Amidoalkylation of Sulfonylheteroarenes with Alkylamides through a Radical Chain Mechanism

Article abstract of DOI:10.1002/ejoc.202001457

In the presence of a substoichiometric amount of a tert-butoxy radical precursor and a base, alkylamides were found to be heteroarylated at their α-C?H bonds with sulfonylheteroarenes through homolytic aromatic substitution, where a radical chain is operative.

Full text of DOI:10.1002/ejoc.202001457

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Amidoalkylation of Sulfonylheteroarenes with Alkylamides
through a Radical Chain Mechanism
Authors: Yuko Ikeda, Yuko Matsukawa, Kyohei Yonekura, and Eiji
Shirakawa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001457
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01/2020

10.1002/ejoc.202001457
European Journal of Organic Chemistry
COMMUNICATION
Amidoalkylation of Sulfonylheteroarenes with Alkylamides
through a Radical Chain Mechanism
Yuko Ikeda,[a] Yuko Matsukawa,[a] Kyohei Yonekura[a] and Eiji Shirakawa*[a]
Dedication ((optional))
[a]
Y. Ikeda, Y. Matsukawa, Dr. K. Yonekura, Prof. Dr. E. Shirakawa
Department of Applied Chemistry for Environment, School of Science and Technology
Kwansei Gakuin University
2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan)
E-mail: eshirakawa@kwansei.ac.jp
https://sci-tech.ksc.kwansei.ac.jp/en/
Supporting information for this article is given via a link at the end of the document.
Abstract: In the presence of a substoichiometric amount of a tert-
butoxy radical precursor and a base, alkylamides were found to be
heteroarylated at their a-C–H bonds with sulfonylheteroarenes
through homolytic aromatic substitution, where a radical chain is
operative.
and report the a-heteroarylation of alkylamides with
methanesulfonylheteroarenes using a substoichiometric amount
of a tert-butoxy radical precursor [Eq. (1)].
a) Minisci Reaction
R2
N
O
R1
t-BuOOH/Fe2+, H2O2/Fe2+
t-BuOOt-Bu, K2S2O8, …
R4
R4
R2
O
N
+
+
+
a-Heteroarylalkylamides are ubiquitous motifs in biologically
active compounds used for medicinal chemistry and
agrochemistry.[1] The Minisci reaction, a formal dehydrogenative
coupling between alkylamides and protonated pyridine
derivatives, readily gives a-heteroarylalkylamides (Scheme 1a).[2]
The reaction proceeds through a homolytic aromatic substitution
(HAS) mechanism consisting of a radical addition and a radical
R3
R1
H
N
H
N
H
R3
b) Photoinduced Reaction (Opatz, Kamijo)
R2
O
R2
N
O
Ph2CO
hν
N
+
X–Ar
R1
R1
H
Ar
R3
R3
X = Cl, SO2Me
elimination. Here
utilization
of heteroarenes
without
Scheme 1. Previous works on the direct a-heteroarylation of alkylamides
through homolytic aromatic substitution (HAS).
prefunctionalization is beneficial, but it is intrinsically difficult that
a particular C–H bond of the heteroarene is regioselectively
substituted. The regioselectivity problem can be solved when a
heteroatom radical is selectively eliminated from the heteroarene.
In recent years, it has been reported that 2-chlorobenzazoles (X
= Cl) or sulfonylheteroarenes (X = SO2Me) are used for the
photoinduced a-heteroarylation of alkylamides through HAS
Our Previous Work
R2
N
R2
1 N
R
R4 t-BuON=NOt-Bu (0.2 equiv)
R1
R4
+
PhSO2
H
R3
R3
1
2
3
utilizing benzophenone as
a photosensitizer, ensuring the
regiochemistry on the aromatic rings (Scheme 1b).[3] In this
context, we have recently reported that the direct a-arylation of
alkylamines with sulfonylarenes proceeds through an HAS
mechanism mediated by a substoichiometric amount of t-BuO•
precursor (Scheme 2).[4] The reaction starts with hydrogen
abstraction from an alkylamine by t-BuO•, generated through
homolysis of t-BuON=NOt-Bu, to give a-aminoalkyl radical I,
which is stabilized by resonance with the lone pair on the nitrogen
atom (step a in Scheme 2). After addition of I to a sulfonylarene
(2) (step b), the resulting cyclohexadienyl radical (II) undergoes
Mechanism
Homolytic Aromatic Substitution (HAS)
R4
R1 R2
PhSO2
N
R4
2
R3
1/2 t-BuON=NOt-Bu
PhSO2
R2
– 1/2 N2
b
II
1 N
R4
R
t-BuO•
R2
R2
R2
+
•
N
c
R3
R1
N
R1
N
R1
a
•
•
3
–
•
H
•
•
R3
R3
R3
O
O
O
t-BuOH
I
Ph
S
1
S
Ph
O
•
elimination to give α-arylalkylamine 3 and PhSO2 (step c).
•
d
Hydrogen abstraction from
1 by the eliminated PhSO2
regenerates I to make a radical chain operative (step d).[5] Here
the stabilities of PhSO2 and I are comparable, and thus both
1
PhSO2–H
•
•
homolytic substitution of PhSO2 with I in steps b and c and
Scheme 2. Direct a-arylation of alkylamines with benzenesulfonylarenes
through a radical chain mechanism involving HAS.
hydrogen abstraction from 1 by PhSO2• to regenerate I in step d
are feasible to achieve the radical chain.[6] Here we have found
•
that, for the a-heteroarylation of alkylamides, MeSO2 instead of
PhSO2• is suitable as a leaving radical to meet the requirements,
1
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10.1002/ejoc.202001457
European Journal of Organic Chemistry
COMMUNICATION
This Work
maximum amount (40%) of t-BuO• generation shows operation of
a radical chain. The reaction of 2-halobenzothiazoles (X = Cl, Br)
resulted in low yields (entries 5 and 6). As for the reaction using
2-benzenesulfonyl- and 2-chlorobenzothiazoles, the use of a
stoichiometric amount of t-BuON=NOt-Bu increased the
conversions and yields (entries 7 and 8 vs. entries 4 and 5),
showing that some problem lies in the operation of a radical chain
with these heteroaryl electrophiles.[6,7] Other bases, weaker or
stronger than KHCO3, are less effective (entries 9–13).[8]
Especially, NaHCO3 The yield was improved to 81% by the use
of a slightly increased amount (0.3 equiv) of t-BuON=NOt-Bu
(entry 14). The reaction also proceeded under an air atmosphere
or a nitrogen atmosphere by use of a nitrogen balloon instead of
a glove box (entries 15 and 16).
O
R2
N
R2
t-BuON=NOt-Bu
(0.3 equiv)
O
N
N
N
Z
MeSO2
+
(1)
H
R1
R1
base
Z
R4
R3
R3
R4
(Z = O, S)
We
first
examined
a-heteroarylation
of
N,N-
dimethylacetamide (1a: DMA) under the conditions that we
employed
benzenesulfonylarenes.
(benzenesulfonyl)benzothiazole with DMA (20 equiv) as
substrate and a solvent in the presence of t-BuON=NOt-Bu (0.2
equiv) at 50 °C for 24 h gave N-(2-benzothiazolylmethyl)-N-
methylacetamide (3aa) but only in 26% yield (Table 1, entry 1).
The use of the MeSO2 derivative (2a) instead of the PhSO2 one
scored a comparable yield (entry 2). Addition of KHCO3 (1 equiv)
as a neutralizer for co-produced sulfinic acid increased the yield
of 3aa with 2a but not with the benzenesulfonyl derivative (entries
3 and 4). The result, using 2a, that the yield of 3aa exceeded the
in
the
a-arylation
of
alkylamines
of
with
2-
Thus,
treatment
a
The a-heteroarylation of DMA (1a: 20 equiv) using 0.3
equivalent of t-BuON=NOt-Bu is applicable to diverse 2-
(methanesulfonyl)azoles (Scheme 3). In addition to 2-
(methanesulfonyl)benzothiazole
(2a),
monocyclic
2-
(methanesulfonyl)thiazoles reacted with 1a to give the
corresponding heteroarylation products (entries 1–3). 2-
(Methanesulfonyl)benzothiazoles having an electron-donating or
-withdrawing group also participated in the a-heteroarylation in
high yields (entries 4–6). 2-(Acetylaminomethyl)oxazoles are also
obtained in high yields (entries 7 and 8).
Table 1. a-Heteroarylation of N,N-dimethylacetamide (1a) with
benzothiazolyl electrophile using t-BuON=NOt-Bu.[a]
a 2-
t-BuON=NOt-Bu (Y equiv)
Base (1 equiv)
O
N
S
O
N
N
S
+
X
N
50 °C, 24 h
t-BuON=NOt-Bu (0.3 equiv)
KHCO3 (1 equiv)
O
O
1a
(20 equiv)
2a (X = MeSO2)
or others
3aa
+
MeSO2 Ar
N
N
50 °C, 24 h
Ar
3
entry) yield
1a
(20 equiv)
2
Entry
1
X
Y
Base
Conv. [%][b]
Yield [%][b]
PhSO2
MeSO2
MeSO2
PhSO2
Cl
0.2
0.2
0.2
0.2
0.2
0.2
1.0
3.0
0.2
0.2
0.2
0.2
0.2
0.3
0.3
0.3
none
26
31
79
30
40
22
>99
89
38
60
40
40
81
90
89
83
26
O
O
O
Ph
N
N
N
N
N
N
S
2
none
31
S
S
3aa
1) 80%
3ab
2) 75%
3ac
3) 70%
3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
NaOAc
NaHCO3
K2HPO4
K2CO3
K3PO4
KHCO3
KHCO3
KHCO3
71
O
O
O
4
28
N
N
S
N
N
N
S
N
5
37
S
CO2Et
OMe
Cl
N
3ad
4) 80%
3ae
5) 85%
3af
6) 84%
6
Br
20
O
O
7
PhSO2
Cl
96
N
N
N
O
8
80
O
Ph
3ag
7) 85%
3ah
8) 85%
9
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
38
10
11
12
13
14
15[d]
16[e]
53
Scheme 3. a-Heteroarylation of N,N-dimethylacetamide (1a) with 2-
(methanesulfonyl)azoles.
37
38
46
Various tertiary alkylamides are a-heteroarylated with 2-
(methanesulfonyl)benzothiazole (2a) (Scheme 4). N,N-
Diethylacetamide (1b) was a-heteroarylated in a high yield (entry
81 (80)[c]
80
1).
N-Ethyl-N-methylacetamide
(1c)
underwent
the
heteroarylation preferentially at the methyl group over the linear
alkyl group but with a low selectivity (entry 2). On the other hand,
the heteroarylation of N-methylated cyclic alkylamides, ureas and
carbamates took place mainly at a cyclic alkyl group over a methyl
group (entries 3–6). The regioselectivity between methyl group
and a linear or cyclic alkyl group as a primary alkyl group is
determined essentially in the hydrogen abstraction step and the
75
[a] The reaction was carried out under a nitrogen atmosphere using a glove box
at 50 °C for 24 h using a 2-benzothiazolyl electrophile (2a or others: 0.25 mmol),
N,N-dimethylacetamide (1a: 5.0 mmol), t-BuON=NOt-Bu and a base (0.25
mmol). [b] Determined by GC. [c] The yield of the isolated product. [d] The
reaction was carried out under an air atmosphere. [e] The reaction was carried
out under a nitrogen atmosphere using a nitrogen balloon.
step of addition of an a-acylaminoalkyl radical to
a
2
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10.1002/ejoc.202001457
European Journal of Organic Chemistry
COMMUNICATION
sulfonylheteroarene. In both steps, the electronic factor favors the
reaction at a primary alkyl group because the stability and the
nucleophilicity are higher with an a-amino primary alkyl radical,
whereas the steric factor favors the reaction at the less hindered
methyl group. High selectivities for the cyclic alkyl group observed
in the reaction of the cyclic amides are likely to be ascribed to the
enhanced electronic factor due to the stereoelectronic effect
derived from the cyclic structure[9] and the reduced steric
hinderance due to the binding effect again derived from the cyclic
structure. N,N,N’,N’-Tetramethylurea (1h) participated in the a-
heteroarylation in a high yield (entry 7). In the reaction of N,N-
dimethylformamide (1i), heteroarylation at a methyl group on
nitrogen is preferred over the formyl group, which also accepts
hydrogen abstraction (entry 8).
heteroarylated butylamine (4) [Eq. (2)]. DMA is heteroarylated in
a high yield compared with the reaction under the previous
conditions (entry 5 vs. entry 14 of Table 1). Under these
conditions, no further a-heteroarylation of the a-heteroarylated
alkylamides took place in all entries in Scheme 5, as in the case
of Scheme 4, even though a lower amount of amides 1 and a
higher amount of the tert-butoxy radical precursor are used.
R2
N
R2
N
t-BuON=NOt-Bu (1 equiv)
KHCO3 (1 equiv)
O
O
N
S
+
MeSO2
R1
R1
H
Ar
chlorobenzene, 50 °C, 24 h
R3
R3
(MeSO2–Ar)
2a
3
entry) yield
1
(1.8 equiv)
O
N
Ph
O
Ph
N
O
O
O
O
N
NH
N
R2
N
R2
N
t-BuON=NOt-Bu (0.3 equiv)
KHCO3 (1 equiv)
O
O
Ar
Ar
Ar
O
Ar
Ar
N
S
Pr
+
MeSO2
R1
R1
H
Ar
50 °C, 24 h
3ja
1) 87% (46%[a]
3ka
2) 85%
3la
3) 78%
3ma
4) 80%
3aa
5) 92%
R3
R3
(MeSO2–Ar)
)
2a
3
1
entry) yield
(isomer ratio)
(20 equiv)
Scheme
5.
a-Heteroarylation
of
alkylamides
with
2-
(methanesulfonyl)benzothiazole (2a) in chlorobenzene. [a] 0.3 equiv of t-
BuON=NOt-Bu was used.
O
N
O
N
Ar
O
Ar
+
+
N
O
N
N
O
Ar
Ar
Ar
3ba
3ca
3'ca
3da
3'da
O
2) 85%
1) 80%
3) 85%
H2N
Pr
N
S
TFA (3 equiv)
NH
Pr
N
S
(3ca:3'ca = 64:36)
(3da:3'da = 84:16)
(2)
O
CH2Cl2, rt, 10 min
N
N
O
N
Ar
N
N
O
3ma
4
95%
Ar
+
+
N
N
N
3ea
O
O
Ar
Ar
3fa
3'fa
3'ea
To gain insight into the reaction mechanism, a radical clock
4) 85%
(3ea:3'ea = 82:18)
5) 70%
(3fa:3'fa = 81:19)
experiment was conducted. The reaction of 2-[3,3-
bis(ethoxycarbonyl)-5-hexene-1-sulfonyl]benzothiazole (2’a) with
DMA (1a) as a substrate and a solvent gave certain amounts of
cyclization products (6–9) derived from the alkanesulfonyl moiety
of 2’a in addition to the normal a-heteroarylation product (3aa)
and 3,3-bis(ethoxycarbonyl)-5-hexene-1-sulfinic acid (5)
O
N
O
O
O
O
Ar
N
+
+
N
N
N
N
O
O
Ar
H
Ar
Ar
Ar
3ga
3'ga
3ha
3ia
3'ia
6) 79%
(3ga:3'ga = 82:18)
7) 87%
8) 75%
(3ia:3'ia = 84:16)
t-BuON=NOt-Bu (0.3 equiv)
KHCO3 (1 equiv)
O
S
Scheme
4.
a-Heteroarylation
of
tertiary
alkylamides
with
2-
N
S
O
+
N
(methanesulfonyl)benzothiazole (2a).
50 °C, 24 h
O
E
E
2'a
1a
(RSO2–Ar; E = CO2Et)
92% conv.
(20 equiv)
The amount of alkylamides can be reduced from 20
equivalents to 1.8 by the use of chlorobenzene as a solvent,
though a stoichiometric amount (1 equiv) of t-BuON=NOt-Bu is
required for high yields (Scheme 5). This protocol is beneficial
especially for alkylamides that are solids and/or expensive. The
a-heteroarylation of N,N-dimethylbenzamide (1j: 1.8 equiv) with
2a in the presence of t-BuON=NOt-Bu (1 equiv) and KHCO3 (1
equiv) in chlorobenzene gave the a-heteroarylation product (3ja)
in 87% yield (entry 1). With a substoichiometric amount (0.3
equiv) of t-BuON=NOt-Bu, 3ja was obtained only in 46% yield
(49% conv. of 2a), showing that an efficient radical chain is not
operative, a probable reason of which is discussed later in the
mechanism section. N-Methylacetanilide also underwent the a-
heteroarylation (entry 2). N-Alkylated carbamates such as tert-
butyl N,N-dimethylcarbamate (1l) and tert-butyl N-butylcarbamate
(1m) were heteroarylated in high yields (entries 3 and 4).
Deprotection of tert-butoxycarbonyl group of 3ma with
trifluoroacetic acid (TFA) in CH2Cl2 gave the corresponding a-
O
S
O
Ar
Ar
O
O
OH
O
O
S
S
+
+
+
+
+
N
Ar
E
E
E
E
E
E
E
E
E
E
3aa
70%
9
5
6
7
8
5%
45%
15%
16%
5%
III
2'a
" H• "
" H• " (H+ + e–)
III
2'a
•
O
" H• "
O
O
S •
O
S
E
E
E
III
E
E
IV
•
•
– SO2
E
E
E
V
VI
Scheme 6. Proof of the involvement of sulfonyl radicals as leaving groups.
3
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10.1002/ejoc.202001457
European Journal of Organic Chemistry
COMMUNICATION
Smith, V. Shanmugasundaram, K. Wade, Bioorg. Med. Chem. Lett. 2011,
21, 5230–5233; c) N. Desroy, F. Moreau, S. Briet, G. L. Fralliec, S.
Floquet, L. Durant, V. Vongsouthi, V. Gerusz, A. Denis, S. Escaich,
Bioorg. Med. Chem. 2009, 17, 1276–1289; d) M. Ikeguchi, M. Sawaki, H.
Nakayama, H. Kikugawa, H. Yoshii, Pest Manag. Sci. 2004, 60, 981–991.
For an early example, see: a) G. P. Gardini, F. Minisci, G. Palla,
Tetrahedron Lett. 1971, 12, 59–62. For reviews, see: b) F. Minisci,
Synthesis 1973, 1–24; c) F. Minisci, E. Vismara, F. Fontana,
Heterocycles 1989, 28, 489–519; d) R. S. J. Proctor, R. J. Phipps, Angew.
Chem. Int. Ed. 2019, 58, 13666–13699; Angew. Chem. 2019, 131,
(Scheme 6). All the cyclization products (6–9) are highly likely to
be produced from 3,3-bis(ethoxycarbonyl)-5-hexene-1-sulfonyl
radical (III). Sulfonylradical III cyclizes, as it stands[10] and after
decomposition to alkyl radical V with elimination of SO2,[11] to give
alkyl radicals IV and VI, which undergo HAS with 2’a giving 6/8
and hydrogen abstraction giving 7/9. The result shows that
alkanesulfonyl radicals are involved as leaving groups in the a-
heteroarylation.
[2]
On the basis of the above experimental results and our
previous report,[4] the a-heteroarylation of alkylamides is likely to
proceed through the mechanism shown in Scheme 7. Thus, the
reaction is initiated by hydrogen abstraction from an alkylamide
(1) by t-BuO• generated through homolysis of t-BuON=NOt-Bu
(step a). The resulting a-(acylamino)alkyl radical (I) adds to a
methanesulfonylheteroarene (2) (step b), followed by elimination
13802–13837. For examples of of the Minisci reaction under
a
photoredox catalysis, see: e) Y. Zhang, K. B. Teuscher, H. Ji, Chem. Sci.
2016, 7, 2111–2118; f) J. Dong, Q. Xia, X. Lv, C. Yan, H. Song, Y. Liu,
Q. Wang, Org. Lett. 2018, 20, 5661–5665. For benzothiazoles: g) J.
Wang, J. Li, J. Huang, Q. Zhu, J. Org. Chem. 2016, 81, 3017–3022.
For recent examples of alkylation of 2-chlorobenzazoles and
alkane(arene)sulfonylheteroarenes, see: a) A. Lipp, G. Lahm, T. Opatz,
J. Org. Chem. 2016, 81, 4890–4897; b) S. Kamijo, K. Kamijo, T. Murafuji,
J. Org. Chem. 2017, 82, 2664–2671; c) S. Kamijo, K. Kamijo, T. Murafuji,
Synthesis 2019, 51, 3859–3864; d) N. P. Ramirez, T. Lana-Villarreal, J.
C. Gonzalez-Gomez, Eur. J. Org. Chem. 2020, 1539–1550.
[3]
•
of MeSO2 from II to give the a-heteroarylation product (3) (step
•
c). Finally, MeSO2 undergoes hydrogen abstraction from 1 to
regenerate I (step d). Step d is likely to be thermodynamically
unfavorable,[7] and thus an excess amount of 1 are required to
step forward.[12]
[4]
[5]
Y. Ikeda, R. Ueno, Y. Akai, E. Shirakawa, Chem. Commun. 2018, 54,
10471–10474.
We had reported, before ref. [4], the direct a-arylation of alkylamines with
aryl halides utilizing a stoichiometric amount of a tert-butoxy radical
precursor. The radical chain is not operative because the eliminated halo
radical oxidizes the a-aminoalkyl radical (I in Scheme 1) to give the
corresponding iminium halide rather than undergoes hydrogen atom
abstraction from the amine. R. Ueno, Y. Ikeda, E. Shirakawa, Eur. J. Org.
Chem. 2017, 4188–4193.
N
O
MeSO2
R2
Z
R4
R1
N
Z = O, S
N
R3
2
1/2 t-BuON=NOt-Bu
Z
R4
MeSO2
– 1/2 N2
II
b
t-BuO•
R2
N
R2
O
O
[6]
We have also reported the direct a-arylation of alcohols with aryl
chlorides (and bromides) by the use of a substoichiometric amount of a
tert-butoxy radical precursor. Here the radical chain is operative because
the stabilities of halo radicals and a-hydroxyalkyl radicals are
comparable. K. Aoki, K. Yonekura, Y. Ikeda, R. Ueno, E. Shirakawa, Adv.
Synth. Catal. 2020, 362, 2200–2204.
c
N
a
R1
R1
H
R3
R3
t-BuOH
R2
N
O
I
1
O
N
R1
S
Me
Me
O
base
d
R3
R4
Z
O
MeSO2H•base
Me
S
e
3
O
H
[7]
[8]
The Gibbs free energy values ΔG (kcal/mol) at 298 K for the reaction of
O
O
R2
O
a sulfonyl radical with DMA are estimated by DFT calculations using
S
N
•
•
R1
(U)B3LYP/6-311+G(d,p) to be +8.6 and +7.9 for PhSO2 and MeSO2 ,
H
R3
•
respectively, whereas that of the reaction of PhSO2 with
1
isopropyldimethylamine is estimated to be +6.2 kcal/mol.
The pKa values of the conjugated acids of KHCO3, K2HPO4, K2CO3 and
K3PO4 are reported to be 6.4, 7.2, 10.3 and 12.7, respectively. a) J. W.
B. Fyfe, E. Valverde, C. P. Seath, A. R. Kennedy, J. M. Redmond, N. A.
Anderson, A. J. B. Watson, Chem. Eur. J. 2015, 21, 8951–8964. The pKa
value of MeSO2H is reported to be 2.3. b) F. Wudl, D. A. Lightner, D. J.
Cram, J. Am. Chem. Soc. 1967, 89, 4099–4101.
Scheme 7. A plausible mechanism.
In conclusion, we have expanded the substrate scope of
nitrogen-containing aliphatic compounds to alkylamides in the a-
arylation with sulfonylarenes by tuning the sulfonyl radical leaving
group.
[9]
For discussion on the radical structures and stabilization energies of
cyclic alkylamines such as pyrrolidine, see: D. D. M. Wayner, K. B. Clark,
A. Rauk, D. Yu, D. A. Armstrong, J. Am. Chem. Soc. 1997, 119, 8925–
8932.
[10] Alkanesulfonyl radicals having an alkene moiety, such as 4-
pentenesulfonyl radical, are reported to undergo the intramolecular
cyclization reaction. A. Tsimelzon, R. Braslau, J. Org. Chem. 2005, 70,
10854–10859.
Acknowledgements
This work has been supported financially in part by Grant-in-Aids
for Scientific Research (B) (16H04151 to E.S.) and Scientific
Research (B) (19H02728 to E.S.).
[11] Methanesulfonyl radical is reported to decompose into SO2 and methyl
radical but a high temperature is required. S. Kim, H.-J. Song, T.-L. Choi,
J.-Y. Yoon, Angew. Chem. Int. Ed. 2001, 40, 2524–2526; Angew. Chem.
2001, 113, 2592–2594.
[12] Considering the operation of a radical chain, we propose the mechanism
shown in Scheme 7. However, another mechanism may be operative,
considering the report that sulfinic acids are good hydrogen atom donors
with alkyl radicals: M. Griesser, J.-P. R. Chauvin, D. A. Pratt, Chem. Sci.
2018, 9, 7218–7229.
Keywords: a-heteroarylation • alkylamides •
sulfonylheteroarenes • radical mechanism • t-BuO• source
[1]
For examples of biologically active compounds: a) F. Ferrigno, I.
Biancofiore, S. Malancona, S. Ponzi, G. Paonessa, R. Graziani, A.
Bresciani, N. Gennari, A. Di Marco, M. Kaiser, V. Summa, S. Harper, J.
M. Ontoria, Bioorg. Med. Chem. Lett. 2018, 28, 3689–3692; b) K. E.
Sexton, S. Barrett, K. Bridgwood, M. Carroll, D. Dettling, D. Du, S.
Fakhoury, V. Fedij, L.-Y. Hu, C. Kostlan, D. Pocalyko, N. Raheja, Y.
4
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10.1002/ejoc.202001457
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
R2
R2
N
t-BuON=NOt-Bu (0.3 or 1 equiv)
KHCO3 (1 equiv)
O
O
N
Z
N
Z
N
R4
+
MeSO2
R1
R4
R1
(PhCl)
H
R3
R3
(Z = O, S)
(20 or 1.8 equiv)
Homolytic Aromatic Substitution
The direct a-heteroarylation of alkylamides through a radical chain mechanism involving homolytic aromatic substitution (HAS) was
accomplished using methanesulfonylheteroarenes and t-BuON=NOt-Bu as arylating reagents and a tert-butoxy radical precursor,
respectively.
5
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