Copper-Catalyzed para-Selective C-H Amination of Electron-Rich Arenes

Article abstract of DOI:10.1021/acscatal.5b01992

A one-pot two-step method for para-selective C-H amination of carbocyclic arenes comprises the in situ formation of unsymmetrical diaryl-λ³-iodanes followed by their Cu(I)-catalyzed reaction with a range of N-unprotected amines.

Full text of DOI:10.1021/acscatal.5b01992

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Article
Copper-Catalyzed para–Selective C–H Amination of Electron-Rich Arenes
Beatrise Berzina, Igors Sokolovs, and Edgars Suna
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01992 • Publication Date (Web): 15 Oct 2015
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CopperꢀCatalyzed para–Selective C–H Amination of ElectronꢀRich Arenes
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Beatrise Berzina, Igors Sokolovs, and Edgars Suna*
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Latvian Institute of Organic Synthesis, Aizkraukles 21, LVꢀ1006, Riga, Latvia
edgars@osi.lv
Abstract: A oneꢀpot twoꢀstep method for paraꢀselective C−H amination of
carbocyclic arenes comprises the in situ formation of unsymmetrical diarylꢀλ3ꢀiodanes
followed by their Cu(I)ꢀcatalyzed reaction with a range of Nꢀunprotected amines.
Keywords: hypervalent iodine, diaryliodonium salts, copper, amination,
regioselectivity
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Introduction
Lateꢀstage modification of pharmaceutically relevant compounds allows for
introduction of a structural diversity at final stages of synthesis and provides a rapid
and straightforward access to a number of analogues. Therefore the lateꢀstage
modification is frequently employed to streamline the leadꢀoptimization process in
drug development.1 Ideally, introduction of structural diversity is to be accomplished
without a preactivation of the lead compound. Hence, the most suitable approach to
the lateꢀstage modification relies on the functionalization of C–H bonds.
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Among a variety of C–H functionalization methods, the intermolecular C–H
amination has become a focus of increasing research during the last years.
Notwithstanding remarkable advances in the field of transition metalꢀcatalyzed Csp2–
H amination,2,3 the majority of the developed methods require the presence of a metalꢀ
coordinating substituent4 which facilitates the cleavage of an orthoꢀC–H bond by
transition metal. Therefore most of the reported catalytic C–H to C–N transformations
in arenes are directed to the orthoꢀposition.5 Recently, auxiliary substituents capable
of directing the CꢀH activation to the metaꢀposition have been designed,6 however the
directed metaꢀC–H amination has not been reported thus far. Likewise, a
complementary paraꢀselective Csp2–H amination methodology is considerably less
developed compared to the directed orthoꢀC–H amination. Thus, there are a handful
of paraꢀselective Csp2–H amination examples in the literature. Early reports describe
electrophilic aromatic substitution of electronꢀrich arenes with azodicarboxylates in
the presence of Lewis acids7 or Brønsted acids,8 and more recently, in a Au(III)ꢀ
catalyzed process (eq 1).9 Zhang has reported an amideꢀdirected Pdꢀcatalyzed paraꢀ
C–H imidation with Nꢀfluorobenzenesulfonimide (NFBS) as a source of nitrogen (eq
2).10 High paraꢀselectivity levels of Csp2–N bond formation in arenes have been
achieved by using hypervalent iodine(III) reagents. Thus, PhI(OAc)2ꢀmediated
oxidative transfer of phthalimide moiety to arene rings proceeded with reasonable
paraꢀselectivity in the presence of Au(I) catalyst (eq 3).11 Relevant to our work is a
transition metalꢀfree paraꢀC−H amidation of arenes in the presence of PhI(OAc)2 (eq
4), which presumably involves formation of a phenylꢀλ3ꢀiodane intermediate
possessing an iodine−nitrogen bond.12 A single example of metalꢀfree paraꢀC−H
imidation using bisꢀtosylimidoꢀλ3ꢀiodane has recently been reported by Muñiz.13
Importantly, in all of the aboveꢀmentioned examples, additional synthetic steps are
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required to elaborate the C–H amination products into Nꢀunsubstituted anilines. These
postꢀamination transformations reduce the synthetic advantages of the direct C–H to
C–N transformation, so a method compatible with Nꢀunprotected amines as the source
of nitrogen would substantially increase the synthetic value of the paraꢀselective
Csp2–H amination methodology.
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In our continuing efforts to develop a synthetic method for the lateꢀstage
functionalization of pharmaceutically relevant heterocycles we recently disclosed a
Cu(I)–catalyzed Csp2–H amination of heteroarenes with Nꢀunprotected amines.14 The
oneꢀpot twoꢀstep method comprised the reaction between arene and hypervalent
iodonium reagent ArI(OH)OTs to form unsymmetrical diarylꢀλ3ꢀiodanes, which
reacted in situ with a range of Nꢀunprotected amines in the presence of Cu(I) catalyst
to afford heteroarylamines. The developed method was suitable also for C–H
amination of certain electronꢀrich carbocyclic arenes in moderate yields. Importantly,
C–N bond formation in arenes proceeded in paraꢀposition with respect to electronꢀ
releasing substituents. Unfortunately, moderate yields and narrow scope of suitable
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arenes compromised the synthetic advantage of the developed paraꢀCsp2–H
amination approach. Herein, we report a further development of the Cu(I)–catalyzed
para–Csp2–H amination methodology (eq 5) which addresses the aboveꢀmentioned
drawbacks. Key to the success was the increase of steric hindrance in iodonium
reagent ArI(OH)OTs and the use of strong acid additives as described below. The new
conditions feature improved yields and are compatible with substantially increased
scope of arenes.
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Results and Discussion
Orthoꢀxylene (1d) was selected as a substrate for the method development
studies because it was unreactive under the published C–H amination conditions
which involved an initial treatment of the arene 1d with MesI(OH)OTs (1.1 equiv) in
anhydrous CH2Cl2 at room temperature to form an unsymmetrical diarylꢀλ3ꢀiodane
2d, followed by addition of catalytic amounts of Cu(MeCN)4BF4, morpholine, DIPEA
and DMSO.14 We reasoned that the lack of reactivity for 1d may be attributed to slow
formation of an intermediate unsymmetrical diarylꢀλ3ꢀiodane 2d in the reaction of 1d
with MesI(OH)OTs reagent. It has been shown that strong acids such as TsOH and
TfOH facilitate the formation of diarylꢀλ3ꢀiodanes from arenes.15 Indeed, addition of
TfOH (1.2 equiv) to a mixture of orthoꢀxylene (1d) and MesI(OH)OTs in acetonitrile
resulted in the formation of diarylꢀλ3ꢀiodane 2d in 83% yield. The latter was isolated
in pure form and was subsequently used for optimization of Cu(I)ꢀcatalyzed reaction
with morpholine as shown in Table 1.
Table 1. Reaction of λ3ꢀiodanes 2d and 3d with morpholine.
λ3ꢀiodane
entry
1
2
catalyst, mol%
solvent
time, temp
4d,%a,b 5,%b 6,%b
Cu(MeCN)4BF4, 10 CH2Cl2–DMSO 4:1 8 days, rt
Cu(MeCN)4BF4, 10 MeCN–DMSO 1:4 8 days, rt
40
49
14
18
ꢀ
ꢀ
2d
2d
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14f
15g
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Cu(MeCN)4BF4, 10 CH2Cl2–DMSO 4:1 8 days, rt
Cu(MeCN)4BF4, 10 MeCN–DMSO 1:4 12 h, 40 °C
39
80
83
84
75c
47d
75
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
3d
3d
3d
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3d
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3d
3d
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3d
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3d
3d
Cu(MeCN)4BF4, 10 DMSO
12 h, 40 °C
Cu(MeCN)4BF4, 5
Cu(MeCN)4BF4, 2
MeCN–DMSO 1:4 40 h, 40 °C
MeCN–DMSO 1:4 48 h, 40 °C
Cu(MeCN)4BF4, 0.5 MeCN–DMSO 1:4 48 h, 40 °C
CuI, 10
MeCN–DMSO 1:4 24 h, 40 °C
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CuBrꢀSMe2, 10
CuOTf, 10
MeCN–DMSO 1:4 130 h, 40 °C 37
MeCN–DMSO 1:4 130 h, 40 °C 26
Cu(OTf)2, 10
Cu(BF4)2•6H2O, 10
MeCN–DMSO 1:4 40 h, 40 °C
MeCN–DMSO 1:4 60 h, 40 °C
74e
31
68
Cu(MeCN)4BF4, 10 MeCN–DMSO 1:4 40 h, 40 °C
Cu(MeCN)4BF4, 10 MeCN–DMSO 1:4 40 h, 40 °C
67
none
MeCN–DMSO 1:4 40 h, 40 °C
<1h
b
a 99% conversion of 2d or 3d. Isolated yield of >95% pure product (NMR assay).
c 90% conversion of 3d. d 50% conversion of 3d. e 49% conversion of 3d after 12 h at
40 C. In the presence of water (10 equiv). Performed under air. 20% conversion
o
f
g
h
of 3d.
The reaction of 2d with morpholine turned out to be very slow and the desired
product 4d was formed in only 40% yield after 8 days at room temperature (entry 1).
Furthermore, a concomitant formation of the undesired Nꢀmesityl morpholine 5d was
also observed (3:1 ratio of 4d:5d). Simple change of solvents did not alter the 4d:5d
ratio (entry 2). Apparently, insufficient electronic and steric differences between the
nontransferable mesityl ligand and xylyl moiety were responsible for the poor
regioselectivity of the Cu–catalyzed reaction between the diarylꢀλ3ꢀiodane 2d and
morpholine. We hypothesized that increase of the steric demand of the
nontransferable aryl ligand in the diarylꢀλ3ꢀiodane 2d could solve the selectivity
issue.16 To this end, unsymmetrical diarylꢀλ3ꢀiodane 3d possessing bulky 2,4,6ꢀ
triisopropylphenyl (TIPP) group was synthesized from orthoꢀxylene (1d) and TIPPꢀ
I(OH)OTs17 in the presence of TfOH (48% yield of recrystallized material). The
structure of 3d was confirmed by Xꢀray crystallographic analysis (Figure 1).
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Figure 1. Xꢀray crystal structure of λ3ꢀiodane 3d (ellipsoids at 50% probability) with
hydrogen atoms omitted for clarity. Selected bond distances (Å) and angles (deg):
I1−C1, 2.131(5); I1−C16, 2.118(6); I1−O1A, 3.359(4); I−O3A, 3.513(4);
C1−I1−C16, 100.1(2). See the Supporting Information for details.
We were pleased to see that the reaction of diarylꢀλ3ꢀiodane 3d with morpholine
in the presence of Cu(MeCN)4BF4 catalyst18 proceeded with excellent selectivity and
formation of the undesired 6 was not observed (Table 1, entry 3). Furthermore, the
long reaction time (8 days) could be decreased to merely 12 hours by simple increase
of temperature to 40 oC (entry 4). The desired C–H amination product 4d was isolated
in 80% yield. The reaction readily proceeded also in pure DMSO (entry 5). Twofold
decrease of the catalyst loading resulted in slower reaction and required longer time to
go to completion (entry 6). Further lowering of the catalyst amount (entries 7 and 8)
resulted in incomplete conversion of 3d. Among various Cu(I) sources tested, only
CuI was efficient as a catalyst (entry 9). Other Cu(I) salts were less efficient (entries
10,11). Cu(OTf)2 could also be used as a catalyst (entry 12), however the Cu(II)ꢀ
catalyzed reaction between λ3ꢀiodane 3d and morpholine required longer time to go to
completion compared to the best Cu(I) source (entry 12 vs. entry 4). Interestingly,
Cu(BF4)2 hexahydrate was far less efficient as a catalyst compared to Cu(MeCN)4BF4
or copper (II) triflate (entry 13 vs. entries 4 and 12, respectively). Poor catalytic
efficiency of Cu(BF4)2 hexahydrate could be attributed to the presence of water (0.6
equiv) in the Cu(II) catalyst, because diminished yields of the product 4d were also
observed if CꢀH amination under the best conditions (with Cu(MeCN)4BF4 as the
catalyst) was performed in the presence of water (10 equiv; entry 14 vs. entry 4). On
the other hand, the CꢀH amination reaction mixture always contains water (1 equiv)
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which forms during the λ3ꢀiodane 3d formation from the starting arene 1d and TIPPꢀ
I(OH)OTs, so the presence of water is likely not responsible for the poor catalytic
efficiency of Cu(BF4)2 hexahydrate. The oxygenꢀfree conditions are important to
achieve high yields of the CꢀH amination product 4d (compare entries 15 and 4).
Finally, the reaction of λ3ꢀiodane 3d with morpholine in the absence of the Cu(I)
catalyst resulted in slow formation of iodoꢀxylene and the formation of the desired 4d
was not observed (entry 16). It should be noted, that the addition of the radical
scavenger TEMPO considerably decelerated the formation of iodoꢀxylene, so the
noncatalyzed reaction of the diarylꢀλ3ꢀiodane 3d with morpholine presumably
proceeds through a radical chain pathway.14
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The Nꢀxylylꢀmorpholine 4d could also be synthesized in a sequential oneꢀpot
mode without isolation of the diarylꢀλ3ꢀiodane 3d. This required careful control of 3d
formation and the addition of Cu(MeCN)4BF4, morpholine, EtN(iꢀPr)2 and DMSO to
the reaction mixture immediately after the conversion of xylene 1d to the intermediate
3d was completed. The sequential oneꢀpot twoꢀstep C–H amination avoided the
isolation and handling of potentially unstable intermediate diarylꢀλ3ꢀiodane 3d and
hence is superior compared to the stepwise approach.
Table 2. Sequential C–H amination of arenes 1a–t.a
HX
time yield 4
(h)
HX
time yield 4
(h)
(%)b
entry arene 1
entry arene 1
(%)b
25
1
2
TfOHc
TfOHc
3
11
12
TsOH 0.2 80(61)d
k
a
3
2
35
62
62
TsOH
2
72(49)d
l
b
3
TfOHc
13
TsOH 0.2 74
c
m
4
5
TfOHc
TfOH
3
3
14f
TfOH
TfOH
3
1
50g
70
d
n
56(41)d 15
e
o
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TfOH
18
2
49
16
TfOH 12
TfOHh
82
44
p
f
7
TsOH
TsOH
TsOH
nonee
80(52)d 17
1
g
q
8
0.3 66
0.5 71
0.2 55
18
19
20
TsOH 0.5 49
TsOH 0.5 44
TfOH 0.5 62
h
i
r
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9
s
10
j
t
a
Conditions: Arene 1 (1.2 equiv); acid (1.05 equiv) and TIPPꢀI(OH)OTs (1.0 equiv)
in MeCN (0.5 M) at room temperature; then Cu(MeCN)4BF4 (10 mol%), morpholine
(1.2 equiv) and DIPEA (2.0 equiv) in 1:4 MeCN:DMSO (0.1 M) at 40 °C for 12 h.
b Average yield of two runs. c λ3ꢀIodane did not form with TsOH as an additive. In
d
e
parenthesis yields from ref. 14. Performed in CF3CH2OH as a solvent without the
acid additive. f With 1 equivalent of Cu(MeCN)4BF4. g Isomeric product 4n’
possessing the morpholine moiety in paraꢀposition to OCF3 group was isolated in
15% yield. h At 0 oC with 3 equiv of TfOH and 4 equiv of DIPEA.
A series of carbocyclic arenes was subsequently subjected to the oneꢀpot
sequential C–H amination to demonstrate the scope of the developed methodology
(Table 2). Yields of the twoꢀstep sequential C–H amination depended on the ease of
the formation of unsymmetrical diarylꢀλ3ꢀiodane intermediates as well as on their
stability. The formation of the iodonium salt intermediates 3a-u was found to be
sensitive to the electronic properties of arene 1.19 Toluene (entry 1) represents a
reactivity borderline: less electronꢀrich arenes than toluene did not react with TIPPꢀ
I(OH)OTs even in the presence of TfOH or TsOH as an additive. Tertꢀbutylbenzene
was slightly more reactive than toluene (entry 2 vs. 1), a result that is consistent with
better electronꢀreleasing ability of tertꢀbutyl group (
σp= –0.20) compared to that of
the methyl group (
σ
p= –0.17).20 Not surprisingly, arenes possessing two alkyl
substituents were readily transformed into diarylꢀλ3ꢀiodane intermediates and, hence,
afforded the C–H amination products in 56ꢀ62% yields (entries 3–5). It should be
noted that all the tested alkylꢀsubstituted arenes (entries 1–5) required TfOH as an
additive to afford the unsymmetrical diarylꢀλ3ꢀiodane intermediates. Moderate C–H
amination yields for Nꢀacetanilide (entry 6) presumably could be attributed to partial
acid hydrolysis of the amide moiety.21 Electronꢀrich alkoxyꢀsubstituted arenes (entries
7–12) readily reacted with TIPPꢀI(OH)OTs in the presence of TsOH as an additive.22
Importantly, the strong electronꢀdonating effect of methoxy group (σ
p= –0.27)20
compensated for the presence of deactivating electronꢀwithdrawing substituents such
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as OCF3 group (
σ
p= +0.35; entry 14) and bromine (σ
p= +0.23, entry 15)23 and even
sulfonamide moiety (σp= +0.65; entry 16). In the latter case, the reaction with TIPPꢀ
6
I(OH)OTs required addition of TfOH and prolonged time to afford the unsymmetrical
diarylꢀλ3ꢀiodane intermediate. Noteworthy, TIPPꢀI(OH)OTs–based conditions
afforded C–H amination products in higher yields than the previously published
method14 (see yields in entries 5,7,11 and 12). Finally, substituted thiophenes also
appeared to be suitable substrates for the developed CꢀH amination reaction (entries
18–20).
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The regioselectivity of the C−H amination is controlled during the formation of
the unsymmetrical diarylꢀλ3ꢀiodane intermediates. Notably, all monosubstituted
arenes underwent highly regioselective paraꢀC–H amination and the formation of
isomeric orthoꢀsubstituted products generally was not observed.24 The C–H amination
in multiply substituted arenes proceeded selectively at the paraꢀposition to the
strongest electronꢀreleasing substituent (entries 11–16). For example, 2,3ꢀ
dihydrobenzofuran (entry 12) and Nꢀtosyl anisidine (entry 13) afforded C–H
amination product in paraꢀposition to the alkoxy group. In tetrahydroisoquinoline
(entry 17) the paraꢀposition with respect to the strongest electronꢀreleasing substituent
(MeO group) is blocked, and the reaction took place regioselectively at the sterically
less hindered orthoꢀposition.25 The regioselective C–H amination of 6ꢀMeOꢀ
tetrahydroisoquinoline is noteworthy, because this substrate usually affords a mixture
of 5– and 7–substituted products in electrophilic halogenation26 and nitration27
reactions. 3ꢀSubstituted thiophenes underwent C–H amination at position 2 (entries
18–20).
The C−H amination conditions were compatible with the presence of Oꢀbenzyl
(entry 8, Table 2), Oꢀallyl (entry 9) and OꢀTBDMS (entry 10) protecting groups as
well as OꢀMe ester moiety (entry 20) and bromide (entry 15). NꢀTrifluoroacetyl (entry
17, Table 2) and NꢀTs (entry 13) protecting groups were also tolerated. A variety of
aliphatic primary amines (entries 1
−
7, Table 3), aliphatic secondary amines (entries 8
16) and imidazole (entry 17) could
−
13), aromatic, heteroaromatic amines (entries 14
−
be employed. Azoles possessing a relatively acidic NꢀH bonds such as tetrazole (entry
18) and 1,2,4ꢀtriazole (entry 19) also reacted in the presence of DIPEA as the base.
Less acidic N−H heterocycles such as indoles did not react under the standard
conditions. The reaction of ammonium trifluoroacetate (1.2 equiv) with diarylꢀλ3
ꢀ
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iodane 3g afforded bis(4ꢀmethoxyphenyl)amine 26 as the major product (entry 20).
Disappointingly, poor conversion (<5%) of the diarylꢀλ3ꢀiodane 3g was observed
when aqueous saturated ammonia (10 equiv) or 2M solution of NH3 in methanol (5
equiv) were used as a source of ammonia. Possibly, a complex formation with the
excess of NH3 inhibited the Cu(I) catalyst. Nevertheless, an introduction of NH2
functional group is possible via the paraꢀCꢀH amination using Nꢀallyl (entry 1) or Nꢀ
benzyl amines (entries 3,4), followed by Nꢀdeprotection of the corresponding anilines
7, 9 and 10, respectively (Table 3).
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Importantly, the CꢀH amination reaction conditions are compatible with alkene
moiety in the amine (entry 1) and Sꢀtrityl (entry 6) protecting group. Various
functional groups such as ethers (entry 4), esters (entry 19) and a bromide (entry 14)
are all tolerated. Amines react chemoselectively in the presence of unprotected amide
(entry 13) and sulfonamide moieties (entry 15). Monoamination with piperazine is
also possible (entry 12).
Table 3. Scope of amines.a
entry amine
product,
entry amine
product,
yield (%)b
yield (%)b
1
2
3
4
7, 77
8, 70
9, 73
10, 77
11
12d
13
14
17, 56
18, 50e
19, 61
20, 74
5
11, 44
12, 42
15
16
21, 49
22, 20
6c
7
13, 72
17c
23, 76
8
9
14, 63
15, 78
18f
19c
24, 79g
25, 39
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16, 80
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26, 33h
a Conditions: Anisole 1g (1.2 equiv); TsOH*H2O (1.05 equiv) and TIPPꢀI(OH)OTs
(1.0 equiv) in MeCN (0.5 M) at room temperature for 30 min; then Cu(MeCN)4BF4
(10 mol%), amine (1.2 equiv) and DIPEA (2.0 equiv) in MeCN/DMSO =1:4 (0.1 M)
b
c
at 40
proceeded within 30 h at 40
used both as the nucleophile and as the base. Accompanied with 18% of 1,4ꢀbis(4ꢀ
°C for 12h. Average yield of two runs. The reaction of 3g with amine
d
°C. DIPEA was not added; piperazine (3.5 equiv) was
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e
methoxyphenyl)piperazine. f The reaction of 3g with amine required 40 h at 50
°C and
2.5 equiv of DIPEA. g A mixture of 1ꢀaryltetrazole 24a (35%) and 2ꢀaryltetrazole 24b
(44%). h Yield of bis(4ꢀmethoxyphenyl)amine 26; the reaction of 3g with NH4ꢀ
OCOCF3 required 30 h at 40 °C and 3.5 equiv of DIPEA.
The developed twoꢀstep sequential paraꢀC–H amination approach provides a
complementary regioselectivity to a Pd–catalyzed method reported by Zhang and coꢀ
workers (Scheme 1 and eq 2).10a Thus, in their work the amideꢀdirected C–H
amination of arene 1u with Nꢀfluorobenzenesulfonimide (NFSI) proceeded at the
paraꢀposition to the amide moiety and afforded paraꢀphenylenediamine 27. In
contrast, regioselectivity of the reaction between arene 1u and TIPPꢀI(OH)OTs was
controlled by methoxy group, the strongest electronꢀreleasing substituent in the arene
1u. Subsequent Cu–catalyzed reaction of the unsymmetrical diarylꢀλ3ꢀiodane 3u
intermediate with morpholine delivered paraꢀanisidine 4u (Scheme 1). Importantly,
o
low temperature (–40 C) was required in the formation step of intermediate 3u in
order to obtain 4u in good yield (61%).28
Scheme 1. Complementary regioselectivity of different C–H amination methods.
Finally, a synthesis of antibiotic Linezolid 32 was performed to demonstrate
the suitability of the developed Cu–catalyzed paraꢀC–H amination method for the
lateꢀstage functionalization of lead structures (Scheme 2). The synthesis featured
installation of the morpholine moiety in a nonꢀprefunctionalized Linezolid core
structure 30 in the final synthetic step. Such approach streamlines structural variations
of the amine moiety and could provide a rapid and straightforward access to a number
of Linezolid analogs. The synthesis commenced with Cuꢀcatalyzed Nꢀarylation of
commercially available oxazolidinone 28,29 followed by cleavage of NꢀBoc protecting
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group and subsequent Nꢀacetylation to provide the key building block 30 (Scheme 2).
The formation of the unsymmetrical diarylꢀλ3ꢀiodane 31 intermediate took prolonged
time (40 h) to go to completion. Subsequent in situ reaction of 31 with morpholine
required presence of stoichiometric amounts30 of Cu(MeCN)4BF4 complex31 to obtain
the Linezolid 32 in 71% yield (Scheme 2).
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Scheme 2. Synthesis of Linezolide 32 by lateꢀstage CꢀH amination.
Higher efficiency of Cu(MeCN)4BF4 complex compared to the representative
Cu(II) complex (entry 12 vs. entry 4, Table 1) suggests that Cu(I) salts are the
catalytically active species and Cu(II) salts are in situ reduced to active Cu(I) catalyst
by amine.32 Such a scenario is consistent with our earlier observation that selective
trapping of Cu(I) species with neocuproine (a highly specific chelating agent for Cu(I)
ions) resulted in complete inhibition of the CꢀH amination reaction.14 Consequently, a
CuI/CuIII catalytic cycle for the reaction between the unsymmetrical λ3ꢀiodanes 3 and
amines is plausible.33 It would start with an initial formation of Cu(I)ꢀdiamine
complex I, followed by oxidative addition of the λ3ꢀiodane 3 to form the Cu(III)
intermediate II and completed by product forming reductive elimination to afford Cꢀ
H amination product and regenerate a catalytically active Cu(I) species (Scheme 3).
Scheme 3. Working mechanism for C–H Amination of Arenes.
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Unfortunately, the proposed transient Cu(III) complexes could not be detected,
presumably because they undergo rapid C−
N bond forming reductive elimination.34
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7
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9
This behavior is expected because related, highly reactive Cu(III) species have only
been observed in chelationꢀstabilized complexes based on stabilizing
triazamacrocyclic ligands.35 Further mechanistic studies are necessary to fully
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elucidate the mechanism of the developed C−H amination approach.
Conclusions
In summary, the use of bulky 2,4,6ꢀtriisopropylphenyl (TIPP) groupꢀcontaining
iodonium reagent TIPPꢀI(OH)OTs together with strong acid additives such as TsOH
and TfOH allowed for substantial increase of substrate scope and improvement of C–
H amination yields compared to the previously published method.14 The new
conditions are suitable for paraꢀselective CꢀH amination of a wide range of relatively
electronꢀrich arenes. The high paraꢀregioselectivity of the C–H amination is
controlled at the stage of the formation of the unsymmetrical diarylꢀλ3ꢀiodane
intermediates. Although the regioselectivity is a result of the combined directing
effects of arene substituents, in general it is consistent with that of electrophilic
aromatic substitution (SEAr) reactions. Thus, the C–H amination takes place at the
paraꢀposition to the strongest electronꢀreleasing substituent. Hammett substituent σꢀ
constants can be used to predict the regioselectivity of the C–H amination in
carbocyclic arenes possessing multiple substituents. The developed method provides a
complementary regioselectivity to the wellꢀdeveloped orthoꢀCꢀH amination approach
and it may be especially useful for lateꢀstage paraꢀregioselective C–H amination of
pharmaceutically relevant carbocyclic arenes.
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Associated Content
Supporting Information
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The following files are available free of charge on the ACS Publications website at
DOI: 10.1021/csXXXXXXX.
Experimental details, characterization data, and NMR spectra (PDF)
Xꢀray crystallographic data for λ3ꢀiodane 3d (CIF)
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Author Information
Corresponding Author
Eꢀmail: edgars@osi.lv
Notes
The authors declare no competing financial interest.
Acknowledgements
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 Xꢀray crystallographic
analysis and Dr. I. Nakurte (Universty of Latvia) for HRMS analyses.
References
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Tran, L. D. Acc. Chem. Res. 2015, 48, 1053
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Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743. f) Engle, K. M.;
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(5) For selected examples of orthoꢀC–H amination with Nꢀunprotected amines, see;
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(6) For recent selected examples see: a) Deng, Y.; Yu, J.ꢀQ. Angew. Chem. Int. Ed.
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Tang, R.ꢀY.; Movassaghi, M.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136, 10807–
10813. c) Tang, R.ꢀY.; Li, G.; Yu, J.ꢀQ. Nature 2014, 507, 215–220. d) Wan,
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(7) a) Mitchell, H.; Leblanc, Y. J. Org. Chem. 1994, 59, 682–687. b) Wang, Z.;
Xing, X.; Xue, L.; Xiong, Y.; Fang, L. Synthesis 2014, 46, 757–760.
(8) Leblanc, Y.; Boudreault, N. Org. Chem. 1995, 60, 4268–4271.
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(10) a) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133,
1694–1697. b) In another recent example the regioselectivity of Pdꢀcatalyzed
C–H imidation of arenes with NFBS did not reach synthetically useful levels:
Boursalian, G. B.; Ngai, M.ꢀY.; Hojczyk, K. N.; Ritter, T. J. Am. Chem. Soc.
2013, 135, 13278–13281.
(11) a) Marchetti, L.; Kantak, A.; Davis, R.; DeBoef, B. Org. Lett. 2015, 17, 358ꢀ
361. b) For a closely related Pdꢀcatalyzed procedure see: Shrestha, R.;
Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc. 2013,
135, 8480ꢀ8483. Poor regioselectivity was observed in the transition metalꢀfree
C−H amination with phthalimide/PhI(OAc)2 system: c) Kim, H. J.; Kim, J.;
Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011, 133, 16382ꢀ16385. d) Kantak, A.
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Ed. 2011, 50, 8605ꢀ8608. c) Samanta, R.; Bauer, J. O.; Strohmann, C.;
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(13) (a) Souto, J. A.; Martínez, C.; Velilla, I.; Muñiz, K. Angew. Chem. Int. Ed.
2013, 52, 1324ꢀ1328. (b) During preparation of the manuscript, iodine(III)ꢀ
mediated paraꢀC−H imidation method using lithium triflimide was published:
Pialat, A.; Bergès, J.; Sabourin, A.; Vinck, R.; Liégault, B.; Taillefer, M. Chemꢀ
Eur. J. 2015, 21, 10014–10018.
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(14) Sokolovs, I.; Lubriks, D.; Suna, E. J. Am. Chem. Soc. 2014, 136, 6920ꢀ6928.
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A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1997, 2463ꢀ
2466. c) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett, 2008, 592ꢀ596.
(16) Replacement of nontransferable mesityl ligand for 2,4,6ꢀtriisopropylphenyl
(TIPP) group in unsymmetrical diarylꢀλ3ꢀiodane helped to improve selectivity in
Cu(II)ꢀcatalyzed arylations: a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J.
Am. Chem. Soc. 2008, 130, 8172ꢀ8174. For related recent nonꢀcatalyzed
arylations with TIPP–containing unsymmetrical diarylꢀλ3ꢀiodanes, see: b)
Matsuzaki, K.; Okuyama, K.; Tokunaga, E.; Shiro, M.; Shibata, N. Chemistry
Open 2014, 3, 233ꢀ237.
(17) Synthesis of TIPPꢀI(OH)OTs has not been reported in the literature. It was
conveniently prepared in a gramꢀscale (up to 10.6 g per batch) using a method
developed for MesꢀI(OH)OTs: Merritt, E. A.; Carneiro V. M. T.; Silva Jr, L. F.;
Olofsson, B. J. Org. Chem. 2010, 75, 7416ꢀ7419. The TIPPꢀI(OH)OTs reagent
o
could be stored at 0 C for 3 months without any signs of decomposition. See
Supporting Information for more details.
(18) Cu(MeCN)4BF4 was synthesized in accordance with literature procedure: (a)
Fortin, D.; Drouin, M.; Turcotte, M.; Harvey, P. D. J. Am. Chem. Soc. 1997,
119, 531ꢀ541. (b) Kubas G. J. Inorg. Synth. 1979, 19, 90.
(19) Correlation between yields of phenyliodonium salts and Hammett σ constants of
substituents has been reported: Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron
2010, 66, 5775ꢀ5785.
(20) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165ꢀ195.
(21) Equimolar amount of water was formed in the reaction of TIPP–I(OH)OTf with
arene.
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(22) Addition of TfOH to electronꢀrich arenes resulted in exotherm and formation of
more sideꢀproducts.
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(23) Trifluoromethoxy benzene and bromobenzene do not react with ArI(OH)OTs in
the presence of TfOH.
(24) The formation of regioisomeric orthoꢀC–H amination sideꢀproduct 4n’ was
observed only for 3ꢀ(trifluoromethoxy)anisole 4n (50:14 para:ortho).
(25) Major sideꢀproduct was the corresponding 3,4ꢀdihydroisoquinoline, which
presumably was formed by acidic hydrolysis of 1q followed by oxidation of the
intermediate 1,2,3,4ꢀtetrahydroisoquinoline by I(III) species. NꢀAcetyl
tetrahydroisoquinoline (related to 1q) was less stable toward the acidic
hydrolysis.
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(26) Berglund, M.; DalenceꢀGuzmán, M. F.; Skogvall, S.; Sterner, O. Bioorg. Med.
Chem. 2008, 16, 2513ꢀ2528.
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2007011290 A1 Jan 25, 2007; Chem. Abstr. 2007, 146, 184376.
(28) At room temperature the intermediate diaryliodonium triflate 3u appeared to be
unstable. Among major decomposition products there was OꢀTf analog of 4u,
which apparently was formed by C–O bond forming reductive elimination from
3u. For thermally unstable intermediate iodanes the use of low temperatures is
recommended.
(29) Mallesham, B.; Rajesh, B. M.; Rajamohan Reddy, P.; Srinivas, D.; Trehan, S.
Org. Lett. 2003,5, 963ꢀ965.
(30) The reaction of the intermediate 31 with morpholine in the presence of catalytic
Cu(I) amounts (10 mol%) stalled after 4 days at 27% conversion suggesting
inhibition of Cu(I) catalyst with substrate. Consequently, the use of
stoichiometric amounts of Cu(MeCN)4BF4 is recommended for substrates
possessing functional groups capable of chelating Cu(I) species.
(31) Copper(I) iodide in stoichiometric amounts is incompatible with the C–H
amination conditions because it acts as a source of iodide and affords C–H
iodination product instead of the desired Linezolid 32. However, CuI can be
employed in catalytic amounts (10 mol%; see entry 9, Table 1).
(32) (a) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496
A. Dalton Trans. 2010, 39, 7873 7875.
−1502. (b) Franc, G.; Jutand,
−
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(33) The CuI/CuIII catalytic cycle in reactions involving diaryliodonium salts has
been recently proposed based on abꢀinitio DFT calculations: see Ichiishi, N.;
Canty, A. J.; Yates, B. F.; Sanford, M. S. Organometallics 2014, 33, 5525–
5534.
(34) For C−N bondꢀforming reductive elimination from wellꢀdefined Cu(III)−aryl
species, see: (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
9196ꢀ9197. (b) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
Ribas, X. Chem. Sci. 2010, 1, 326ꢀ330. (c) King, A. E.; Huffman, L. M.;
Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132,
12068ꢀ12073. (d) Huffman, L. M.; Stahl, S. S. Dalton Trans. 2011, 40, 8959ꢀ
8963.
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(35) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136,
2555ꢀ2563. (a) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahia, H.; Parella, T.;
Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Angew.
Chem., Int. Ed. 2002, 41, 2991ꢀ2994. (b) Huffman, L. M.; Casitas, A.; Font, M.;
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