α-Arylation of alkylamines with sulfonylarenes through a radical chain mechanism

Article abstract of DOI:10.1039/c8cc03604g

In the presence of a substoichiometric amount of a tert-butoxy radical precursor, the reaction of alkylamines with sulfonylarenes was found to give α-arylated alkylamines through homolytic aromatic substitution, where a radical chain is operative.

Full text of DOI:10.1039/c8cc03604g

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-Arylation of Alkylamines with Sulfonylarenes through a Radical
Chain Mechanism
Yuko Ikeda,a Ryota Ueno,b Yuto Akaia and Eiji Shirakawa*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
In the presence of a substoichiometric amount of a tert-butoxy
radical precursor, the reaction of alkylamines with sulfonylarenes
was found to give -arylated alkylamines through homolytic
aromatic substitution, where a radical chain is operative.
Many reports are available for -arylation of alkylamines,
reflecting its importance in organic synthesis. Methods to
activate alkylamines getting ready for -arylation are divided
into three types: -aminoalkyl anions, cations and radicals. The
most popular method is utilization of the anions to obtain -
arylated secondary alkylamines representatively through a
sequence consisting of acylation of a secondary alkylamine,
deprotonation by butyllithium, transmetalation of the resulting
-(acylamino)alkyllithium with zinc chloride, the Negishi
coupling with an aryl halide, and deacylation.1 In contrast to the
anion protocol, which requires a laborious process including
acylation–deacylation, -aminoalkyl cations, i.e. iminium salts,
are available directly from alkylamines through facile 2e–
oxidation by the combination of a transition metal catalyst with
an oxidant. The in situ-generated cationic species undergo
electrophilic aromatic substitution with arenes but only with
highly electron-rich ones such as indoles and pyrroles due to the
low electrophilicity of the cationic species2 -Aminoalkyl
radicals, which are also readily available through hydrogen
abstraction from alkylamines by an oxy radical, have potential to
undergo homolytic aromatic substitution (HAS), consisting of
radical addition and radical elimination, to give -arylation
products.3 In this context, we have recently reported that
Scheme 1 -Arylation of alkylamines through homolytic aromatic substitution
(HAS).
radical precursor such as t-BuOOt-Bu and t-BuON=NOt-Bu to
give -arylation products (
starts with homolysis of a tert-butoxy radical precursor to give t-
BuO•, which abstracts an -hydrogen from
(Scheme 1,
middle). Addition of the resulting -aminoalkyl radical ( ) to
3
) (eq. 1 in Scheme 1).4,5 The reaction
1
I
2
(Y = X) is followed by elimination of the halogen radical (X•) to
give 3.6 Here X• does not undergo -hydrogen abstraction that
would make a radical chain to be operative. Instead, X• oxidizes
alkylamines (1: 10 equiv) react with aryl halides (2) having an
electron-withdrawing group and/or a polycyclic structure in the
presence of a stoichiometric amount (1 equiv) of a tert-butoxy
another molecule of
equivalent of
is sacrificed, and thus 2 equivalents of t-BuO• and
an excess amount (2 equiv at least) of
are required.7 The use of
a leaving group that is sufficiently stable to leave as a radical and
is sufficiently reactive in hydrogen abstraction from makes it
I to give an iminium halide (III), where 1
I
a.Department of Applied Chemistry for Environment, School of Science and
Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan.
E-mail: eshirakawa@kwansei.ac.jp
1
b.Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan.
1
† Footnotes relating to the title and/or authors should appear here.
possible to promote the reaction through a radical chain
mechanism and to reduce the amounts of the t-BuO• precursor
Electronic
Supplementary
Information
(ESI)
available:.
See
DOI: 10.1039/x0xx00000xœ
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and the amine. We expected a sulfonyl radical to act as a leaving resulted in a moderate yield (50%) under the standard conditions
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group that realizes a radical chain mechanism (Scheme 1, broken but the use of twice amounts of t-BDuOOIN: 1=0.N10O39t-/CB8uCCa0n3d6041Ga
line box).8 Here we report -arylation of alkylamines (1.8 equiv) improved the yield to 85% (entry 5). (Benzo)thiazoles having an
with sulfonylarenes in the presence of a substoichiometric electron-withdrawing or -donating group also participated in the
amount (0.2 equiv) of t-BuON=NOt-Bu through a radical chain -arylation in high yields (entries 6–8).9
mechanism (eq. 2 in Scheme 1).
Table 2 -Arylation of isopropyl(dimethyl)amine with sulfonylarenes.
Treatment of 2-(benzenesulfonyl)benzothiazole (2a) with
isopropyl(dimethyl)amine (1a: 1.2 equiv) and t-BuON=NOt-Bu
(0.2 equiv) in methanol at 50 °C for 8 h gave (2-
benzothiazolylmethyl)(isopropyl)(methyl)amine (3aa) in 75%
yield with 80% conversion of 2a, where a regioisomer, 2-(1-
dimethylamino-1-methylethyl)benzothiazole, was not observed
(Table 1, entry 1). The result that the yield of 3aa exceeded the
maximum amount (40%) of t-BuO• generation shows operation
of a radical chain. The use of other solvents such as ethanol, 2-
propanol, acetonitrile, dimethyl sulfoxide, 1,2-dichloroethane
at-BuON=NOt-Bu (0.4 equiv) and 1a (3.6 equiv) were used. bEthanol was used
instead of methanol.
and benzene was less effective (entries 2–7). The yield was
improved to 98% by the use of an increased amount (1.8 equiv)
of 1a (entry 8). On the other hand, the use of 2-
The reaction is also applicable to six-membered aromatic
chlorobenzothiazole (2’a) instead of 2a drastically lowered the
sulfones, though some modification of the reaction conditions is
conversion and the yield, even with an increased amount (3.6
required (Table 3). The reaction of 4-(benzenesulfonyl)-
equiv) of 1a (entries 9 and 10). The result that a high yield is
benzonitrile (2j) with isopropyl(dimethyl)amine (1a: 1.8 equiv)
accomplished with 2’a by the use of 1 equiv of t-BuON=NOt-Bu
under the conditions employed in Table 2 gave the -arylation
product (3aj) at a methyl group of 1a only in 31% yield with 39%
conversion of 1a (entry 1). In contrast, the use of the twice
(entry 11) shows that a radical chain does not work with chlorine
as a leaving group.
Table
1
-Arylation of isopropyl(dimethyl)amine (1a) with
a
2-benzothiazolyl amount (3.6 equiv) of the amine and addition of NaH2PO4 (1
equiv) largely improved the yield of 3aj to 88% with 90%
conversion of 1a (entry 1).10 Other sulfonylbenzenes having an
electron-withdrawing group participated in the -arylation
(entries 2 and 3). No substitution takes place on the phenyl group
electrophile (2a or 2’a) using t-BuON=NOt-Bua
of the benzenesulfonyl moiety in all the sulfonylarenes (
undergo -arylation, showing that the nucleophilic character of
-aminoalkyl radicals ( in Scheme 1), due to the carboanionic
2) that
entry
X
1a
(equiv)
solvent
conv. yield
(%)b
80
67
63
66
18
67
40
98
3
(%)b
75
I
resonance structure as shown in Scheme 1, favors electrophilic
aromatic rings as reaction partners in the aromaticity-breaking
radical addition step.11 However, 1-(benzenesulfonyl)-
naphthalene participated in the -arylation with no aid of an
electron-withdrawing group because radical intermediate II (in
Scheme 1), which is both benzylic and allylic, is relatively stable
(entry 4). -Deficient N-heterocycles such as pyrimidine,
pyridine and isoquinoline also participated in the -arylation in
moderate to high yields (entries 5–7).
1
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
PhSO2 (2a)
Cl (2’a)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.8
1.8
3.6
3.6
MeOH
EtOH
2
65
3
i-PrOH
MeCN
DMSO
ClCH2CH2Cl
C6H6
54
4
56
5
18
6
65
7
35
98 (96)c
8
MeOH
MeOH
MeOH
MeOH
9
<1
Table
3
-Arylation of isopropyl(dimethyl)amine with sulfonylbenzene or
10
11d
Cl (2’a)
20
92
11
sulfonylpyridine derivatives.
Cl (2’a)
87
aThe reaction was carried out under a nitrogen atmosphere at 50 °C for 8 h using a
2-benzothiazolyl electrophile (2a or 2'a: 0.25 mmol), isopropyl(dimethyl)amine
(1a) and t-BuON=NOt-Bu (0.050 mmol) in a solvent (0.5 mL). bDetermined by GC.
cThe yield of the isolated product. d t-BuON=NOt-Bu (0.25 mmol) was used.
The -arylation of isopropyl(dimethyl)amine (1a: 1.8 equiv)
in the presence of 0.2 equiv of t-BuON=NOt-Bu is applicable to
various 2-benzenesulfonylazoles including benzannulated ones
(Table 2). Non- or phenyl-substituted thiazoles, oxazoles and
benzimidazoles underwent the coupling in high yields (entries 1–
4). The reaction of sterically hindered N-methylbenzimidazole
b
a1a (1.8 equiv) was used without NaH2PO4. t-BuON=NOt-Bu (0.4 equiv) and 1a
(5 equiv) were used.
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Various tertiary alkylamines are applicable to the -arylation
(Table 4). tert-Butyl(dimethyl)amine 1b and
cyclohexyl(dimethyl)amine 1c were -arylated with 2-
Table 5 -Arylation of primary alkylamines through tert-butyldimethylsilyl protection–
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DOI: 10.1039/C8CC03604G
deprotection.
(
)
(
)
(benzenesulfonyl)benzothiazole (2a) exclusively at a methyl
group in high yields (entries 1 and 2). Dimethyl(n-alkyl)amines
underwent the arylation at a methyl group in high preference to
the primary alkyl group probably due to the steric reason (entries
3
and 4). However, this does not hold true for N-
methylpyrrolidine (1f), the five-membered primary alkyl group
of which gives an exceptionally stable alkyl radical with a
relatively compact size (entry 5).12,13 Functional groups such as
methoxy, cyano, methoxycarbonyl and dimethylamino on
dimethyl(alkyl)amines are tolerated (entries 6–9). Rather
Involvement of sulfonyl radicals as leaving groups is strongly
supported by the following result. The reaction of 2-[3,3-
bis(ethoxycarbonyl)-5-hexenesulfonyl]benzothiazole (2"a) with
isopropyl(dimethyl)amine (1a) under the standard conditions
surprisingly,
the
arylation
of
N,N,N’,N’-
tetramethylethylenediamine (TMEDA: 1j
)
took place
exclusively at a methyl group in a high yield, being free from
diarylation (entry 9).14 N,N-Dimethylaniline
1k also
(
)
gives certain amounts of cyclized products (
to the -arylation product (3aa) and 3,3-bis(ethoxycarbonyl)-5-
hexenesulfinic acid part of 3,3-
(Scheme 2).16
6 and 7) in addition
participated in the -arylation in a high yield (entry 10). The
reaction of dibutylamine (1l) resulted in a low yield (17%) under
the standard conditions but the use of an increased amount (1
equiv) of t-BuON=NOt-Bu improved the yield to 90% (entry11),
showing that a radical chain is not operative. This observation is
likely to be ascribed to high -C–H bond dissociation energies
of secondary amines compared with the corresponding tertiary
(
5
)
A
bis(ethoxycarbonyl)-5-hexenesulfonyl radical (IV), generated
upon HAS, is considered to decompose into SO2 and 3,3-
bis(ethoxycarbonyl)-5-hexenyl radical
cyclization, undergoes hydrogen abstraction and HAS on 2"a to
give and , respectively.
(V), which, after
6
7
•
amines,15 preventing hydrogen abstraction by PhSO2 .
Secondary amines having a relatively low -C–H bond
dissociation energy such as tert-butyl(methyl)amine (1m) and N-
butylaniline (1n) underwent the -arylation in moderate yields
even by the use of 0.2 equiv of t-BuON=NOt-Bu (entries 12 and
13).15 The -arylation of primary alkylamines is accomplished
through a sequence consisting of tert-butyldimethylsilylation of
primary alkylamines, the -arylation and desilylation with an
aqueous work-up (Table 5). -Benzothiazolylation products of
primary alkylamines including those having a functional group
such as alkoxy, amino and ester were obtained in high yields.
Table
4
-Arylation of tertiary and secondary alkylamines with 2-
(benzenesulfonyl)benzothiazole.
Scheme 2 Involvement of sulfonyl radicals as leaving groups.
On the basis of the above result as well as the operation of a
radical chain derived from the observation that just
a
substoichiometric amount of a tert-butoxy radical precursor
b
aThe reaction time = 24 h. 2-(Methanesulfonyl)benzothiazole was used instead of
c
d
2a. t-BuON=NOt-Bu (1 equiv) was used. Methanol/1,2-dichloroethane (1:1, 0.5
Scheme 3 A plausible mechanism.
mL) was used instead of methanol (0.5 mL).
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6
7
8
Addition does not always take place at the carbon atom
DOI: 10.1039/C8CC03604G
elsewhere inevitably go back to the original state.
The production of certain amounts of the corresponding
secondary amine and ketone derived from the iminium halides
works, the -arylation is likely to proceed through the
mechanism we initially expected (Scheme 3). Homolysis of t-
BuON=NOt-Bu gives t-BuO•, which undergoes hydrogen
abstraction from a carbon atom adjacent to the nitrogen atom of
connected to the halogen but the intermediates afVteierwaAdrtdicilteioOnnlitnoe
an alkylamine (
1
). Addition of the resulting -aminoalkyl radical
) is followed by elimination of
PhSO2 to give the corresponding -arylation product ( ).
to
(
III in Scheme 1) is confirmed. See ref. 4.
Sulfonyl radicals are reported to act as leaving groups in HAS
but they do not undergo hydrogen abstraction to regenerate the
radicals attacking the aromatic ring. For an early examples,
see: (a) M. Fiorentino, L. Testaferri, M. Tiecco and L. Troisi,
J. C. S., Chem. Comm., 1977, 316. For a review, see: (b) M.
Tiecco, Acc. Chem. Res., 1980, 13, 51. See also ref. 5e.
(
I
) to a benzenesulfonylarene (2
•
3
•
Finally, PhSO2 undergoes hydrogen abstraction from
regenerate -aminoalkyl radical I 17
1
.
In conclusion, we have developed -arylation of alkylamines
with sulfonylarenes through homolytic aromatic substitution just
by the use of a substoichiometric amount of a tert-butoxy radical
precursor and methanol as a solvent. Compared with the previous
related method using aryl halides, remarkable reduction of the
amounts of the tert-butoxy radical precursor and the amine has
been accomplished by making a radical chain operative.
This work has been supported financially in part by Grand-
in-Aid for Challenging Exploratory Research (26620082 to E.S.)
and Grand-in-Aid for Scientific Research (B) (16H04151 to
E.S.). R.U. thanks the JSPS for a Research Fellowship for Young
Scientists.
9
In the reaction of 1a with 2g having an ethyl ester moiety in
methanol (cf. Table 2, entry 6), -arylation was accompanied
by ester exchange to give 3ag and the corresponding methyl
ester with 76:24 ratio in 93% total yield.
10 The use of other bases such as Na2HPO4, KH2PO4, NaHCO3,
Na2CO3 and NaOAc resulted in lower yields. The reaction of
2-(benzenesulfonyl)benzothiazole
(
2a
)
with
isopropyl(dimethyl)amine (1a) under these conditions (Table
3) gave a slightly lower yield (93%) of 3aa than the reaction
under the reaction conditions employed in Table 2. NaH2PO4
possibly convert sulfinic acid, generated upon hydrogen
abstraction from an amine by a sulfonyl radical, into the
sulfinate to eliminate it from the equilibrium, though it is
unclear why such a role is not required in the reaction of
sulfonylazoles such as 2a
.
11 This requirement for the aromatic rings as reaction partners is
strict: benzenesulfonylarenes (PhSO2–Ar), Ar of which is
phenyl, 4-methoxyphenyl, 2-thienyl, 2-pyrrolyl, 2-indolyl, 1-
methyl-5-pyrazolyl or 1-methyl-2-imidazolyl, gave alpha-
arylation products of isopropyl(dimethyl)amine (1a) in <10%
yield, <1% in most cases, under the conditions of Table 2 or 3.
12 For discussion on the radical structures and stabilization
energies of alkylamines including pyrrolidine, see: D. D. M.
Wayner, K. B. Clark, A. Rauk, D. Yu and D. A. Armstrong, J.
Am. Chem. Soc., 1997, 119, 8925.
Notes and references
1
For an early example, see: (a) K. R. Campos, A. Klapars, J. H.
Waldman, P. G. Dormer and C.-Y. Chen, J. Am. Chem. Soc.,
2006, 128, 3538. For a review, see: (b) E. A. Mitchell, A.
Peschiulli, N. Lefevre, L.Meerpoel and B. U. W. Maes, Chem.
Eur. J., 2012, 18, 10092.
2
3
For an example, see: (a) Z. Li and C.-J. Li, J. Am. Chem. Soc.,
2005, 127, 6968. For a review, see: (b) S. A. Girard, T.
Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014, 53, 74.
One of the most important reactions utilizing HAS with a sp3-
carbon radical adjacent to a hetroatom (N, O, S, ...) is the
13 The yield of the
bezenesufonylbenzothiazole
methansulfonyl derivative, was lower (65%, 3fa
due to coproduction of benzothiazole (26% yield) through
reduction of 2a

-arylation products by the use of 2-
2a), instead of the 2-
3’fa = 77:23)
(
:
Minisci reaction, where -arylation of heteroatom-containing
aliphatic compounds such as amides, ethers and sulfides with
pyridine derivatives takes place in the presence of a
stoichiometric amount of an oxidant, “H•” acting as a leaving
group. For reviews, see: (a) F. Minisci, Synthesis, 1973, 1; (b)
.
14 The homogeneity of the reaction mixture looked low with this
combination of the substrates compared with other
combinations. A possible reason that no diarylation takes place
is that low solubility of monoarylation product 3ja drives itself
out of the reaction mixture.
15 The bond dissociation energies of a C–H bond of a methyl
group in methylamines are reported as follows (kcal/mol):
Me2NH (94.2), Me3N (93.2), t-BuNMe2 (90.0), PhNMe2
(91.7). Y.-R. Luo in Comprehensive Handbook of Chemical
Bond Energies; CRC Press: Boca Raton, 2007; chap. 3.6, pp
102–105.
F. Minisci, E. Vismara and F. Fontana, Heterocycles, 1989, 28
489. For a recent example, giving -arylation products of
,

alkylamides with benzothiazole derivatives, see: (c) J. Wang,
J. Li, J. Huang and Q. Zhu, J. Org. Chem., 2016, 81, 3017.
R. Ueno, Y. Ikeda and E. Shirakawa, Eur. J. Org. Chem., 2017,
4188.
4
5
There is an emerging area on the photoredox catalysis that
accomplishes the
-arylation of heteroatom-containing
aliphatic compounds with heteroaryl electrophiles under
photoredox catalysis, where an HAS mechanism is considered
to be operative. For the reaction of aryl halides, see: (a) A.
Singh, A. Arora and J. D. Weaver, Org. Lett., 2013, 15, 5390;
16 For an example of the use of 3,3-bis(ethoxycarbonyl)-5-
hexenesulfonyl radical for a radical clock experiment, see: D.
Crich and D. Grant, Tetrahedron Lett., 2008, 49, 2999.
17 Addition of TEMPO (1 equiv) to the reaction mixture of
(b) C. K. Prier and D. W. C. MacMillan, Chem. Sci., 2014, 5,
isopropyl(dimethyl)amine
(benzenesulfonyl)benzothiazole (2a) under the conditions of
entry 8 of Table 1 completely inhibited the -arylation with no
conversion of 2a
(
1a
)
and
2-
4173; (c) A. Lipp, G. Lahm and T. Opatz, J. Org. Chem., 2016,
81, 4890. For aryl cyanides, see: (d) A. McNally, C. K. Prier
and D. W. C. MacMillan, Science, 2011, 334, 1114. For the
reaction of 2- or 4-(methanesulfonyl)pyrimidine, see: (e) S.

.
Kamijo, K. Kamijo and T. Murafuji, J. Org. Chem,. 2017, 82
2664. For the -arylation in combination with a nickel
catalysis, see: (f) D. T. Ahneman and A. G. Doyle, Chem. Sci.,
2016, , 7002; (g) Y.-Y. Gui, L.-L. Liao, L. Sun, Z. Zhang, J.-
,

7
H. Ye, G. Shen, Z.-P. Lu, W.-J. Zhou and D.-G. Yu, Chem.
Commun., 2017, 53, 1192.
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