193.
4CzIPN (5 mol%)
n-Bu3N (2.0 equiv.)
TMG (2.0 eq.)
O
P
OR
OR
X
+
P(OR)3
Ar
Ar
DMSO–H2O (10:1, 0.1 M)
r.t., 16 h
(1.0 equiv.)
(15 equiv.)
40–45
blue LEDs
6. (a) C. Galli, Chemical Reviews, 1988, 88, 765-792; (b) I. Ghosh, L.
Marzo, A. Das, R. Shaikh and B. König, Accounts of Chemical Research,
2016, 49, 1566-1577.
O
O
P
O
P
O
OEt
OEt
OEt
OEt
OEt
OEt
OEt
P
P
OEt
Ac
MeO
NC
7. (a) M. Hartmann, Y. Li, C. Mück-Lichtenfeld and A. Studer,
Chemistry – A European Journal, 2016, 22, 3485-3490; (b) D. Wang,
F. Szillat, J. P. Fouassier and J. Lalevée, Macromolecules, 2019, 52,
5638-5645.
8. Á. Péter, G. J. P. Perry and D. J. Procter, Advanced Synthesis &
Catalysis, 2020, 362, 2135-2142.
9. X.-Q. Hu, Z.-K. Liu, Y.-X. Hou and Y. Gao, iScience, 2020, 23,
101266.
10. (a) A. A. Bondarev, E. V. Naumov, A. Z. Kassanova, E. A.
Krasnokutskaya, K. S. Stankevich and V. D. Filimonov, Organic Process
Research & Development, 2019, 23, 2405-2415; (b) C. Schotten, S. K.
Leprevost, L. M. Yong, C. E. Hughes, K. D. M. Harris and D. L. Browne,
40
42
43
41
X = I : 99%
X = Br : 60%
X = Cl : 12%
X = I : 49%
X = Br : 35%
X = Cl : 36%
X = I : 98%
X = Br : 30%
X = I : 35%
O
P
O
OMe
OMe
Oi-Pr
P
Oi-Pr
44
90%
45
95%
Scheme 5. XAT-initiated radical chain phosphonylation of aryl
halides.
Conclusions
Organic Process Research
&
Development, 2020, DOI:
10.1021/acs.oprd.0c00162.
11. G. Sun, S. Ren, X. Zhu, M. Huang and Y. Wan, Org. Lett., 2016, 18,
544-547.
12. F. Yu, R. Mao, M. Yu, X. Gu and Y. Wang, J. Org. Chem., 2019, 84,
9946-9956.
13. (a) J. A. Murphy, S.-z. Zhou, D. W. Thomson, F. Schoenebeck, M.
Mahesh, S. R. Park, T. Tuttle and L. E. A. Berlouis, Angew. Chem., Int.
We have reported here that the photoredox generation of -
aminoalkyl radicals can be used as initiation step for the
development of aryl-radical-based chain propagations. This
approach by-passes the requirement for strongly reducing
photocatalysts if an appropriate chain-carrier radical species is
generated. In the case of the coupling with pyrroles, these
results point for a unique ability of -aminoalkyl radicals to Ed., 2007, 46, 5178-5183; (b) D. S. Lee, C. S. Kim, N. Iqbal, G. S. Park,
K.-s. Son and E. J. Cho, Org. Lett., 2019, 21, 9950-9953.
14. (a) H. Kim, H. Kim, T. H. Lambert and S. Lin, J. Am. Chem. Soc.,
2020, 142, 2087-2092; (b) N. G. W. Cowper, C. P. Chernowsky, O. P.
Williams and Z. K. Wickens, J. Am. Chem. Soc., 2020, 142, 2093-2099.
15. D. P. Hari, T. Hering and B. Konig, in Visible Light Photocatalysis
in Organic Chemistry, DOI: 10.1002/9783527674145.ch8, pp. 253-
281.
16. (a) J. M. R. Narayannam and C. R. J. Stephenson, Chem. Soc. Rev.,
2008, 40, 102; (b) J. D. Nguyen, E. M. D'Amato, J. M. R. Narayanam
and C. R. J. Stephenson, Nature Chemistry, 2012, 4, 854-859.
17. (a) I. Ghosh, T. Ghosh, J. I. Bardagi and B. König, Science, 2014,
346, 725-728; (b) R. S. Shaikh, S. J. S. Düsel and B. König, ACS
Catalysis, 2016, 6, 8410-8414; (c) C. J. Zeman, S. Kim, F. Zhang and K.
S. Schanze, J. Am. Chem. Soc., 2020, 142, 2204-2207.
participate as both initiators and then chain carriers owing to
their high nucleophilicity. In light of these results, we suggest
that this alternative mechanism should be taken in
consideration when benchmarking new photoredox catalysts
with the radical arylation of pyrroles in the presence of
alkylamines.
We believe the results presented here demonstrate that XAT–
based aryl radical generation using simple alkylamines and
photocatalysis can be used as an entry point for radical chains
and we expect that might be extended to other
transformations.
18. C. Chatgilialoglu, in Radicals in Organic Synthesis, 2001, DOI:
10.1002/9783527618293.ch3, pp. 28-49.
19. C. Chatgilialoglu, C. Ferreri, Y. Landais and V. I. Timokhin,
Chemical Reviews, 2018, 118, 6516-6572.
Conflicts of interest
There are no conflicts to declare.
20. (a) C. Le, T. Q. Chen, T. Liang, P. Zhang and D. W. C. MacMillan,
Science, 2018, 360, 1010-1014; (b) J. J. Devery, J. D. Nguyen, C. Dai
and C. R. J. Stephenson, ACS Catalysis, 2016, 6, 5962-5967; (c) D. J. P.
Kornfilt and D. W. C. MacMillan, J. Am. Chem. Soc., 2019, 141, 6853-
6858.
21. (a) T. Constantin, M. Zanini, A. Regni, N. S. Sheikh, F. Juliá and D.
Leonori, Science, 2020, 367, 1021-1026; (b) R. K. Neff, Y.-L. Su, S. Liu,
Acknowledgements
D.L. thanks EPSRC for a Fellowship (EP/P004997/1), and the
European Research Council for a research grant (758427). We
thank Dr Anne-Laure Barthelemy for help with the UV/Vis
studies.
6 | J. Name., 2012, 00, 1-3
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ARTICLE
M. Rosado, X. Zhang and M. P. Doyle, J. Am. Chem. Soc., 2019, 141,
16643-16650; (c) J. Lalevée, D. Gigmes, D. Bertin, B. Graff, X. Allonas
and J. P. Fouassier, Chemical Physics Letters, 2007, 438, 346-350.
22. (a) I. Ghosh, R. S. Shaikh and B. König, Angew. Chem., Int. Ed.,
2017, 56, 8544-8549; (b) M. Neumeier, D. Sampedro, M. Májek, V. A.
deꢀlaꢀPeñaꢀO'Shea, A. JacobiꢀvonꢀWangelin and R. Pérez-Ruiz,
Chemistry – A European Journal, 2018, 24, 105-108; (c) S. O. Poelma,
G. L. Burnett, E. H. Discekici, K. M. Mattson, N. J. Treat, Y. Luo, Z. M.
Hudson, S. L. Shankel, P. G. Clark, J. W. Kramer, C. J. Hawker and J.
Read de Alaniz, J. Org. Chem., 2016, 81, 7155-7160; (d) Z. Tang, J. Li,
F. Lin, W. Bao, S. Zhang, B. Guo, S. Huang, Y. Zhang and Y. Rao, Journal
of Catalysis, 2019, 380, 1-8; (e) R. Matsubara, T. Yabuta, U. Md Idros,
M. Hayashi, F. Ema, Y. Kobori and K. Sakata, J. Org. Chem., 2018, 83,
9381-9390; (f) Z.-J. Li, S. Li, E. Hofman, A. Hunter Davis, G. Leem and
W. Zheng, Green Chemistry, 2020, 22, 1911-1918.
View Article Online
DOI: 10.1039/D0SC04387G
23. An additional chain-carrying step would involve XAT between E2
and F2. However, this process was determined to be highly
endothermic.24
24. See SI for more information.
25. (a) J. Haimerl, I. Ghosh, B. König, J. Vogelsang and J. M. Lupton,
Chemical Science, 2019, 10, 681-687; (b) X. Guo and O. S. Wenger,
Angew. Chem., Int. Ed., 2018, 57, 2469-2473.
26. (a) G. E. M. Crisenza, D. Mazzarella and P. Melchiorre, J. Am.
Chem. Soc., 2020, 142, 5461-5476; (b) C. G. S. Lima, T. de M. Lima, M.
Duarte, I. D. Jurberg and M. W. Paixão, ACS Catalysis, 2016, 6, 1389-
1407; (c) J. Davies, S. G. Booth, S. Essafi, R. W. A. Dryfe and D. Leonori,
Angew. Chem. Int. Ed., 2015, 54, 14017.
27. S. P. Pitre, C. D. McTiernan, W. Vine, R. DiPucchio, M. Grenier and
J. C. Scaiano, Scientific Reports, 2015, 5, 16397.
28. We have performed intermittent irradiation experiments to
support an inefficient initiation step.24
29. A. T. Balaban, D. C. Oniciu and A. R. Katritzky, Chemical Reviews,
2004, 104, 2777-2812.
30. D. P. Hari, P. Schroll and B. Konig, J. Am. Chem. Soc., 2012, 134,
2958.
31. According to our calculations, the XAT reactions between Ph–I
and H1/J1 are significanlty more endothermic than the one between
Ph–I and E3.24
32. (a) D. Dolenc and B. Plesničar, J. Org. Chem., 2006, 71, 8028-
8036; (b) T. Nakamura, H. Yorimitsu, H. Shinokubo and K. Oshima,
Synlett, 1999, 1415-1416.
33. (a) A. Inial, F. Morlet-Savary, J. Lalevée, A. C. Gaumont and S.
Lakhdar, Org. Lett., 2020, 22, 4404-4407; (b) A. F. Garrido-Castro, N.
Salaverri, M. C. Maestro and J. Alemán, Org. Lett., 2019, 21, 5295-
5300; (c) W. G. Bentrude, J.-J. L. Fu and C. E. Griffin, Tetrahedron Lett.,
1968, 9, 6033-6036.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Page 8 of 9
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DOI: 10.1039/D0SC04387G
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(a) T. Constantin, M. Zanini, A. Regni, N. S. Sheikh, F. Juliá
and D. Leonori, Science, 2020, 367, 1021-1026; (b) R. K.
Neff, Y.-L. Su, S. Liu, M. Rosado, X. Zhang and M. P. Doyle,
J. Am. Chem. Soc., 2019, 141, 16643-16650; (c) J. Lalevée,
D. Gigmes, D. Bertin, B. Graff, X. Allonas and J. P. Fouassier,
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Ed., 2017, 56, 8544-8549; (b) M. Neumeier, D. Sampedro,
M. Májek, V. A. deꢀlaꢀPeñaꢀO'Shea, A. JacobiꢀvonꢀWangelin
and R. Pérez-Ruiz, Chemistry – A European Journal, 2018,
24, 105-108; (c) S. O. Poelma, G. L. Burnett, E. H. Discekici,
K. M. Mattson, N. J. Treat, Y. Luo, Z. M. Hudson, S. L.
Shankel, P. G. Clark, J. W. Kramer, C. J. Hawker and J. Read
de Alaniz, J. Org. Chem., 2016, 81, 7155-7160; (d) Z. Tang,
J. Li, F. Lin, W. Bao, S. Zhang, B. Guo, S. Huang, Y. Zhang and
Y. Rao, Journal of Catalysis, 2019, 380, 1-8; (e) R.
Matsubara, T. Yabuta, U. Md Idros, M. Hayashi, F. Ema, Y.
Kobori and K. Sakata, J. Org. Chem., 2018, 83, 9381-9390;
(f) Z.-J. Li, S. Li, E. Hofman, A. Hunter Davis, G. Leem and W.
Zheng, Green Chemistry, 2020, 22, 1911-1918.
, E2 + F2.
s. S. f. m. information, see SI for more information.
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and O. S. Wenger, Angew. Chem., Int. Ed., 2018, 57, 2469-
2473.
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Am. Chem. Soc., 2020, 142, 5461-5476; (b) C. G. S. Lima, T.
de M. Lima, M. Duarte, I. D. Jurberg and M. W. Paixão, ACS
Catalysis, 2016, 6, 1389-1407; (c) J. Davies, S. G. Booth, S.
Essafi, R. W. A. Dryfe and D. Leonori, Angew. Chem. Int. Ed.,
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5.
6.
21.
22.
7.
8.
9.
10.
Research
&
2020,
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11.
12.
13.
23.
24.
25.
(a) J. A. Murphy, S.-z. Zhou, D. W. Thomson, F.
Schoenebeck, M. Mahesh, S. R. Park, T. Tuttle and L. E. A.
Berlouis, Angew. Chem., Int. Ed., 2007, 46, 5178-5183; (b)
D. S. Lee, C. S. Kim, N. Iqbal, G. S. Park, K.-s. Son and E. J.
Cho, Org. Lett., 2019, 21, 9950-9953.
(a) H. Kim, H. Kim, T. H. Lambert and S. Lin, J. Am. Chem.
Soc., 2020, 142, 2087-2092; (b) N. G. W. Cowper, C. P.
Chernowsky, O. P. Williams and Z. K. Wickens, J. Am. Chem.
Soc., 2020, 142, 2093-2099.
26.
14.
27.
S. P. Pitre, C. D. McTiernan, W. Vine, R. DiPucchio, M.
Grenier and J. C. Scaiano, Scientific Reports, 2015, 5, 16397.
, intermittent.
A. T. Balaban, D. C. Oniciu and A. R. Katritzky, Chemical
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, DG for furan.
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2012, 4, 854-859.
30.
31.
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Page 9 of 9
Chemical Science
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Journal Name
ARTICLE
32.
(a) D. Dolenc and B. Plesničar, J. Org. Chem., 2006, 71,
8028-8036; (b) T. Nakamura, H. Yorimitsu, H. Shinokubo
and K. Oshima, Synlett, 1999, 1415-1416.
View Article Online
DOI: 10.1039/D0SC04387G
33.
(a) A. Inial, F. Morlet-Savary, J. Lalevée, A. C. Gaumont and
S. Lakhdar, Org. Lett., 2020, 22, 4404-4407; (b) A. F.
Garrido-Castro, N. Salaverri, M. C. Maestro and J. Alemán,
Org. Lett., 2019, 21, 5295-5300; (c) W. G. Bentrude, J.-J. L.
Fu and C. E. Griffin, Tetrahedron Lett., 1968, 9, 6033-6036.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins