Copper-catalyzed intermolecular C-H amination of (Hetero)arenes via transient unsymmetrical λ3-iodanes

Article abstract of DOI:10.1021/ja502174d

A one-pot two-step method for intermolecular C-H amination of electron-rich heteroarenes and arenes has been developed. The approach is based on a room-temperature copper-catalyzed regioselective reaction of the in situ formed unsymmetrical (hetero)aryl-λ³-iodanes with a wide range of primary and secondary aliphatic amines and anilines.

Full text of DOI:10.1021/ja502174d

Article
pubs.acs.org/JACS
Copper-Catalyzed Intermolecular C−H Amination of (Hetero)arenes
via Transient Unsymmetrical λ3‑Iodanes
Igors Sokolovs, Dmitrijs Lubriks, and Edgars Suna*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
S
* Supporting Information
ABSTRACT: A one-pot two-step method for intermolecular
C−H amination of electron-rich heteroarenes and arenes has
been developed. The approach is based on a room-temper-
ature copper-catalyzed regioselective reaction of the in situ
formed unsymmetrical (hetero)aryl-λ3-iodanes with a wide
range of primary and secondary aliphatic amines and anilines.
arylation of amines.10 Symmetrical diaryl-λ3-iodanes are
INTRODUCTION
Hypervalent iodine(III) species possessing an iodine−nitrogen
■
preferred for N-arylation because unsymmetrical diaryl-λ3-
iodanes usually form a mixture of N-arylation products.10d,e
bond are efficient reagents in oxidative C−H amination of
nonprefunctionalized arenes and heteroarenes.1 The most
widely used are preformed or in situ generated sulfonylimino-
λ3-iodanes, which effect C−H to C−N bond transformations in
the presence of transition metal catalyst (eq 1).2 Phenyl-λ3-
We envisioned that a versatile method for C−H amination of
(hetero)arenes with unprotected amines as the source of
nitrogen could be developed, provided that the issue of
regioselectivity of amine transfer to the desired aromatic ring of
the unsymmetrical diaryl-λ3-iodanes could be solved. Recently,
we reported that a Cu(I) catalyst ensures complete regiocontrol
in a reaction of azides with unsymmetrical diaryl-λ3-iodanes.11
During this study, it became evident that nucleophiles other
than azide could be reacted regioselectively with a variety of
unsymmetrical heteroaryl-λ3-iodanes that are generated as
intermediates using suitable ArI(OH)OTs reagent. Herein,
we report a mild and versatile Cu(I)-catalyzed method for
intermolecular C−H amination of electron-rich heterocycles
(pyrroles, pyrrolopyridines, thienopyrroles, pyrrolopyrimidines,
and uracil) as well as simple arenes, comprising a one-pot two-
step room-temperature reaction between the (hetero)aryl-λ3-
iodanes formed in situ and a wide range of primary and
secondary amines (eq 4). The reactivity pattern of the
developed C−H amination approach is consistent with that
of an electrophilic aromatic substitution (SEAr) reaction.
Because of the operational simplicity, mild reaction conditions,
and wide substrate scope, our C−H amination approach
provides a convenient way for C−H functionalization of
heteroarenes,12 a topic of high importance in medicinal and
pharmaceutical chemistry given the drug-like properties of
heteroarenes and abundance of heterocycles in drugs.
iodane (formed in situ from PhI(OAc)2 and N-acetanilide) has
been proposed as a precursor of acylnitrenium species in a
transition metal-free C−H amination of arenes (eq 2).3−5
Analogous phenyl-λ3-iodanes possessing an iodine−nitrogen
bond have also been suggested as plausible intermediates in an
oxidative transfer of the phthalimide moiety to arene rings.6,7
Recently, a well-defined bis-tosylimido-λ3-iodane has been
RESULTS AND DISCUSSION
■
introduced by Muniz for a metal-free oxidative amination of
̃
arenes and heteroarenes (eq 3).8 All of the above-mentioned
approaches, however, have a serious limitation: only amides,
imides, and sulfonamides can be transferred to arenes or
heteroarenes by hypervalent iodine(III) species. Simple amines
are not compatible with these C−H amination conditions, as
they are oxidized by monoaryl-λ3-iodane reagents.9 In contrast,
amines are oxidatively stable toward diaryl-λ3-iodanes, and
these hypervalent iodine(III) species have been used for the N-
At the outset of our investigation, we synthesized the
indolyliodonium tosylate 2a in a pure form from MesI(OH)-
OTs13 and indole 1a. The structure of 2a was confirmed by X-
ray crystallographic analysis (Figure 1). λ3-Iodane 2a is stable in
MeCN, DCM, and DMSO solutions at room temperature for
Received: September 23, 2013
© XXXX American Chemical Society
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2, Table 1). Both Cu(I) and Cu(II) salts could be utilized;
however, the Cu(I) species ensured faster reaction (entry 3 vs
4). Faster formation of 3a helped to improve the 3a:4a ratio by
diminishing an impact of the competing noncatalyzed back-
ground formation of 4a (entry 2). The determined initial rates
of the noncatalyzed background reaction of 2a with morpholine
in DMSO (initial rate coefficient kobs = 1.98 × 10−7 mmol mL−1
s−1, DMSO-d6, 25 °C) evidence that the background reaction
delivers ca. 10% of 4a within 90 min. By this time, the Cu(I)-
catalyzed conversion of 2a to 3a is almost quantitative, so the
faster is 3a formation, the higher is 3a:4a selectivity. Screening
of various Cu(I) sources helped to identify the relatively stable
Cu(MeCN)4BF4 as the most efficient catalyst (entry 5). λ3-
Iodane 2a′ containing a Ph ligand instead of the mesityl group
could also be used at the expense of slightly diminished
selectivity (entry 6). However, Pd(II), Ni(II), and Sc(III) salts
were inefficient as catalysts (entries 7−9, Table 1).14
Indolylamine 3a could also be synthesized in a sequential
one-pot approach without isolation of the iodonium salt 2a.
Accordingly, Cu(MeCN)4BF4, morpholine, and EtN(i-Pr)2
were added to the reaction mixture after the corresponding
λ3-iodane 2a had been formed.15 The one-pot sequential C−H
amination approach afforded lower yields of 3a as compared to
the two-step synthesis (74% vs 85%), but avoided the isolation
and handling of potentially unstable intermediate λ3-iodanes.
This advantage compensates for the decreased yields.
Various amines were subsequently examined in the Cu(I)-
catalyzed two-step one-pot C−H amination of indole 1a (Table
2). A wide variety of aliphatic secondary amines (entries 1−11),
aliphatic primary amines (entries 12−26), primary and
secondary aromatic amines (entries 27−35), as well as a
heteroarylamine (entry 36) and ammonia (entry 37) could be
employed. Importantly, the reaction conditions are compatible
with alkene and alkyne moieties in the amine (entries 10, 22,
23).16 N-Boc (entry 17), N-acetyl (entry 5), and S-trityl (entry
20) protecting groups, acetals (entry 21), ketals (entry 2), as
well as various functional groups such as esters (entry 30),
nitriles (entries 9,15), nitro (entry 31), and halides (entries 24,
25, 28) are all tolerated. Sterically hindered amines (entries 14,
Figure 1. X-ray crystal structure of λ3-iodane 2a (ellipsoids at 50%
probability) with hydrogen atoms omitted for clarity. Selected bond
distances (Å) and angles (deg): I16−C3, 2.086(7); I16−C17,
2.108(8); I16−O12, 2.713(7); I−O1A, 3.088(9); I−O2A, 3.001(8);
C3−I16−C17, 98.2(3). See the Supporting Information for details.
at least 72 h, but addition of morpholine and DIPEA to a DCM
solution of 2a brought about its slow transformation to
iodoindole 4a (entry 1, Table 1). The process was facilitated by
using DMSO as solvent (entry 2). The conversion of 2a to 4a
was highly selective, and only traces of indolylamine 3a were
observed. In striking contrast, addition of CuOTf (10 mol %)
resulted in complete reversal of selectivity favoring the
formation of the desired 3a. Furthermore, the copper catalyst
considerably decreased the reaction time (entry 3 vs entries 1−
Table 1. Reaction of λ3-Iodane 2a with Morpholine
ab
,
bc
,
entry
catalyst (10 mol %)
solvent, time
CH2Cl2, 24 h
conversion %
3a:4a ratio, (yield %)
1
2
3
4
5
none
15
81
60
22
92
93
5
1:99 (8)
1:99 (67)
97:3 (46)
93:7 (14)
none
DMSO, 24 h
CuOTf·PhH
Cu(OTf)2
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Pd(OCOCF3)2
Ni(OTf)2
CH2Cl2−DMSO 4:1, 1.5 h
CH2Cl2−DMSO 4:1, 1.5 h
CH2Cl2−DMSO 4:1, 1 h
CH2Cl2-DMSO 4:1, 1.5 h
CH2Cl2−DMSO 4:1, 1.5 h
CH2Cl2−DMSO 4:1, 1.5 h
CH2Cl2−DMSO 4:1, 1.5 h
d
97:3 (85)
e
6
89:11 (76)
1:99 (3)
1:99 (5)
1:99 (5)
7
8
9
5
Sc(OTf)3
7
a
b
Conditions: λ3-iodane 2a (1.0 equiv), morpholine (1.2 equiv), solvent (10 mL/1 mmol of 2a), room temperature. Determined by LC−MS assay.
c
d
e
Yield of the major product. Isolated yield of >95% pure indole 3a. λ3-Iodane 2a′ possessing Ph ligand instead of a mesityl group (Mes = Ph) was
used.
B
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a
Table 2. Sequential One-Pot Synthesis of Indolylamines 3a−3ak
a
Conditions: Indole 1a (1.0 equiv), MesI(OH)OTs (1.1 equiv), CF3COOH (1.2 equiv), CH2Cl2 (4 mL/1 mmol of 1a), room temperature, 15 min;
then amine (1.2 equiv), EtN(i-Pr)2 (2.0 equiv), Cu(MeCN)4BF4 (0.1 equiv), 1:1 CH2Cl2:DMSO (4 mL/1 mmol of 1a), room temperature, 2 h.
b
c
Reaction time for the formation of 3h from λ3-iodane: 18 h. 3 equiv of EtN(i-Pr)2 was used.
33, 34) are also suitable as substrates.17 Amines react
chemoselectively in the presence of unprotected alcohol
(entry 16), amide (entry 6), and sulfonamide moieties (entry
32), and monoamination with piperazine is also possible (entry
7). It should be noted that moderate yields were obtained for
bi- and tridentate amines potentially capable of chelating the
Cu(I) catalyst (entries 8, 18).
MesI(OH)OTs could be facilitated by addition of CF3COOH
(1.2 equiv). This did not work always, and pyrroles possessing
several electron-withdrawing substituents such as N-tosyl-1H-
pyrrole-2-carboxylic acid ethyl ester did not give substantial
conversion to the corresponding iodonium salt under our
standard conditions with added CF3COOH. Furthermore,
potential substrates such as N-methylbenzimidazole, benzo[b]-
thiophene, and ethyl thiophene-2-carboxylate were also
unreactive. Apparently, the latter heterocycles are insufficiently
electron-rich to produce iodonium salts in the reaction with
MesI(OH)OTs. On the other hand, we were especially pleased
to find that electron-rich carbocyclic arenes undergo C−H
amination as exemplified in Table 4. Surprisingly, even the
simple substrates such as tetraline (entry 1) and N-Boc-N-
methylaniline (entry 2) could be employed in the C−H
amination reaction. The formation of the intermediate diaryl-
λ3-iodane from tetraline (entry 1) required prolonged time (18
h) apparently because of insufficiently electron-rich nature of
tetraline. The presence of electron-releasing alkoxy groups
facilitates considerably the formation of intermediate diaryl-λ3-
iodane (entries 3−5 vs entry 1). Further improvement of C−H
amination yields was achieved for arenes containing two
electron-releasing substituents (entries 6−9, Table 4). In
general, the more electron-rich is (hetero)arene, the shorter
are the times required to produce the intermediate diaryl-λ3-
iodane. However, transient λ3-iodanes formed from electron-
rich (hetero)arenes usually are unstable and are prone to
undesired decomposition if the addition of Cu catalyst and/or
Next, the scope of substrates for the C−H amination was
surveyed employing morpholine, cyclopropylmethylamine, and
4-bromoaniline as representative amines (Table 3). All
heterocycles that react with MesI(OH)OTs and form iodonium
salts that survive in solution are suitable as substrates, including
2-substituted indoles (entries 1−6),18 pyrroles (7−14), thieno-
[3,2-b]pyrrole (entries 15, 16), pyrrolo[2,3-b]pyridines (entries
17, 18), pyrrolo[2,3-d]pyrimidine (entry 19), pyrazoles (entries
20−22), and N,N-dimethyluracil (entry 23). The formation of
the intermediate iodonium salts was found to be sensitive to the
electronic properties of heterocycle.19 Thus, relatively electron-
rich N-alkyl pyrroles (entries 7−10, 12−14) and pyrrolo[2,3-
b]pyridine (entry 18) reacted rapidly and produced the
intermediate iodonium salts within 5 min. In contrast,
introduction of an electron-withdrawing N-acyl moiety in
pyrrole (entry 11) increased the reaction time to 30 min. The
formation of iodonium salts from less electron-rich heterocycles
such as indoles (entries 1−6), pyrrolo[2,3-b]pyridine (entry
17), pyrrolo[2,3-d]pyrimidine (entry 19), pyrazoles (entries
20−22), and N,N-dimethyluracil (entry 23) was considerably
slower. However, the reaction of these substrates with
C
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Table 3. C−H Amination of Heterocycles
a
Conditions: Heteroarene (1.0 equiv), MesI(OH)OTs (1.1 equiv), CH2Cl2 (4 mL/1 mmol of the starting heteroarene), 15 min; then amine (1.2
equiv), EtN(i-Pr)2 (2.0 equiv), Cu(MeCN)4BF4 (0.1 equiv), 2:1 CH2Cl2:DMSO (4 mL/1 mmol of the starting heteroarene), room temperature, 2
b
c
h. In the presence of CF3COOH (1.2 equiv). λ3-Iodane was formed at −20 °C.
amine is delayed. Therefore, it is important to establish the
optimum conversion time of the starting (hetero)arene into λ3-
iodane.
possess two different electron-releasing substituents. The
observed regioselectivity of C−H amination in meta-anisidines
(entries 10, 11) might also be attributed to stabilization of
intermediate λ3-iodane by the adjacent N-Boc moiety.
However, we regard such stabilization unlikely because N-
Boc-N-methylaniline underwent C−H amination in the para-
position, and not next to the aniline nitrogen (entry 2, Table
4). Notably, all of the other C−H amination products (Tables 3
and 4) were likewise obtained as pure regioisomers, and the
The regioselectivity of the C−H amination is controlled at
the stage of the formation of the intermediate iodonium salts.
Although the regioselectivity is a result of the combined
directing effects of substituents in heterocycles and arenes, in
general, it is consistent with that of electrophilic aromatic
substitution (SEAr) reactions. Thus, λ3-iodanes are formed at
the β-position of indoles (entries 1−6, Table 3) and fused
pyrroles (entries 15−19), at the α-position of pyrroles20a
(entries 9, 10, 12−14), and at position 5 of uracil20b (entry 23),
while 2,5-disubstituted pyrroles (entries 7, 8, 11) produce
iodonium salts at the β-position. In the case of simple arenes,
intermediate λ3-iodanes are selectively formed in the para-
position to the strongest electron-releasing substituent in the
molecule, for example, alkyl moiety (entry 1, Table 4), N-Boc-
N-methylamino group (entry 2), alkoxy (entry 4), and MeO
groups (entries 3, 5−8).21 Interestingly, C−H amination
proceeds in para-position to the MeO group also in N-
protected methoxyanilines (entries 9−11), substrates that
1
formation of minor isomers was not observed within H NMR
detection limits.
The C−H amination conditions are compatible with the
presence of O-allyl (entry 1, Table 3), O-tert-butyl (entry 2,
Table 3), O-alkyl ester moieties (entries 5−10, 12−17, Table
3), as well as amides (entries 7, 8, Table 4) and tert-butyl
carbamates (entries 2, 10, 11, Table 4). The successful C−H
amination of substrates containing secondary amide (entry 7,
Table 4) and carbamate (entry 10, Table 4) moieties is
noteworthy, because structurally related N-acetanilides react
with PhI(OAc)2 and generate highly reactive acylnitrenium
species.3b,d Bromine and chlorine substituents in the substrate
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the Cu(OTf)2-catalyzed formation of 3a in the presence of
neocuproin was observed, evidencing that the catalytically
active species are indeed Cu(I) salts.
Table 4. C−H Amination of Arenes
A radical inhibition test was performed to exclude the
possibility of C−H amination of 2a via a radical chain pathway.
Accordingly, the addition of radical scavengers such as 2,6-di-
tert-butyl-4-methylphenol (BHT)26 and TEMPO27 (both in 10-
fold excess with respect to Cu(I)) did not affect the rate of
Cu(MeCN)4BF4-catalyzed conversion of 2a to 3a in CH2Cl2−
DMSO = 4:1. These data strongly argue against the
involvement of a radical chain process. Notably, the addition
of radical scavengers considerably decelerated the background
noncatalyzed reaction of λ3-iodane 2a with morpholine to
produce 4a (Table 1, entry 2). Thus, only 27% of 4a was
formed in the presence of TEMPO after 24 h at room
temperature (at 31% conversion of 2a), and 15% of 4a (at 24%
conversion) was observed after 12 h at room temperature with
added BHT (both radical scavengers were added in equimolar
amounts to the starting 2a). Presumably, the noncatalyzed
reaction of λ3-iodane 2a with morpholine proceeds through a
radical chain pathway.
Kinetic studies were also carried out to establish the kinetic
order of Cu(I)-catalyzed C−H amination of 2a in each reaction
component. Morpholine was employed both as a nucleophile
and as a base, and (CuOTf)2·PhH was used as a catalyst. The
reactions were monitored by NMR spectroscopy, and the
method of initial rates was used to determine rate coefficients.
The Cu(I)-catalyzed conversion of 2a to 3a in DMSO-d6 at 25
°C was found to be first-order in (CuOTf)2·PhH (see
Supporting Information, Figure S2), first-order in morpholine
(see Supporting Information, Figure S3), and zeroth-order in
λ3-iodane 2a (see Supporting Information, Figure S4). These
data indicate that the Cu(I) catalyst and morpholine are both
involved in the rate-limiting step of the catalytic cycle, whereas
the subsequent reactions of λ3-iodane 2a are fast. It is likely that
(CuOTf)2·PhH and morpholine form a complex I, which exists
in equilibrium with the bis-amine complex II. Assuming that II
is a resting state of the catalyst,28 dissociation of morpholine
under equilibrium conditions would produce a catalytically
active complex I (Scheme 1).
Several plausible pathways for Cu(MeCN)4BF4-catalyzed C−
H amination of 2a are consistent with the data above (Scheme
1). In pathway A, Cu(I)−amine complex I coordinates with the
electron-rich indole moiety in the λ3-iodane 2a, forming a η2-
complex III. Subsequent substitution of tosylate by amine in
the intermediate III and reductive elimination from the highly
unstable λ3-iodane IV29 would lead to aminoheterocycle 3a.
The formation of η2-coordinated species such as III and IV has
been proposed in the transition state for the oxidative addition
of aryl halides to Cu(I) complexes.28a,30 π-Interaction between
the Cu(I)−amine complex I and indole 2a should increase
electrophilicity of the heterocycle ipso-carbon in the putative
intermediates III and IV, thus facilitating C−N bond forming
reductive elimination from λ3-iodane IV. However, other Lewis
acids such as Pd(OCOCF3)2, Ni(OTf)2, and Sc(OTf)3 did not
catalyze the formation of 3a (Table 1, entries 7−9), so the
involvement of η2-coordination between Cu(I) species and the
indole moiety in intermediates III or IV can be questioned.
In an alternative possibility, pathway B involves direct
oxidative addition of the λ3-iodane 2a to Cu(I)−amine complex
I to form the Cu(III) intermediate V.31 For unsymmetrical
diaryl-λ3-iodanes, regioselectivity of the oxidative addition to
Cu(I) species can be controlled by the use of a mesityl group as
a
Conditions: Arene (1.0 equiv), MesI(OH)OTs (1.1 equiv), CH2Cl2
(4 mL/1 mmol of the starting arene), 15 min; then amine (1.2 equiv),
EtN(i-Pr)2 (2.0 equiv), Cu(MeCN)4BF4 (0.1 equiv), 2:1
CH2Cl2:DMSO (4 mL/1 mmol of the starting arene), room
temperature, 2 h. In the presence of CF3COOH (1.2 equiv). At
70% conversion.
b
c
as well as N-benzoyl, N-benzyl, N-tosyl, and N-SEM protecting
groups are also tolerated (Tables 3 and 4).
Mechanistic Studies. Although both Cu(I) and Cu(II)
salts can be employed as catalysts in the C−H amination
reaction, the considerably faster formation of 3a in the presence
of Cu(I) species as compared to Cu(II) (entry 3 vs entry 4,
Table 1) suggests that Cu(I) salts are the catalytically active
species. The slow formation of 3a in the Cu(II)-catalyzed
reaction (entry 4, Table 1) could be ascribed to an in situ
reduction of Cu(II) to active Cu(I) catalyst by amine.22,23 To
verify the catalytic efficiency of Cu(I) species, the Cu(OTf)2-
catalyzed C−H amination of 2a was performed in the presence
of 2 equiv of neocuproin, a highly specific chelating agent for
Cu(I) ions. Neocuproin (2,9-dimethyl-1,10-phenanthroline) is
a bidentate ligand that forms a stable bright orange-colored
complex of formula CuI(neocuproin)2,24 thus acting as an
inhibitor of Cu(I)-catalyzed reactions.25 Complete inhibition of
E
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Scheme 1. Plausible Pathways for C−H Amination of Heteroarenes
Scheme 2. C−H Amination of λ3-Iodane 32 Containing a Radical Probe
a nontransferable aryl ligand.31c−f,32 The Cu(III) intermediate
V undergoes N−H deprotonation of the Cu(III)-coordinated
amine with EtN(i-Pr)2.33 Product-forming reductive elimina-
tion from the resulting Cu(III)−amide complex VI would
afford 3a and regenerate a catalytically active Cu(I) species.34
However, the proposed transient Cu(III) complexes V or VI
could not be detected, presumably because they undergo rapid
C−N bond forming reductive elimination.35 This behavior is
expected because related, highly reactive Cu(III) species have
only been observed in chelation-stabilized complexes based on
stabilizing triazamacrocyclic ligands.36
As a third option, pathway C involves a Cu(I)/Cu(II)
catalytic cycle, which starts with an inner-sphere single-electron
transfer (SET) from Cu(I)-complex22,25b,37 to the λ3-iodane 2a,
generating an intimate radical anion−Cu(II) complex VII.38
Experimental redox potentials versus SCE were determined by
cyclic voltammetry for λ3-iodane 2a (E = −0.76 V) and for
Cu(MeCN)4BF4 (E = +0.85 V),39 and they support the
feasibility of SET between Cu(I) catalyst and iodonium salt 2a.
The radical anion−Cu(II) complex VII might undergo
fragmentation to a radical pair VIII, which couples with the
amine moiety with a second SET that regenerates the Cu(I)
species.40 To test for the intermediacy of heteroaryl radicals in
the Cu(I)-catalyzed C−H amination reaction, diaryl-λ3-iodane
32 containing an O-allyl moiety as a radical clock probe was
employed as substrate in the reaction with morpholine in the
presence of equimolar and catalytic (10 mol %, not shown)
amounts of Cu(MeCN)4BF4 (Scheme 2, eq 5). It has been
demonstrated that the λ3-iodane 32-derived aryl radical IX
undergoes extremely rapid 5-exo-trig cyclization (rate constant k
9
= 9.6 × 10 s−1) to furnish 3-methyl-2,3-dihydrobenzofurane
33 after abstraction of the hydrogen atom from the medium
(Scheme 2, eq 6).41 In our hands, N-substituted morpholine 34
was obtained as the major product, and no detectable amount
of the cyclization product 33 was observed (Scheme 2, eq 5).42
These data provide strong evidence that the Cu(I)-catalyzed
C−H amination occurs without involvement of free heteroaryl
radicals such as VIII (Scheme 1, pathway C). On the other
hand, the putative radical anion−Cu(II) complex VII may
undergo a radical recombination to furnish aryl−Cu(III)
species V.43 The subsequent steps would involve the same
conversion from V to VI as in pathway B. Although we regard
the latter scenario as the most probable, neither pathway A nor
pathway C could be ruled out. Further mechanistic studies are
necessary to fully elucidate the mechanism of the newly
developed C−H amination approach.
CONCLUSIONS
In summary, a versatile method for an intermolecular C−H
amination of electron-rich heteroarenes and arenes has been
■
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mol %) and a magnetic stirbar, and the source flask was rinsed with
CH2Cl2 (1 mL). To the resulting well-stirred suspension was
immediately added a solution of amine or aniline (0.6 mmol, 1.2
equiv) in anhydrous CH2Cl2 (1 mL) (Important: Decomposition of
the formed λ3-iodane begins if the addition of Cu catalyst and/or
amine is delayed!). Finally, neat DIPEA (174 μL, 1.00 mmol, 2 equiv)
was added, followed by DMSO (1 mL). The resulting solution was
stirred at room temperature under argon atmosphere, and the progress
of the reaction was monitored by TLC (the intermediate λ3-iodanes
have Rf = 0.4−0.6; mobile phase 20:80:5 MeOH/CH2Cl2/AcOH). In
most cases, the reaction was completed in 2 h. The solution was
poured into 50 mL of water and 20 mL of saturated aqueous ammonia
solution, extracted with CH2Cl2 (3 × 30 mL), and combined organic
extracts were dried over Na2SO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel.
developed. The one-pot sequential two-step procedure
comprises the in situ formation of unsymmetrical (hetero)-
aryl-λ3-iodanes followed by their Cu(I)-catalyzed reaction with
a wide range of primary and secondary aliphatic amines and
anilines. The Cu(I) catalyst ensures the desired selectivity in
the reaction between the intermediate unsymmetrical λ3-
iodanes and amines. Initial mechanistic studies point toward a
stepwise oxidative addition and involvement of single electron
transfer from Cu(I) catalyst to unsymmetrical (hetero)aryl-λ3-
iodanes. The reaction proceeds at room temperature and
tolerates a number of functional groups both in the amine and
in the (hetero)arene. The regioselectivity of the C−H
activation is typical for electrophilic aromatic substitution
(SEAr) reactions. Our C−H amination approach is an
alternative and complementary method to transition metal-
catalyzed direct intermolecular Csp2−H amination of arenes,44
which often requires the presence of a metalation-directing
group in substrate45 and employs imides, amides, sulfonamides,
as well as organic azides or preactivated amino precursors such
as N-chloroamines as sources of nitrogen.46 In cases where the
transition metal-catalyzed amination is not applicable, our
method may be especially useful for late-stage amination of
pharmaceutically relevant aromatics, and especially hetero-
cycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization data, 1H and
13C NMR spectra, X-ray crystallographic data for λ3-iodane 2a
(CIF), cyclic voltammograms (CV), and details of the kinetic
experiments. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
edgars@osi.lv
■
EXPERIMENTAL SECTION
■
Notes
Ethyl 5-Bromo-1-methyl-3-({[(4-methylphenyl)sulfonyl]oxy}-
(2,4,6-trimethylphenyl)-λ3-iodanyl)-1H-indole-2-carboxylate
(2a). To a solution of MesI(OH)OTs (2.39 g, 5.50 mmol, 1.1 equiv)
in CH2Cl2 (10 mL) was added TsOH·H2O (1.05 g, 5.50 mmol, 1.1
equiv), and the resulting suspension was stirred for 5 min at room
temperature. Next, a solution of indole 1a (1.41 g, 5.00 mmol, 1 equiv)
in CH2Cl2 (10 mL) was added rapidly to the well-stirred suspension.
The progress of the reaction was monitored by TLC (disappearance of
the starting material spot, Rf = 0.55, 1:5 EtOAc/petroleum ether), and
complete conversion of the starting 1a was observed within 30 min.
Solvent was concentrated to ca. 2/3 of the original volume, and Et2O
was added (50 mL). Formed precipitate was filtered, washed with
Et2O (100 mL), and dried in vacuo to afford 2a as a white powder
(3.30 g, 95% yield); analytical TLC on silica gel, 20:80:5 MeOH/
CH2Cl2/AcOH, Rf = 0.49. Pure material was obtained by
crystallization from CH2Cl2/diethyl ether: mp 125 °C. dec IR (film,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Latvian Science Council Grant
No. 274/2012. I.S. thanks the European Social Fund for a
scholarship within the project “Support for Doctoral Studies at
University of Latvia”. We thank Dr. S. Belyakov for X-ray
crystallographic analysis, Dr. B. Turovska for voltammetry
experiments, Dr. I. Nakurte (Universty of Latvia) for HRMS
analyses, and I. Goba for assistance with NMR experiments. We
also thank Prof. E. Vedejs for helpful discussions.
REFERENCES
■
1
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