Copper(II)-Photocatalyzed N-H Alkylation with Alkanes

Article abstract of DOI:10.1021/acscatal.0c01924

We report a practical method for the alkylation of N-H bonds with alkanes using a photoinduced copper(II) peroxide catalytic system. Upon light irradiation, the peroxide serves as a hydrogen atom transfer reagent to activate stable C(sp3)-H bonds for the reaction with a broad range of nitrogen nucleophiles. The method enables the chemoselective alkylation of amides and is utilized for the late-stage functionalization of N-H bond containing pharmaceuticals with good to excellent yields. The mechanism of the reaction was preliminarily investigated by radical trapping experiments and spectroscopic methods.

Full text of DOI:10.1021/acscatal.0c01924

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Article
Copper(II)-Photocatalyzed N-H Alkylation with Alkanes
Yiwen Zheng, Rok Narobe, Karsten Donabauer, Shahboz Yakubov, and Burkhard König
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01924 • Publication Date (Web): 08 Jul 2020
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ACS Catalysis
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Copper(II)-Photocatalyzed N–H Alkylation with Alkanes
Yi-Wen Zheng, Rok Narobe, Karsten Donabauer, Shahboz Yakubov and Burkhard König*
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Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg,
Germany
KEYWORDS C–H activation, amination, alkylation, copper catalysis, photocatalysis
ABSTRACT: We report a practical method for the alkylation of N–H bonds with alkanes using a photoinduced copper(II)-
peroxide catalytic system. Upon light irradiation, the peroxide serves as a hydrogen atom transfer (HAT) reagent to activate
stable C(sp3)–H bonds for the reaction with a broad range of nitrogen nucleophiles. The method enables the chemoselective
alkylation of amides and was utilized for the late-stage functionalization of N–H bond containing pharmaceuticals with good
to excellent yields. The mechanism of the reaction was preliminarily investigated by radical trapping experiments and
spectroscopic methods.
The efficient synthesis of carbon-nitrogen bonds is
important in organic synthesis as C–N bonds are a typical
motif in natural products, pharmaceuticals and functional
materials.1 Accordingly, a variety of powerful approaches
for C(sp3)–N bond formations have been developed and
advanced over the last decades. Examples include the
coupling of nitrogen nucleophiles with alkyl halides,2
reductive amination,3 olefin hydroamination4 and nitrene
insertion.5 Copper catalysis provides an alternative
approach for the construction of C–N bonds. In recent
years, Fu and coworkers have reported photoinduced
copper-catalyzed alkylations of different nitrogen
nucleophiles with alkyl halides6 and a decarboxylation of
N-hydroxyphthalimide (NHPI) esters7 to afford N-alkylated
products. The groups of Hu and MacMillan used dual
strategy to derive new bioactive molecules from natural
products or
Scheme 1. Nitrogen nucleophile alkylation using
copper-peroxide systems
Previous work
[CuI], peroxide
3
+
C(sp3)–H
RNHR'
RR'N–
C(sp )
high temperature
radical trapping
ligand exchange
radical trapping
[CuI]
[CuII]
[CuIII]
reductive elimination
This work
[CuII], DTBP
C(sp3)–H
C(sp )
3
RNHR'
+
RR'N–
h, rt
copper and photoredox catalysis to achieve
a
radical trapping
initiation
step
decarboxylative alkylation of nitrogen nucleophiles with
[CuII]
[CuII]-phth
[CuIII]
NHPI esters8 or alkyl carboxylic acids.9
reductive
radical trapping
ligand exchange
Compared to the use of alkyl halides, NHPI esters and
alkyl carboxylic acids as alkylating reagents, copper-
[CuI]
elimination
peroxide catalytic systems provide
a straightforward
broad scope of nitrogen nucleophilies
approach for the N–H alkylation using unfunctionalized
chemoselective alkylation of multiple NH containing nucleophiles
use in late-stage functionalization
10
3
C(sp )–H bonds. The proposed mechanism for these
transformations usually starts with [CuI] and includes a
sequence of tert-butoxy radical trapping, ligand exchange,
alkyl radical trapping and reductive elimination to
complete the copper-catalytic cycle (Scheme 1). However,
drugs,12 and to the best of our knowledge no
copper-peroxide catalytic method was so far applied for
the late-stage functionalization of N–H bond containing
pharmaceuticals to demonstrate the utility of this
approach. Furthermore, complex starting materials for
late-stage functionalization may contain several N–H
bonds with similar reactivities, requiring the use of a
the compatibility of
a
[CuII]-catalyst with these
transformations is elusive.
The copper-peroxide system requires high temperatures
in order to decompose the peroxide to produce alkoxy
radicals, which abstract the hydrogen atom.10g-j The use of
high temperatures imposes potential dangers11 and
substrate limitations, which may impede the synthetic use
of this catalytic system, especially regarding late-stage
catalytic system that functions in
a chemoselective
manner.13
Herein, we report the use of peroxide as HAT reagent
under light irradiation at room temperature, a [CuII]
complex as metal catalyst and unactivated alkanes as
functionalizations. Late-stage functionalization is
a
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reaction partners to achieve alkylations of various
9
0.35 W 400 nm instead of 36[c]
385-390 nm
5.0 W 455 nm instead of 385- 31[c]
390 nm
1
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3
4
5
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7
8
nitrogen-containing compounds including amides,
sulfonamides, phosphinic amides, aminophthalimide,
indoles, azoles, purines, and imines (Scheme 1). We
explored the chemoselectivity of the nitrogen nucleophiles
and the late-stage functionalization of selected N–H bond
containing pharmaceuticals. Further, mechanistic studies
to arrive at a hypothesis for the copper(II)-peroxide
reaction were conducted.
10
Conditions: 1a (0.2 mmol), 2a (2 mmol). [a] NMR yield
using 1,3,5-trimethoxybenzene as internal standard. [b]
Isolated yield. [c] 24 h.
We began our investigation guided by the absorption
spectra of Cu(AcO)2 and 4,4'-di-tert-butyl-2,2'-bipyridine
(dtbbpy) in acetonitrile, which shows an absorption band
at 360-450 nm (Figure S1). To our delight, irradiation of
With the optimized catalytic system, different nitrogen
atom containing substrates were explored (Scheme 2).
Benzamides and alkyl amides provided the corresponding
cyclohexylamides in good yields (3b-3f, 55-85% yield),
and a heteroaromatic amide gave the coupling product in a
high yield as well (3g, 87%). Both nitrogen atoms of urea
were alkylated in a moderate yield (3h, 58% yield), and
phthalimide was converted to its cyclohexyl congener in
75% yield (3i). Sulfonamides bearing aromatic and
aliphatic substituents could both be employed in the
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the
acetonitrile
solution
containing
benzamide,
cyclohexane, Cu(AcO)2, dtbbpy and di-tert-butyl peroxide
(DTBP) at 25 ℃ using a 385 nm LED for 12 h gave 81% of
N-cyclohexylbenzamide (3a) (Table 1, entry 1). No product
was detected in the absence of either light, copper or
DTBP, demonstrating the necessity of all components
(entry 2-4). Without ligand, a low product yield was
observed (entry 5, 12% yield). The reaction does not
proceed without light even at 100 ℃ (entry 6). Intensity
and wavelength of the irradiation were important for the
reaction (entry 7-10), as a lower intensity LED led to a
reduced reaction yield of 38% (entry 7) for the same
reaction time, and the use of an LED with a slightly longer
emission wavelength decreased the yield slightly to 63%
(entry 8). The reaction was also feasible by irradiation
with visible light (400 nm and 455 nm), albeit in low yields
3
C(sp )–H amidation (3j-3l, 62-80% yield). In addition to
amides, nitrogen-containing heterocyclic compounds, such
as indoles (3m-3o), azoles (3p-3u) and purines (3v-3w)
gave the alkylation products in 17-78% yield. Imines,
phosphinic amides and aminophthalimide were tolerated
as well (3x-3z, 36-78% yield). However, no reaction was
observed when aniline or ammonium carbamate was used.
Further, secondary amides and sulfonamide (1aa-1ad)
were also unsuitable substrates for this copper catalytic
system, with the only exception being the planar
phthalimide (1i), indicating the selectivity of the catalytic
N–H bond alkylation for primary over secondary amides,
likely due to steric effects.
(entry 9-10).
A comparable reaction outcome was
observed using CuI instead of Cu(AcO)2 (80%, Table S1,
entry 2). Due to the intense absorption of the CuI/dtbbpy
solution in the visible light region (Figure S2), we expected
a higher product yield under irradiation of 455 nm LEDs
using this copper complex, yet only 24% of the product
was formed (Table S1, entry 3). A detailed screening of
reaction conditions is given in the supporting information
(Table S1) and the reaction conditions shown in entry 1 of
Table 1 provided the best result.
Table 1. Reaction optimization for cyclohexane
amidation
5 mol% Cu(AcO)2,
10 mol% dtbbpy
2.0 equiv. DTBP
O
O
N
NH2
+
H
CH3CN 3 mL,
3.8 W LED (385-390 nm)
N2, 25 C, 12 h
1a
2a
3a
Entry
Deviations
none
Yield (%)[a]
1
2
3
4
5
6
7
8
81[b]
0
no light
no Cu(AcO)2
0
no DTBP
0
no dtbbpy
12
0
no light at 100 ℃
1.0 W instead of 3.8 W
38
390-395 nm instead of 385- 63
390 nm
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ACS Catalysis
Scheme 2. Scope of nitrogen nucleophiles for
copper(II)-photocatalyzed N–H alkylation with
cyclohexane
Scheme 4. Late-stage functionalization of N–H bond
containing pharmaceuticals via photoinduced
copper(II)-peroxide catalysis
1
2
3
4
5
6
7
8
R
R
5 mol% Cu(AcO)2, 10 mol% dtbbpy, 2 equiv. DTBP
5 mol% Cu(AcO)2, 10 mol% dtbbpy, 2 equiv. DTBP
+
N alkyl
N
RNHR'
alkyl-H
RNHR'
+
R'
3b-3ad
CH3CN 3 mL, 3.8 W LED (385-390 nm)
R'
CH3CN 3 mL, 3.8 W LED (385-390 nm)
2
4
N2, 25 C 12 h
N2, 25 C, 12 h
1b-1ad
2a
O
H
O
O
N
O
OH
H
N
H
H
N
N
O
O
N
H
R
N
O
N
O
O
N
H
H
R
3b,
3c
O
9
O
O
3d
3e
R = 2-Me, 85%
, R = 4-Cl, 74%
, R = t-BuO, 63%
, R = Me, 60%
3f
3g, 87%
, 55%
4a
Methocarbamol, , 55%
4b
Carisoprodol, , 60%
10
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R
O
N
O
H
R
2
R
O
O
N
N
3
S
R =
N
R
R
N
N
O
N
H
N
H
N
O
4e
, 52%
O
4c
, 74%
R
4d
, 53%
R
3j
, R = Ph, 76%
3k
C2/C3 = 1.3
O
O
3m
, R = H, 78%
O
a
b
3h
, R = 4-MePh, 73%
, 58%
3i
, 75%, 90%
N
3n
, R = CO2Me, 34%
3l
, R = Me, 62%
O
OH
N
3
2
O
O
4f
, 45%
C2/C3 = 2.6
4g
N
N
Olmesartan medoxomil
R' =
48% (16%)a
N
N
N
N
Ph
F
R'
R'
1
F
F
R'
R'
O
H
N
2
N
S
N
b
3r
, 44%
3o
3q
, 60%
N
, 67%
3p
, 75%, 24%
O
Cl
c
4k
N
N
N
, 84%
4h
4i
4j
, 29%
, 94%
, 52%
N
Cl
Celecoxib
N
C1/C2 = 2.2
gram scale
62% (20%)b
N
Br
N
N
N
N
N
Br
a
Conditions: Amide (0.2 mmol), 2 (2 mmol). THF was used
c
3s
3t
3u
, 44%
, 76%
, 17%
O
3v
, 26%
O
b
as solvent. Reaction temperature is ca. 45 ℃ measured from
O
the reaction solution; the yield in parentheses is N-methylated
N
N
N
product. cAcetone was used as solvent.
N
P
NH
N
NH
O
N
O
Amides and sulfonamides possessing primary and
secondary amide N–H bonds were exclusively alkylated on
the primary amide or sulfonamide (3ae-3ai; 44-96%,
Scheme 3). Besides the preference for primary positions,
chemoselectivity was also observed in the presence of two
different N–H functional groups. We employed compound
1aj having one indole N–H bond and one primary amide.
To our delight, the alkylation proceeded only at the indole
N–H in 57% yield (3aj). When the amide contains an
indazole N–H bond (1ak), the alkylation occurred
preferentially on the N–H bond of the indazole (3ak, 57%
yield). In competition with a primary amide, a primary
sulfonamide moiety gave the alkylation product in 74%
yield (3al). The pKa values of indole, indazole and
sulfonamide N–H are lower than that of benzamide
(Scheme S1). Combined with the results of 3aj-3al, the
alkylation of the more acid N–H seems to be preferred
using this approach.
d
e
3y
3z
, 36%
, 55%
O
3w
3x
, 46%
, 78%
O
O
O
O
O
S
N
N
N
N
O
3aa
3ad
, 0%
, 0%
3ab
3ac
, trace
, 0%
Conditions: 1 (0.2 mmol), 2a (2 mmol). a4 equiv. DTBP was
b
c
used. CuI instead of Cu(AcO)2 was used. CH3CN / H2O = 10 /
1 (V / V). dCH3CN / H2O = 15 / 1 (V / V). eNMR yield.
Scheme 3. Chemoselective alkylation of amide and
sulfonamide containing two N–H bonds
R
5 mol% Cu(AcO)2, 10 mol% dtbbpy, 2 equiv. DTBP
N
RNHR'
+
R'
CH3CN 3 mL, 3.8 W LED (385-390 nm)
1ae-1al
2a
3ae-3al
N2, 25 C, 12 h
O
O
H
O
O
O
O
N
NH
O
5
H
N
N
N
H
H
N
H
O
O
3ae
3af
3ag
, 96%
, 55%
, 60%
To illustrate the applicability of this N–H alkylation
strategy further, late-stage alkylations of N–H containing
pharmaceuticals
H
O
O
N
H
O
S
N
O
S
N
O
H
O
were
examined
(Scheme
4).
N
H
3ah
3ai
, 82%
, 44%
Methocarbamol and Carisoprodol were alkylated at the
primary nitrogen atoms in good yields (4a and 4b, 55%
and 60% yield, respectively). Next, we examined the
alkylation of Olmesartan medoxomil and Celecoxib using
different alkanes. Olmesartan medoxomil reacted with
different alkanes and both cycloalkanes and open chain
alkanes gave good yields of the coupling products (4c-4f,
45-74% yield). Only the secondary C–H bond amination
O
NH2
H
O
O
O
S
N
H2N
N
N
NH2
O
N
O
O
3aj
3ak
3al
, 74%
, 57%
, 57%
Conditions: 1 (0.2 mmol), 2a (2 mmol).
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ACS Catalysis
products of n-pentane and n-hexane were isolated and
Page 4 of 9
radical. Therefore, a radical trapping experiment with
TEMPO was performed (Scheme 5d).
1
2
3
4
5
6
7
8
separated. Ethers such as THF are also compatible
substrates (4g, 48% yield). Celecoxib was functionalized
with cyclohexane, cyclopentane and cyclooctane in
moderate to excellent yields (4h-4j, 29-94% yield). When
adamantane was employed as alkylating reagent, acetone
instead of acetonitrile was used as solvent to increase the
solubility, which gave the alkylated product in a good yield
(4k, 84% yield). A gram scale late-stage functionalization
of Celecoxib was carried out and gave 62% yield of 4h with
20% of the N-methylated byproduct.14 In most of the above
N–H alkylations, the N-methylated byproduct was detected
as well. A likely origin of the methyl radical is through β-
methyl scission of the tert-butoxy radical.15
Scheme 5. Photolysis of DTBP and radical trapping
experiment with TEMPO
(a) Photolysis of DTBP in acetonitrile
3.8 W LED
(385-390 nm)
NC
CH3CN
+
DTBP
CN
N2, 25 °C, 12 h
86% GC yield
0.4 mmol
based on DTBP
conv. 90%
(b) Methyl radical trapping with styrene in the absence of a copper complex
3.8 W LED (385-390 nm)
or 5 W LED (455 nm)
9
+
DTBP
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH3CN 3 mL, N2, 25 °C, 12 h
0.2 mmol
100% conv.
2 equiv.
or other isomers
observed in GC-MS
O
-
h
O
Me
O
O
Concerning the reaction mechanism, a previous report
proposed that Cu(II) is oxidized to Cu(III) by DTBP at
115 ℃.10h Further, the bond dissociation enthalpy (BDE) of
the O–O bond in DTBP is 37.5±2.4 kcal/mol,16 and the
energy of 385 nm light (74.3 kcal/mol) and 455 nm light
(62.9 kcal/mol) are sufficient to photolyze DTBP to form
tert-butoxy radicals. Therefore, there are two possible
ways the transformation is initiated under our catalytic
conditions: reduction of DTBP by the excited state of the
copper complex or photolysis of DTBP to generate tert-
butoxy radicals. Emission quenching experiments with the
copper complexes ([CuI] and [CuII]) and DTBP showed no
quenching of the emission of the copper complexes (Figure
S4 and S5). This indicates that DTBP is not reduced by
electron transfer from the excited state of the copper
complexes. Thus, the tert-butoxy radical may be produced
by the photolysis of DTBP under irradiation. A solution of
DTBP in acetonitrile was irradiated by a 385-390 nm LED
under N2 for 12 h (Scheme 5a) resulting in 90% conversion
of DTBP and 86% of acetonitrile homo-coupling product
(Figure S6). According to the BDEs of acetonitrile (97
kcal/mol) and tert-butanol (106 kcal/mol),17 the tert-
radical-radical
coupling
Me
(c) Methyl radical trapping with styrene in the presence of a copper complex
5 mol% Cu(AcO)2
10 mol% dtbbpy
5 W LED (455 nm)
+
DTBP
+
CH3CN 3 mL
N2, 25 °C, 12 h
0.2 mmol
low conv.
2 equiv.
or other isomers
observed in GC-MS
(d)a Radical trapping with TEMPO
O
O
+
N
5 mol% Cu(AcO)2
10 mol% dtbbpy
2 equiv. DTBP
N
H
H
5%
O
34%
2 equiv. TEMPO
NH2
+
O
N
3.8 W LEDs (385-390 nm)
CH3CN 3 mL, N2, 25 °C, 12 h
O
+
0.2 mmol
N
10 equiv.
Exact Mass: 171.162 Exact Mass: 239.225
20%b
(a) Photolysis of DTBP in acetonitrile. (b) Methyl radical
trapping with styrene in the absence of a copper complex. (c)
Methyl radical trapping with styrene in the presence of a
copper complex. (d) Radical trapping with TEMPO. aProducts
observed by GC-MS and 1H-NMR; NMR yields were derived
using 1,3,5-trimethoxybenzene as internal standard. bYield is
based on the initial amount of TEMPO.
butoxy radical can abstract
a hydrogen atom from
acetonitrile giving an acetonitrile radical, which produces
succinonitrile via radical-radical coupling. In addition, an
acetonitrile solution of DTBP and styrene was irradiated
by a 385-390 nm LED or 455 nm LED under N2 for 12 h
(Scheme 5b). After the reaction, 3,4-diphenylhexane was
detected by GC-MS in both cases (Figure S8 and S9),
indicating the formation of methyl radicals from DTBP.
When DTBP and styrene were irradiated by a 455 nm LED
in the presence of the copper complex, traces of 3,4-
When 2 equiv. of TEMPO were added to the model
reaction, the yield of the alkylated benzamide decreased
from 81% to 34% and both the methyl radical and the
cyclohexyl radical were captured by TEMPO and detected
1
by GC-MS and H-NMR (Figure S11 and S12). This result
diphenylhexane were produced as well with
a low
indicates that the tert-butoxy radical acts as a HAT reagent.
Further it supports that it is the source of methyl radicals
giving rise to the observed N-methylated reaction by-
products.
conversion of styrene (Scheme 5c and Figure S10).18 The
photolysis could be further supported by assessing the
conversion of DTBP under different reaction conditions
(Table S2). A lower light intensity (Table S2, entry 6) and
higher wavelength (455 nm, Table S2, entry 9) decreased
the DTBP conversion. Further, DTBP is converted also in
the absence of Cu(AcO)2 without the formation of product
(Table S2, entry 3). The DTBP conversion is even higher in
this case, likely due to the absence of the competing light
absorption of the copper complex. Overall, the
experimental results sugest that tert-butoxy radicals are
produced by the photolysis of DTBP.
As [CuII] is, in contrast to [CuI] and [CuIII], paramagnetic,
electron paramagnetic resonance (EPR) spectroscopy was
used to investigate the mechanism of this [CuII]-peroxide
system. The EPR spectrum of Cu(AcO)2 and dtbbpy in
acetonitrile shows the characteristic four-line signal
(Figure 1a).19 The spectrum does not change upon addition
of DTBP (Figure S14), but the resonance signals vanished
after 10 h of irradiation (Figure 1b), indicating the
formation of putative [CuIII] species by radical addition. As
a second step, after the irradiation of this solution,
phthalimide was added in the dark and a new [CuII] signal
As next step, the tert-butoxy radical is proposed to
abstract a hydrogen atom from an alkane, yielding an alkyl
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ACS Catalysis
appeared with a hyperfine splitting (Figure 1c), which was
from cyclohexane to generate a cyclohexyl radical, which is
trapped by A producing a [CuIII] complex (B). The coupling
product 3i is then generated via reductive elimination
from B, simultaneously forming a [CuI] complex (C).
According to previous reports10, tert-butoxy radicals are
able to add to [CuI] complexes to form a [CuII]OtBu species
(D). The [CuII] species A is then regenerated by ligand
exchange of the [CuII]OtBu complex D with phthalimide,
accompanied by the formation of tBuOH. This step is
supported by the formation of A by the irradiation of a
solution containing CuI, dtbbpy, DTBP and phthalimide
(Figure S16).
similar to the [CuII]-NHAd hyperfine splitting in a previous
report.20 Therefore, this hyperfine splitting is likely to
originate from a [CuII]-phth complex (compound A in
Figure 2). To support this, the EPR spectrum of Cu(AcO)2,
dtbbpy and phthalimide in the presence of KOtBu in
acetonitrile was measured after 6 h of stirring. The
identical hyperfine splitting as depicted in Figure 1c was
obtained (Figure 1d and Figure S21) suggesting that [CuII]-
phth was formed. Upon irradiation of a solution of
1
2
3
4
5
6
7
8
9
Cu(AcO)2, dtbbpy, DTBP and phthalimide,
a similar
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resonance signal of [CuII]-phth was detected as well
(Figure S16). In order to investigate if a [CuII]-phth
complex is the catalytically active species, in situ generated
[CuII]-phth was subjected to the model reaction conditions
instead of the combination of Cu(AcO)2 as catalyst and
phthalimide as substrate (Scheme 6). Indeed, 3i was
obtained in 22% yield under these conditions (Figure S23),
and no product was observed when the reaction was
carried out in dark, indicating that [CuII]-phth is likely to be
a key intermediate for this transformation.
phth [CuIII]X
B
Initiation step
tBuOH
Catalytic cycle
tBuOOtBu
[CuII]X2
+
phth-[CuII]X
phthH
A
tBuO
tBuOOtBu
tBuOH
phthH
tBuO
X = AcO
phth:
O
O
tBuO-[CuII]X
[CuI]X
N
N
D
C
3i
O
O
Figure 2. Proposed reaction mechanism.
LCu(AcO)2
(a)
In conclusion, a mild photoinduced copper(II)-peroxide
strategy was developed for the alkylation of amides and
other nitrogen nucleophiles with unactivated alkanes. The
reaction is applicable to the late-stage N-alkylation of N–H
bond containing drugs. In amides containing more than
one N–H bond a chemoselective reaction of primary
amides, sulfonamides and N–H bonds in heterocycles was
observed. The preliminary mechanistic studies for this
transformation reveal a photoinduced initiation step for
the copper(II)-peroxide system in comparison to the
copper(I)-peroxide system, and the key component for this
reaction might be a [CuII]-phth complex.
DTBP
385-390 nm LED
N2, 25 °C, 10 h
LCu(AcO)2
LCu(AcO)2
(b)
(c)
(d)
(1) DTBP
(2) phthalimide
dark
N2, rt, 12 h
385-390 nm LED
N2, 25 °C, 10 h
KOtBu
N2, rt, 6 h
LCu(AcO)2
+
phthalimide
260
280
300
320
340
360
380
Magnetic field (mT)
Figure 1. X-band EPR spectra (9.45 G, 293 K) of Cu complexes
under different conditions [0.04 mmol Cu(AcO)2, 0.04 mmol L,
0.4 mmol DTBP, 0.08 mmol phthalimide, 0.08 mmol KOtBu, 3
mL CH3CN]. L = dtbbpy. EPR spectra were measured at 20 ℃
under N2. Previously irradiated samples were measured at
least one hour after irradiation (3.8 W 385-390 nm LED) to
avoid interference caused by transient radicals.
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental procedures, characterization data, 1H and 13C
NMR spectra for compounds (PDF)
Scheme 6. Reaction from in situ generated [CuII]-phth
1) KOtBu
O
cyclohexane
N2, rt, 6 h
DTBP
phthalimide
+
N
AUTHOR INFORMATION
Corresponding Author
*E-mail: burkhard.koenig@ur.de
Notes
The authors declare no competing financial interest.
LCu(AcO)2
0.04 mmol
2) filtration
385-390 nm LED
N2, 25 °C, 12 h
3i
O
NMR yield
22% (based on phthalimide)
0% (in dark)
L = dtbbpy
Based on the above experimental results and
mechanistic studies, we propose a mechanism for the
alkylation of nitrogen nucleophiles via a photoinduced
copper(II)-peroxide catalytic system as shown in Figure 2
for the example of phthalimide. During an initiation step a
[CuII]-phth complex (A) is formed from a copper source
and the amide under the influence of peroxide and light.
The catalytic cycle begins with photolysis of DTBP. The
generated tert-butoxy radical abstracts a hydrogen atom
ACKNOWLEDGMENT
This work was supported by the German Science Foundation
(DFG, KO 1537/18-1). Y.-W-Z. thanks for the support of Sino-
German (CSC-DAAD) Postdoc Scholarship Program. R.N.
thanks DAAD for One-Year Research Grant scholarship.
ABBREVIATIONS
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HAT, hydrogen atom transfer; NHPI, N-hydroxyphthalimide;
1
2
3
dtbbpy, 4,4'-di-tert-butyl-2,2'-bipyridine; DTBP, di-tert-butyl
peroxide; TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy free
radical; EPR, electron paramagnetic resonance.
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ACS Catalysis
Protected Amines: An Alternative to the Curtius Rearrangement. J.
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sec-butylbenzene were also detected. This may be due to the
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ACS Catalysis
Table of Contents (TOC)
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8
CuII
RNHR' = amides, sulfamides, indoles,
C(sp3)-H
3
azoles, purines, imine, phosphinic amide
and aminophthalimide
-
RNHR'
+
RR'N C(sp )
Late-stage Functionalization
Chemoselective Alkylation
alkyl
N
N
N
N
O
O
O
O
O
O
S
O
NH2
O
NH2
O
O
O
H2N
NH2
N
O
N
N
H
H
OH
N
O
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