tert-Butoxy-Radical-Promoted α-Arylation of Alkylamines with Aryl Halides

Article abstract of DOI:10.1002/ejoc.201700548

In the presence of a tert-butoxy radical precursor, the reaction of alkylamines with aryl halides was found to give α-arylated alkylamines through homolytic aromatic substitution of the halogen atoms.

Full text of DOI:10.1002/ejoc.201700548

A Journal of
Accepted Article
Title: tert-Butoxy Radical-Promoted alpha-Arylation of Alkylamines with
Aryl Halides
Authors: Ryota Ueno, Yuko Ikeda, and Eiji Shirakawa
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10.1002/ejoc.201700548
European Journal of Organic Chemistry
COMMUNICATION
α
tert-Butoxy Radical-Promoted -Arylation of Alkylamines with Aryl
Halides
Ryota Ueno, Yuko Ikeda and Eiji Shirakawa*
Abstract: In the presence of a tert-butoxy radical precursor, the reaction of
alkylamines with aryl halides was found to give α-arylated alkylamines
through homolytic aromatic substitution of the halogen atoms.
Homolytic aromatic substitution (HAS), consisting of addition of an
aliphatic sp3-carbon radical adjacent to a heteroatom to an aromatic
compound (Ar–Y) followed by elimination of radical Y•, has high
potential as a synthetic method to achieve α-arylation of heteroatom-
containing aliphatic compounds (Scheme 1, top).[1] The most successful
example is the Minisci reaction, which employs sp3-carbon radicals
adjacent to a heteroatom in combination with protonated pyridine
derivatives to give α-pyridination products of amides, ethers and
alcohols, H• being leaving group Y• here (Scheme 1, a).[2] The Minisci
reaction utilizes readily available sp3-carbon radicals generated through
hydrogen abstraction from heteroatom-containing aliphatic compounds
such as amides and ethers. However, the unfavorable aromaticity-
breaking radical addition step requires high electrophilicity for aromatic
compounds to facilitate the reaction with the nucleophilic sp3-carbon
radicals having a heteroatom at α-position. This requirement limits its
scope essentially to protonated pyridine derivatives. In this context, we
have recently reported that use of a strong base such as NaOt-Bu as a
promoter reduces the limitation to expand the scope to benzene
derivatives having electron-withdrawing groups and/or a polycyclic
structure (Scheme 1, b).[3] The both methods, employing H• as leaving
group Y•, suffer from production of a mixture of regioisomers because
Scheme 1. α-Arylation of heteroatom-containing aliphatic compounds
through homolytic aromatic substitution (HAS).
selection of an optional C–H bond is intrinsically difficult. The
During the course of the investigation on the α-arylation of ethers
regioselectivity problem can be solved by use of aryl halides [Y =
halogen (X)], making the halogen atom to leave as the radical (X•).[4,5]
we found that the reaction of 4-bromobenzonitrile (1a) with
Here we report α-arylation of alkylamines with aryl halides having an
with arenes through the dehydrogenative coupling in (b) of Scheme 1,[3]
tetrahydrofuran (THF: 80 equiv) in the presence of t-BuOOt-Bu (1
electron-withdrawing group and/or a polycyclic structure with the aid of
a tert-butoxy radical precursor, where an HAS mechanism with X• as a
equiv) and NaOt-Bu (1 equiv) at 120 °C for 24
dehydrobrominative coupling product,
tetrahydrofuranyl)benzonitrile (2a: 6%), in addition to
dehydrogenative coupling product, 4-bromo-2-(2-
h
gave
a
leaving group is operative.[6,7]
4-(2-
a
tetrahydrofuranyl)benzonitrile (3a: 22%) (Scheme 2). The reaction in
the absence of NaOt-Bu, which had been shown to be indispensable for
the effective dehydrogenative coupling, gave 2a exclusively but only in
a low yield (26%). The eliminated bromine atom (Br•) is likely to be
reduced to Br– by THF. We anticipated that alkylamines, which are more
electron-rich than alkyl ethers, readily reduce Br •, or successively
generated Br2, to Br–, and examined the α-arylation of alkylamines with
aryl halides with the aid of t-BuOOt-Bu.
[*]
Dr. R. Ueno
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo-ku, Kyoto 606-8502 (Japan)
Y. Ikeda, Prof. Dr. E. Shirakawa
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
http://sci-tech.ksc.kwansei.ac.jp/en/
Scheme 2. The reaction of tetrahydrofuran with 4-bromobenzonitrile
using t-BuOOt-Bu in the presence or absence of NaOt-Bu.
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the document.((Please delete this text if not appropriate))
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Treatment of 4-bromobenzonitrile (1a) with N-methylpyrrolidine
(4a: 10 equiv) and t-BuOOt-Bu (1 equiv) at 120 °C for 24 h gave N-
9 and 10). The reaction is applicable also to aryl chlorides, though a high
temperature is required. For example, the yield in the reaction of 4-
chlorobenzonitrile (1’a) was improved from 57% to 88% by raising the
temperature from 60 °C to 120 °C using t-BuOOt-Bu instead of
t-BuON=NOt-Bu (Table 2, entries 11 and 12).[11] Other aryl chlorides
underwent the α-arylation with 4a under these conditions (Table 2,
entries 13–15).
methyl-2-(4-cyanophenyl)pyrrolidine
(5aa)
and
N-(4-
cyanophenylmethyl)pyrrolidine (5’aa) (85:15) in 79% combined yield,
where no dehydrogenative coupling products were observed (Table 1,
entry 1).[8] The conversion and the yield were much lowered by use of a
decreased amount (0.2 equiv) of t-BuOOt-Bu (Table 1, entry 2), showing
that only a short radical chain is operative. No reaction took place in the
absence of t-BuOOt-Bu or at a low temperature (60 °C) of which
homolysis of t-BuOOt-Bu is negligible (Table 1, entries 3 and 4). The
reaction using t-BuON=NOt-Bu, which undergoes much more facile
homolysis than t-BuOOt-Bu to give t-BuO•,[9] at 60 °C scored a high
yield with a high regioselectivity (Table 1, entry 5). These results show
that the reaction proceeds at 60 °C when t-BuO• is available. In the
following investigation, we used the reaction conditions of entry 1 or 5
in Table 1 according to the combination of substrates.
Table 2: α-Arylation of N-methylpyrrolidine with aryl halides.[a]
Entry
1
1
yield of 5 + 5’ [%][b]
5:5’[c]
93:7
O
O
Br
78
H3C
1b
CN
Table 1: α-Arylation of N-methylpyrrolidine with 4-bromobenzonitrile using a
t-BuO• source.[a]
2
3
83
16[d]
3[d]
<1[d]
88
79:21
77:23
78:22
—
Br
1c
NC
Br
1d
F3C
Br
4
conv. of
1a
(%)[b]
yield of
5aa + 5’aa
(%)[b]
1e
t-BuO• source
temp.
(°C)
Entry
(equiv)
5aa:5’aa[c]
85:15
79:21
—
Br
5
1f
1
2
3
4
5
t-BuOOt-Bu (1)
t-BuOOt-Bu (0.2)
none
120
120
120
60
100
37
79
Br
35
6
90:10
88:12
88:12
82:18
83:17
94:6
<1
<1
99
<1
1g
t-BuOOt-Bu (1)
t-BuON=NOt-Bu (1)
<1
98 (95)[d]
—
Br
60
94:6
7
81
1h
[a] The reaction was carried out under a nitrogen atmosphere for 24 h
using 4-bromobenzonitrile (1a: 0.25 mmol), N-methylpyrrolidine (4a: 2.5
mmol) and t-BuO• source. [b] Determined by 1H NMR. [c] Determined by
GC and confirmed by 1H NMR. [d] The yield of the isolated product.
Br
8
22[d]
95
1i
S
N
Br
9
1j
The α-arylation of N-methylpyrrolidine (4a) using
t-BuON=NOt-Bu at 60 °C for 24 h was applied to various aryl bromides
(Table 2). Bromobenzenes having a conjugating electron-withdrawing
group such as cyano and methoxycarbonyl at para or ortho underwent
the reaction in high yields, whereas a cyano group at meta position or an
inductively electron-withdrawing trifluoromethyl group at para position
did not work effectively as a promoting substituent (Table 2, entries 1–
4; Table 1, Entry 5). These results show that the radical addition to
monocyclic aryl halides has a character of nucleophilic conjugate
addition.[10] Besides this type, another mode to accept addition of an α-
aminoalkyl radical is available when aryl halides have a polycyclic
structure. Nonsubstituted bromobenzene (1f) was unreactive toward 4a,
whereas 1-naphthyl and 9-anthryl bromides participated in the coupling
without the aid of a conjugating electron-withdrawing group (Table 2,
entries 5–7). The radical addition step is advantageous for these
polycyclic aromatics over monocyclic ones because the loss of
aromaticity upon addition is less severe. However, the yield was much
lower with 2-bromonaphthalene than with 1-bromonaphthalene (Table
2, entries 6 and 8), due to the difference in the stability of the
intermediates after the radical addition: just a benzylic radical for the
former and a benzylic as well as an allylic radical for the latter.
Heteroaryl bromides also participated in the α-arylation (Table 2, entries
Br
10
11
12[e]
13[e]
85
N
1k
NC
Cl
57
1'a
NC
Cl
88
85:15
90:10
1'a
O
O
Cl
70
H3C
1'b
Cl
14[e]
80
53
85:15
95:5
1'g
N
15[e,f]
Cl
1'l
[a] The reaction was carried out under a nitrogen atmosphere for 24 h
using an aryl halide (1 or 1’: 0.25 mmol), N-methylpyrrolidine (4a: 2.5
mmol) and t-BuON=NOt-Bu (0.25 mmol). [b] The yield of the isolated
products. [c]Determined by GC and confirmed by 1H NMR. [d] Determined
by
1H
NMR.
[e]
t-BuOOt-Bu
was
used
instead
of
t-BuON=NOt-Bu at 120 °C. [f] t-BuOOt-Bu (2 equiv) was used.
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10.1002/ejoc.201700548
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COMMUNICATION
Acyclic trialkylamines were also employed (Scheme 3). tert-
Butyl(dimethyl)amine (4b) and triethylamine (4c) underwent the α-
arylation with aryl and heteroaryl halides in moderate to high yields
(Scheme 3, entries 1–5). Dimethyl(sec-alkyl)amines (4d and 4e) were
arylated at a methyl group in high preference to the secondary alkyl
group (Scheme 3, entries 6–8). Preference for methyl over primary alkyl
groups was observed but in low selectivities (Scheme 3, entries 9–11).
The regioselectivity in the α-arylation of dissymmetric alkylamines is
well-understood, considering the regioselectivity of the hydrogen
abstraction as well as the rates in which the resulting radicals add to an
aryl halide. In the hydrogen abstraction step, the steric factor, which
favors the reaction order of methyl > primary >> secondary, seems to
slightly surpass the electronic factor, which depends on the stability of
the resulting radicals in order of secondary > primary > methyl. The
same tendencies of the steric and electronic factors are likely to be
operative in the addition step, where the electronic factor seems to
slightly surpass the steric factor. As a consequence, the steric factor in
the both steps makes secondary alkyl groups less reactive, whereas
methyl and primary alkyl groups show similar reactivities due to the
conflicting reaction orders in the steric and electronic factors. This does
not hold true for N-methylpyrrolidine (4a in Tables 1 and 2), the five-
membered primary alkyl group of which gives an exceptionally stable
alkyl radical,[12] making it electronically favored in both the hydrogen
abstraction and the addition steps.
reactivities toward aryl bromides with increased nucleophilicities.[14]
Primary amines such as butyl, isopropyl and cyclohexylamines were
subjected to the silyl protection–α-arylation–deprotection protocol to
give the corresponding α-arylated primary alkylamines (Scheme 4,
entries 1–3). The protocol is applicable also to secondary alkylamines
(Scheme
4,
entries
4–8).
The
arylation
of
cyclohexyl(methyl)(trimethylsilyl)amine (6n) took place exclusively at
the methyl group (Scheme 4, entry 7). The selectivity of methyl over a
primary
alkyl
was
high
in
the
reaction
of
butyl(methyl)(trimethylsilyl)amine
(6o)
compared
with
dibutyl(methyl)amine (4f) (Scheme 4, entry 8; cf. Scheme 3, entry 9).
Scheme 4. α-Arylation of trimethylsilylamines to give α-arylated primary
and secondary alkylamines.
In order to elucidate the stoichiometry of the α-arylation, we
pursued the products derived from an alkylamine (Scheme 5). In the
reaction of 4-bromobenzonitrile (1a) with cyclohexyl(dimethyl)amine
(4e) (cf. Scheme 3, entry 8), cyclohexyl(methyl)amine (7e) and
cyclohexanone (8e) were obtained in 62% and 6% yields, respectively.
Products 7e and 8e are most likely to be obtained through hydrolysis of
methylidene- and cyclohexylidene-containing iminium bromides
(Scheme 5, III), respectively, showing that an extra equivalent of the
alkylamine is consumed to reduce X• into X–.
Scheme 3. α-Arylation of acyclic tertiary alkylamines.
Scheme 5. Elucidation of the stoichiometry of the α-arylation of alkylamines.
Although no α-arylation took place with primary and secondary
alkylamines,[13] trimethylsilylated ones reacted with aryl bromides (1) to
give the corresponding desilylated α-arylation products after aqueous
work-up (Scheme 4). The resonance effect by the β-silyl group is likely
to facilitate formation of the radical intermediates and enhance the
On the basis of these results, the α-arylation of alkylamines with
aryl halides is likely to proceed through the mechanism we initially
expected (Scheme 6). Homolysis of t-BuOOt-Bu or t-BuON=NOt-Bu
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10.1002/ejoc.201700548
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COMMUNICATION
gives t-BuO•, which abstracts a hydrogen atom from a carbon–hydrogen
bond adjacent to the nitrogen atom of an alkylamine (4 or 6) (Scheme 6,
step a). The resulting α-aminoalkyl radical (I) adds to an aryl halide (1
or 1’) to give cyclohexadienyl radical intermediate II (Scheme 6, step b).
Although attack of I toward 1/1’ takes place also on carbon atoms having
a hydrogen atom (Scheme 6, step b’), the addition products such as II’
do nothing but going back to I and 1/1’ as the radical addition step is
reversible and its equilibrium lies far to I. Elimination of the halogen
radical (X•) gives α-arylation product 5 (Scheme 6, step c). Although it
is unclear how the eliminated X•, or the successively generated X2, is
reduced into X–, alkylamine 4/6 accept two electron oxidation directly
or indirectly by X• and t-BuO• to give iminium halides III, which are
converted into the corresponding dealkylated amine (7) and
aldehyde/ketone (8) by aqueous workup.[15]
cyclohexylbenzene and bromo(cyclohexyl)benzenes (1:5). J. R. Shelton, C. W.
Uzelmeier, J. Am. Chem. Soc. 1966, 88, 5222–5228.
[6]
Several research groups have recently reported the α-arylation of heteroatom-
containing aliphatic compounds with heteroaryl halides under photoredox
catalysis. Although an HAS mechanism is considered to be operative, how the
elimination of the halogen atom proceeds is not clarified. The reaction requires
a rather complicated photoredox system and the scope of aryl halides is limited
to heteroaryl chlorides containing more than two heteroatoms on the aromatic
ring. a) A. Singh, A. Arora, J. D. Weaver, Org. Lett. 2013, 15, 5390–5393; b) C.
K. Prier, D. W. C. MacMillan, Chem. Sci. 2014, 5, 4173–4178; c) A. Lipp, G.
Lahm, T. Opatz, J. Org. Chem. 2016, 81, 4890–4897. As a similar example
under photoredox catalysis, α-arylation of alkylamines with benzonitriles
having an electron-withdrawing group has been reported, where the proposed
mechanism includes single electron reduction of a benzonitrile to give the
corresponding anion radical, which undergoes coupling with α-aminoalkyl
radical, and the following elimination of cyanide (CN–) gives the α-arylation
product. d) A. McNally, C. K. Prier, D. W. C. MacMillan, Science 2011, 334,
1114–1117. Recently, α-arylation of alkylamines with aryl halides using a
photoredox and nickel catalyst has been reported, where an α-aminoalkyl radical
was transformed into an α-aminoalkyl nickel species to undergo the cross-
coupling reaction with an aryl halide. e) D. T. Ahneman, A. G. Doyle, Chem.
Sci. 2016, 7, 7002–7006. For a related example, see: f) D. R. Heitz, J. C. Tellis,
G. A. Molander, J. Am. Chem. Soc. 2016, 138, 12715–12718.
[7]
α-Arylation of secondary alkylamines is achieved e.g., through acylation of a
secondary amine, deprotonation by butyllithium, transmetalation of the resulting
α-(acylamino)alkyllithium with ZnCl2, the Negishi coupling with a heteroaryl
halide, and deacylation. a) K. R. Campos, A. Klapars, J. H. Waldman, P. G.
Dormer, C.-Y. Chen, J. Am. Chem. Soc. 2006, 128, 3538–3539. For a review,
see: b) E. A. Mitchell, A. Pœeschiulli, N. Lefevre, L. Meerpoel, B. U. W. Maes,
Chem. Eur. J. 2012, 18, 10092–10142.
Scheme 6. A plausible mechanism.
[8]
[9]
The reaction of 1a with a reduced amount (2 equiv) of 4a resulted in a much
lower yield (19%, 5aa:5’aa = 84:16) with a low conversion (28%) of 1a under
the conditions of entry 1 of Table 1.
In conclusion, we have disclosed α-arylation of tertiary
alkylamines or silylated primary and secondary alkylamines with aryl
halides utilizing a t-BuO• source. The reaction proceeds through
chemoselective homolytic aromatic substitution, where halogen atoms
(Br and Cl) act as leaving groups.
H. Kiefer, T. G. Traylor, Tetrahedron Lett. 1966, 6163–6168.
[10] Aryl halides having an electron-donating group such as 4-bromoanisole did not
participate in the α-arylation at all.
[11] Use of t-BuON=NOt-Bu (1 equiv) at 120 °C in the reaction of 4-
chlorobenzonitrile (1’a) with N-methylpyrrolidine (4a: 10 equiv) scored a lower
yield of 5aa and 5’aa (64%, 88:12), probably because supply of t-BuO• through
homolysis is too fast mismatching other steps.
Acknowledgements
[12] Facility in generating the corresponding radical from pyrrolidine compared with
structurally similar compounds is discussed on the basis of stereoelectronic
effect by the lone pair on the nitrogen atom. a) D. Griller, J. A. Howard, P. R.
Marriott, J. C. Scaiano, J. Am. Chem. Soc. 1981, 103, 619–623. For discussion
on the radical structures and stabilization energies of alkylamines including
pyrrolidine, see: b) D. D. M. Wayner, K. B. Clark, A. Rauk, D. Yu, D. A.
Armstrong, J. Am. Chem. Soc. 1997, 119, 8925–8932.
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.
[13] The reaction of butylamine or diethylamine (10 equiv) with 4-bromobenzonitrile
(1a: 1 equiv) in the presence of t-BuON=NOt-Bu (1 equiv) at 60 °C for 24 h
gave no α-arylated products with no consumption of 1a.
Keywords: α-arylation• alkylamines• aryl halides • radical
mechanism • t-BuO• source
[14] N. Auner, R. Walsh, J. Westrup, J. Chem. Soc., Chem. Commun. 1986, 207–208.
[15] The possibility that the halogen atom (X) undergoes elimination in a form of X–
after single electron reduction of cyclohexadienyl radical II by α-aminoalkyl
radical I, giving α-arylation products 5 and iminium salts III, cannot be
excluded. A similar mechanism has been proposed in the reduction of alkyl
halides into alkanes using α-aminoalkyl radicals. a) J. Lalevée, J. P. Fouassier,
N. Blanchard, K. U. Ingold, Chem. Phys. Lett. 2011, 511, 156–158. In the
reaction of dihalobenzenes (X–C6H4–X’) with dibenzylmercury giving PhCH2–
C6H4–X’ through an HAS mechanism, benzyl radical, which is generated in situ
and acts as the radical attacking X–C6H4–X’, is considered to work also as a
single electron reductant toward X-substituted cyclohexadienyl radicals to give
PhCH2–C6H4–X’ and PhCH2X. b) R. Henriquez, D. C. Nonhebel, Tetrahedron
1993, 49, 6497–6500.
[1]
For reviews, see: a) Free Radicals in Organic Chemistry (Eds.: J. Fossey, D.
Lefort, J. Sorba), John Wiley and Sons, Chichester, 1995, chap. 14, pp. 166–
180; b) R. Bolton, G. H. Williams, Chem. Soc. Rev. 1986, 15, 261–289; c) W.
R. Bowman, J. M. D. Storey, Chem. Soc. Rev. 2007, 36, 1803–1822.
For selected examples, see: a) G. P. Gardini, F. Minisci, G. Palla, A. Arnone, R.
Galli, Tetrahedron Lett. 1971, 59–62. b) A. Arnone, M. Cecere, R. Galli, F.
Minisci, M. Perchinunno, O. Porta, G. Gardini, Gazz. Chim. Ital. 1973, 103, 13–
29. For reviews, see: c) F. Minisci, Synthesis 1973, 1–24; d) F. Minisci, E.
Vismara, F. Fontana, Heterocycles 1989, 28, 489–519.
[2]
[3]
[4]
R. Ueno, E. Shirakawa, Org. Biomol. Chem. 2014, 12, 7469–7473.
For reviews on HAS with a halogen leaving group, see: a) J. G. Traynham, Chem.
Rev. 1979, 79, 323–330; b) M. Tiecco, Acc. Chem. Res. 1980, 13, 51–57; c) M.
Tiecco, Pure Appl. Chem. 1981, 53, 239–258.
[5]
For example, the reaction of bromobenzene (6.2 equiv) with cyclohexane (5
equiv) in the presence of t-BuOOt-Bu (1 equiv) gives
a mixture of
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10.1002/ejoc.201700548
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
R1
R1
R
R
t-BuOOt-Bu or t-BuON=NOt-Bu
+
X
H
α
-Arylation of Alkylamines
NR2R3
NR2R3
X = Br, Cl
Ryota Ueno, Yuko Ikeda and Eiji
Shirakawa*
R
R1
X
R1
NR2R3
R
t-BuO•
– X•
– t-BuOH
X
NR2R3
Page No. – Page No.
tert-Butoxy Radical-Promoted -
α
Just adding a tert-butoxy radical precursor, alkylamines react with aryl halides to
give α-arylalkylamines. The reaction proceeds through chemoselective homolytic
aromatic substitution of the halogen atom (Br or Cl) by an α-aminoalkyl radical.
Arylation of Alkylamines with Aryl
Halides
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