Copper-catalyzed oxidative amination and allylic amination of alkenes

Article abstract of DOI:10.1002/chem.201301800

Enamines and enamides are useful synthetic intermediates and common components of bioactive compounds. A new protocol for their direct synthesis by a net alkene C-H amination and allylic amination by using catalytic Cu ^II in the presence of MnO₂ is reported. Reactions between N-aryl sulfonamides and vinyl arenes furnish enamides, allylic amines, indoles, benzothiazine dioxides, and dibenzazepines directly and efficiently. Control experiments further showed that MnO₂ alone can promote the reaction in the absence of a copper salt, albeit with lower efficiency. Mechanistic probes support the involvement of nitrogen-radical intermediates. This method is ideal for the synthesis of enamides from 1,1-disubstituted vinyl arenes, which are uncommon substrates in existing oxidative amination protocols. A new protocol for the direct synthesis of enamides and allylic amines by oxidative N-H/C-H coupling of N-sulfonylanilines with vinylarenes is presented. The reaction works in both inter- and intramolecular modes and is catalyzed by copper salts by using MnO₂ as the stoichiometric oxidant (see scheme). Nitrogen heterocycles including indoles, benzothiazine dioxides, and dibenzazepines can be formed. Copyright

Full text of DOI:10.1002/chem.201301800

FULL PAPER
Synthetic Methods
T. W. Liwosz,
S. R. Chemler* ................ &&&& — &&&&
Copper-Catalyzed Oxidative Amina-
tion and Allylic Amination of Alkenes
A new protocol for the direct synthesis
of enamides and allylic amines by oxi-
catalyzed by copper salts by using
MnO2 as the stoichiometric oxidant
(see scheme). Nitrogen heterocycles
including indoles, benzothiazine diox-
ides, and dibenzazepines can be
formed.
À
À
dative N H/C H coupling of N-sulfo-
nylanilines with vinylarenes is pre-
sented. The reaction works in both
inter- and intramolecular modes and is
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DOI: 10.1002/chem.201301800
Copper-Catalyzed Oxidative Amination and Allylic Amination of Alkenes
Timothy W. Liwosz and Sherry R. Chemler*[a]
Abstract: Enamines and enamides are
useful synthetic intermediates and
common components of bioactive com-
pounds. A new protocol for their direct
enamides, allylic amines, indoles, ben-
zothiazine dioxides, and dibenzazepines
directly and efficiently. Control experi-
ments further showed that MnO2 alone
can promote the reaction in the ab-
sence of a copper salt, albeit with
lower efficiency. Mechanistic probes
support the involvement of nitrogen-
radical intermediates. This method is
ideal for the synthesis of enamides
from 1,1-disubstituted vinyl arenes,
which are uncommon substrates in ex-
isting oxidative amination protocols.
À
synthesis by a net alkene C H amina-
tion and allylic amination by using cat-
alytic CuII in the presence of MnO2 is
reported. Reactions between N-aryl
sulfonamides and vinyl arenes furnish
Keywords: amination · copper · en-
amides · indoles · oxidation
Introduction
Compounds containing the enamine and enamide function-
alities participate in diverse chemical reactions.[1] More
stable enamines, which contain electron-withdrawing sub-
stituents or those that make up aromatic rings, are frequent-
ly found in biologically active compounds (e.g., Figure 1).[2]
The synthesis of enamines by oxidative coupling of
amines with alkenes appears straightforward and efficient
(Scheme 1), but in practice, such direct couplings are sur-
prisingly infrequently used, possibly because the scope of
À
Scheme 1. Regioselectivity in alkene C H aminations.
such methods is often limited to monosubstituted alkenes or
acrylates.[3] Although the reactions with electron-deficient
acrylates tend to favor the anti-Markovnikov product,[3a–c]
reactions of terminal alkenes and vinylarenes are generally
selective for the Markovnikov product (1,1-disubstitu-
tion).[3d–g]
The metal-catalyzed oxidative-amination mechanism
often involves aminometallation of the alkene,[3a–g] and steric
hindrance on the alkene can impede reactivity. The synthesis
of more highly substituted enamines thus often entails cou-
pling the amine to more activated and synthetically ad-
vanced haloalkenes or vinylboronic acids.[4] We envisioned
that the direct anti-Markovnikov oxidative coupling of vinyl
arenes with amines could be accomplished through nitro-
gen-radical addition to the alkene followed by oxidation of
the resulting radical to provide an enamine directly. Such a
strategy would favor addition to 1,1-disubstituted alkenes to
give 2,2-disubstituted-1-aminoalkenes. This kind of strategy
has been recently demonstrated in limited scope for the Ru-
catalyzed synthesis of N-(4-methoxyphenyl)indoles via intra-
molecular oxidative amination[3p] and for the Ag-promoted
synthesis of nitroalkenes via intermolecular oxidative cou-
plings.[3h] Herein, we report a copper-catalyzed inter- and in-
tramolecular coupling of a number of substituted anilines
with various vinyl arenes for the efficient synthesis of N-
aryl-b-aryl-enamides. Concurrently, we obtained intermolec-
ular allylic amination products in the coupling reactions of
substituted anilines with 1-alkyl-1-arylalkenes. We provide
evidence for a mechanism involving nitrogen-radical addi-
tion to the alkenes (see below).
Figure 1. Representative bioactive enamines.
[a] T. W. Liwosz, Prof. S. R. Chemler
Department of Chemistry
The State University of New York at Buffalo
Buffalo, NY 14260 (USA)
Fax : (+1)716-645-6963
E-mail: schemler@buffalo.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301800.
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Copper-Catalyzed Oxidative Amination
FULL PAPER
Table 1. Oxidative amination optimization.[a]
Results and Discussion
In recent years, our group has investigated the copper(II)-
catalyzed intramolecular additions of amines to alkenes for
the synthesis of functionalized nitrogen heterocycles.[5] In
these reactions, a carbon-radical intermediate is formed and
reacts with various radical acceptors, for example, diphenyl-
ethylene (DPE, 2a, Scheme 2).[5a] When 1,1-bis(4-methoxy-
Entry CuX2·ligand
Base
Solvent
T
[8C]
Yield
[%][b]
1
Cu
N
K2CO3 CF3Ph 120
K2CO3 CF3Ph 120
K2CO3 CF3Ph 120
K2CO3 CF3Ph 120
–
–
–
–
65
70
50
2
Cu(eh)2
Cu(eh)2
3[c]
4
Cu
Cu
Cu
Cu
Cu
Cu
Cu
–
N
90[d]
90[d]
80
5
CH3Ph 120
CH3Ph 120
CH3Ph 120
6[e]
7[f]
8
25
65
DCE
105
105
105
9
K2CO3 DCE
65
10
11[g]
12[h]
13[i]
14[j]
15[k]
16
8
–
–
–
–
-
DCE
85[d]
20
CH3Ph 120
CH3Ph 120
CH3Ph 120
CH3Ph 120
CH3Ph 120
CH3Ph 120
–
n.r.
60
70
67
85
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
A
E
G
-
line
Cu(OTf)2·7
(OTf)2·7
(OTf)2·7
17[l]
U
8
–
–
DCE
CH3Ph 120
CH3Ph 120
105
15
50
trace
À
Scheme 2. Discovery of the copper-catalyzed C H amination.
18[m] Cu
19[n]
Cu
phenyl)ethylene (p-MeO-DPE, 2b) was used, enamide 4, a
net oxidative amination product, was formed competitively
along with the expected indoline 3b (Scheme 2). We were
[a] Conditions: Cu(X)2 (0.04 mmol) and ligand (0.05 mmol) in solvent
(1 mL) were heated for 2 h at 608C under Ar. Sulfonamide 5a
(0.20 mmol), MnO2 (0.60 mmol), solvent (1 mL), base (0.20 mmol), and
flame-dried 4 ꢁ molecular sieves (40 mg) were added. The solution was
heated for 24 h in a sealed tube, then filtered through SiO2 and concen-
trated. [b] Conversion [%] based on crude NMR analysis. [c] Used cop-
per(II) 2-ethylhexanoate [Cu(eh)2] (3 equiv) and no oxidant. [d] Isolated
yield following flash chromatography on silica gel. [e] Run with 15 mol%
CuACHTNUTGRNEN(UG OTf)2 and 18 mol% 7. [f] Run with 50 mol% CuACHTUNTGERN(NUGN OTf)2·7 in the ab-
sence of MnO2. [g] Run in the absence of a copper salt. [h] Run in the
absence of MnO2 and CuX2. [i] Run with 2b (1 equiv). [j] Run with 2b
(2 equiv). [k] Run with 2b (1 equiv), CuACHTUNGETRN(UNNG OTf)2 (30 mol%), and 7
À
both intrigued by the fact that enamide 4 is a net C H ami-
nation product and by the possibility of developing an oxi-
dative coupling reaction that was entirely intermolecular,
À
even in the C N alkene addition step.
Our initial reaction optimization studies focused on the
À
alkene C H amination of N-tosylaniline 5a and 1,1-bis(4-
methoxyphenyl)ethene (2b; Table 1). The initial trial used
CuACHTUNGTRENNUNG(OTf)2 (30 mol%) with 2,2’-bipyridine as the ligand,
(38 mol%). N.r.=no reaction. [l] O2 (1 atm, balloon) was used instead of
MnO2. [m] Run with MnO2 (60 mol%) under O2 (1 atm, balloon).
[n] Run with 60 mol% MnO2.
MnO2 (3 equiv) as the stoichiometric oxidant, K2CO3
(1 equiv) as the base in CF3Ph at 1208C for 24 h and gave a
65% conversion of 5a to 6a (Table 1, entry 1). A brief
screen of copper salts revealed that Cu
with bis(oxazoline) ligand 7 was superior to Cu(2-ethylhexa-
noate)2 and Cu(OTf)2·2,2’-bipyridine (Table 1, entries 1–4).
ACHTUNGRTEN(NUNG OTf)2 (20 mol%)
ACHTUNGTRENNUNG
We further determined that the reaction was as efficient in
toluene, and base was unnecessary to obtain a 90% isolated
yield of 6a (Table 1, compare entries 4 and 5). Reducing the
copper loading to 15 mol% gave 80% conversion to 6a
(Table 1, entry 6). The reaction was also run without oxidant
Although simple alkenes are readily available, other
alkene substrates might not be. Therefore, we investigated
lowering the loading of 2b. Use of one equivalent of 2b
under the optimal conditions (Table 1, entry 5) gave a 60%
conversion of 5a to 6a, whereas use of two equivalents of
2b gave a 70% conversion to 6a, indicating that the reac-
tion will proceed substantially at lower alkene stoichiometry
(Table 1, entries 13 and 14). Raising the catalyst loading to
30 mol% with one equivalent of alkene led to a marginal in-
crease in yield (67% conversion, entry 15). We also found
that the commercially available 1,10-phenanthroline ligand
performs almost as well as the bis(oxazoline) ligand 7 and is
superior to 2,2’-bipyridine (Table 1, compare entries 1, 4,
and 5 to entry 16). The remainder of the material was start-
ing 5a in entries 1–16 (Table 1).
with 50 mol% CuACHTUNGTRENNUNG(OTf)2·7 to determine if MnO2 was requi-
site for the reaction to proceed. The reaction went to 25%
conversion, confirming that MnO2 makes the reaction more
efficient (Table 1, entry 7). Continued screening revealed
that the reaction could be run in dichloroethane at 1058C
with the addition of 2,6-di-tert-butyl-4-methylpyridine (8) as
the base, providing 6a in 85% isolated yield (Table 1, en-
tries 8–10). Additionally, the reaction went to 20% conver-
sion when only MnO2 was added (Table 1, entry 11). There-
fore, MnO2 is capable of promoting this reaction, albeit less
efficiently than when copper is present. In the absence of
copper and MnO2, there was no reaction (Table 1, entry 12).
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S. R. Chemler and T. W. Liwosz
Table 2. Scope of the oxidative and allylic amination coupling.[a]
An attempt to replace MnO2 with O2 (1 atm, balloon) led
to only 15% conversion to 6a (Table 1, entry 17). Use of
both O2 (1 atm) and substoichiometric MnO2 (0.6 equiv) led
to 50% conversion to 6a, and significantly less conversion
was observed without the O2 atmosphere under these condi-
tions (Table 1, entries 18 and 19). Use of O2 as oxidant in
different solvents often led to oxidation of the alkene to the
corresponding ketone (see the Supporting Information for
details). Other oxidants were screened, but none were as ef-
fective as MnO2 (see the Supporting Information for de-
tails).
Entry Amine
Alkene
Product
Yield
[%][b]
1
2
3
4
5
6
7
8
5a, X=H,
R=Ts
2b, Ar=4-
MeOC6H4
2b
6a, X=H, R=Ts
6b, X=H, R=PMBS
6c, X=H, R=Ns
6d, X=H, R=SES
6e, X=p-F, R=Ts
90
70
65
47
84
5b, X=H,
R=PMBS
5c, X=H,
R=Ns
5d, X=H,
R=SES
5e, X=p-F,
R=Ts
5 f, X=p-
OMe, R=Ts
5g, X=p-
CF3, R=Ts
2b
2b
2b
2b
2b
Following the optimized conditions A (Table 1, entry 5), a
À
series of substituted N-sulfonylanilines underwent C H ami-
nation coupling with 1,1-bis(4-methoxyphenyl)ethylene (2b)
(Table 2). Different arylsulfonamides 5a–c reacted efficient-
ly (Table 2, entries 1–3), whereas the 2-trimethylsilylethyl-
sulfonylaniline reacted with somewhat lower efficiency
(Table 2, entry 4). The reaction tolerates both electron-with-
drawing, as well as electron-donating, substituents on the
aniline ring with yields ranging from 60–84% (Table 2, en-
6 f, X=p-OMe, R=Ts, 67
6g, X=p-CF3, R=Ts,
6h, X=o-Br, R=Ts
74
60
5h, X=o-Br, 2b
R=Ts
À
tries 5–8). N-tosyl-2-naphthylamine undergoes C H amina-
tion efficiently to give 6i in 85% yield (Table 2, entry 9).
À
Sulfamide 5j underwent a double C H amination to give
enamide 6j, albeit in only 21% yield (Table 2, entry 10).
After assessing the electronic effect of the aniline substrates,
we turned to varying the nature of the alkene. An electronic
trend emerged with regards to the nature of the alkene.
Electron-rich 1,1-diaryl alkenes were higher yielding than
electron-deficient 1,1-diaryl alkenes. When the alkene was
changed from 2b (4-MeO-DPE) to 2a (DPE) to 2c (4-F-
DPE), the yield of the enamide products drops from 90 to
60 to 32% for 6a, 6k and 6l, respectively (Table 2, entries 1,
11, and 12). At this juncture, it was unclear if the observed
trend of decreasing yield with decreasing alkene electron
density was the result of decreased reactivity in electrophilic
addition of CuII or decreased reactivity with an electron-
deficient nitrogen radical. Attempts to trap radical inter-
mediates by adding (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) and 1,4-cyclohexadiene to the reaction mixture
of 5a and 2b gave only 6a (reactions not shown). The un-
symmetrical diaryl alkene 2d produced a 2:1 E/Z mixture of
enamides 6m in 79% yield (Table 2, entry 13).
9
5i
2b
6i
85
10
11
5j
5a
2b
6j
21
60
2a (DPE)
Ar=Ph
2c, Ar=4-
FC6H4
2d, Ar=4-
MeOC6H4, Ph Ar=4-MeOC6H4, Ph
6k, X=H, R=Ts,
Ar=Ph
6l, X=H, R=Ts,
Ar=4-FC6H4
6m, X=H, R=Ts,
12
13
5a
5a
30
79[c]
14
15
16
5a
5a
5a
2e
2 f
2g
9a
9b
9c
65
71
89
The scope of the alkenes was further extended to unsym-
metrical 1,1-disubstituted alkenes, in which one of the sub-
stituents was an alkyl group. Phenylsulfonamide 5a under-
À
went intermolecular alkene C H amination with exocyclic
alkene 2e. Interestingly, the major product 9a is the product
[6]
À
17
18
10a, R=TBS 2b
11
11
53
of a net allylic C H amination (Table 2, entry 14). The
10b,
2b
50[d]
scope was extended to alkenes 2 f and 2g, in which the allyl-
ic C H amination products 9b and 9c were 3-substituted
indene and benzofuran derivatives, respectively (Table 2, en-
tries 15 and 16). In all three cases, the internal alkene prod-
uct was exclusively observed.
R=butyl
À
[a] Conditions A, same as in Table 1 for entry 5. [b] Isolated yield. [c] A
2:1 mixture of alkene (E/Z) isomers was obtained. [d] Conversion (%,
NMR). Ns=4-nitrophenylsulfonyl, SES=2-trimethylsilylethanesulfonyl,
and PMBS=4-methoxyphenylsulfonyl.
Hydroxylamines 10a and 10b were also explored in this
reaction (Table 2, entries 17 and 18). The isolated product
from these reactions was vinylsulfone 11. We hypothesize
that the hydroxylamines might degrade in situ to give sul-
fonyl radicals that add to the alkene intermolecularly. Addi-
tion of sulfonyl radicals to alkenes is known.[7] N-alkylsulfo-
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Copper-Catalyzed Oxidative Amination
FULL PAPER
Table 3. Synthesis of indoles and larger ring enamides.[a]
that the N-phenyl-(2-(prop-1-en-2-yl)aniline 12e reacted
À
well in the intramolecular C H amination reaction (Table 3,
entry 6). Conversely, 2-(prop-1-en-2-yl)aniline, N-benzoyl-
(2-(prop-1-en-2-yl)aniline, and N-Cbz-2-(prop-1-en-2-yl)ani-
Entry Substrate
Product
Yield
[%][b]
À
line were unreactive under our C H amination conditions
(not shown).
Next, we envisaged that larger cyclic enamides might be
1
12a, R1, R2 =H, R3 =Ts
13a, R1, R2 =H, R3 =Ts
13b, R1 =Me, R2 =H,
R3 =Ts
66
90
À
2[c]
12b, R1 =Me, R2 =H,
R3 =Ts
constructed using this oxidative alkene C H amination. Syn-
thesis of benzothiazine dioxide 15 from sulfonamide 14 oc-
curred very efficiently, demonstrating a new and direct
method for the synthesis of this medicinally important ring
system (Table 3, entry 7).[2b] A seven-membered cyclic en-
amide would contain the core structure of dibenzazepines, a
common motifs found in both natural products and pharma-
ceuticals.[10] The unsaturated dibenzazepine has been pre-
dicted to be aromatic and thus stable.[11] As illustrated in
Table 3, when substrate 16 was submitted to the optimized
reaction conditions A, cyclic enamide 17 was observed
along with dibenzoazepine 18 (5:1 ratio) in 94% yield. The
appearance of 18 seemed to indicate that a potential carbon
radical intermediate was abstracting an H-atom from tol-
uene, giving the saturated product. To probe this hypothesis,
we ran the reaction in a,a,a-trifluorotoluene, eliminating
the possibility of H-atom abstraction from solvent, and saw
exclusively enamide product 17 (Table 3, entry 9). We also
ran the reaction in a,a,a-trifluorotoluene with the addition
of 1,4-cyclohexadiene, and 18 was again present in the crude
reaction mixture along with starting sulfonamide and 17 (re-
action not shown). These reactions provide evidence for a
carbon radical intermediate and, by inference, a nitrogen
radical intermediate.
3[c]
12c, R1 =Ph, R2 =H,
13c, R1 =Ph, R2 =H,
97
R3 =Ts
R3 =Ts
13c
4[d]
5
12c
70
41
12d, R1 =H, R2 =Ph,
R3 =Ts
13d, R1 =H, R2 =Ph,
R3 =Ts
6[c]
12e, R1 =Me, R2 =H,
R3 =Ph
13e, R1 =Me, R2 =H,
R3 =Ph
95
82
7[c]
14
15
8
16
16
17 (unsaturated)/
18 (saturated)
17 (exclusively)
94
(5:1)
90
9[e]
10
19
n.r.
[a] Same conditions as in Table 1 for entry 5 were used, except no exter-
nal alkene 2 was added. [b] Isolated yield. [c] Reaction run with 5 mol%
CuACHTUNGTRENNUNG(OTf)2·7. [d] Reaction run in the absence of copper. [e] Reaction run
in CF3Ph instead of CH3Ph.
We probed the use of the N-alkyl sulfonamide 19 in the
À
intramolecular C H amination (Table 3, entry 10) and
found it to be unreactive under the reaction conditions. An
N-(2-aryl)phenylsulfonamide previously shown to undergo
À
namides and 1,1-dialkylalkenes do not participate in the in-
termolecular coupling reaction.[8,9]
Cu/PhI
G
also proved unreactive under our conditions.[12]
Next, we explored the intramolecular variation of the re-
action for the synthesis of indoles (Table 3). When N-tosyl-
2-vinylaniline 12a was submitted to the optimized reaction
conditions A, indole 13a was formed in 66% yield. The re-
action was extended to give N-tosyl-3-methylindole 13b, N-
tosyl-3-phenylindole 13c, and N-tosyl-2-phenylindole 13d in
moderate to high yields (Table 3, entries 2–5). We had estab-
lished that MnO2 can partially facilitate the intermolecular
During this study, it became apparent that MnO2 can acti-
À
vate N-arylsulfonamides to undergo C H amination of vinyl
arenes to a certain extent. In point of fact, there are reports
of MnO2 oxidizing anilines, and nitrogen-radical intermedi-
ates have been proposed in these instances.[13] The formation
of nitrogen-radical intermediates under the conditions of
our previously reported copper-catalyzed enantioselective
alkene difunctionalization reactions (e.g., Scheme 1)[5] could
lead to a “background” cyclization process. Such a back-
ground reaction could potentially erode reaction enantiose-
lectivity levels (see the Supporting Information for an exper-
imental examination and further discussion).
À
C H amination reactions (Table 1, entry 11). We reasoned
the intramolecular nature of the indole-forming reaction
should be more facile, so we probed the sole use of MnO2
as oxidant in this reaction as well. From this trial, we found
that MnO2 promoted the reaction of 12c to an even greater
conversion (70%), albeit still not as high as when CuII is
present (Table 3, entry 4). This result prompted us to de-
crease the copper loading in this intramolecular reaction.
The copper(II) loading was reduced to 5 mol% without loss
of yield (Table 3, entries 2 and 3).
It is apparent that both copper and manganese complexes
are promoting the reaction in a cooperative manner. One
possible mechanistic pathway is shown in Scheme 3, in
which copper is catalyzing the reaction and MnO2 is the
stoiACTHNUGTNERcNUNG hiACHTGNUTRENNUNoG ACHUTNRTGEGmNNUN etACHTUNGTRENrNUNG ic oxidant. Another pathway, in which copper is
not involved and MnO2 is oxidizing the amine that can sub-
sequently add to the alkene, is also feasible. In the former
We investigated the scope of the N-substitution in the in-
À
tramolecular alkene C H amination reaction. We found
scenario, complexation of CuACTHUNGTRENNU(G OTf)2 with bis(oxazoline) 7
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S. R. Chemler and T. W. Liwosz
Allylic sulfonamide 9a was isolated as the major product
in 33% yield. This product is likely the result of cyclopro-
pane ring opening followed by intramolecular addition of
the carbon radical to the phenyl ring.
Conclusion
Scheme 3. Proposed copper-catalyzed oxidative amination mechanism.
This article discloses development of the first intermolecular
À
À
copper-catalyzed alkene C H/N H oxidative coupling reac-
tion.[3i,16,17] A number of enamides, allylic amines, and unsa-
turated nitrogen heterocycles can be formed by this relative-
ly simple reaction. Nitrogen- and carbon-radical intermedi-
ates have been implicated in the reaction mechanism. Con-
trol experiments revealed that MnO2 can also promote these
reactions, albeit less efficiently than when the copper(II)
catalyst is present. The reaction is chemoselective, favoring
reaction of amines and alkenes that can form stabilized radi-
gives complex A. Ligand exchange with N-tosylaniline 5a
gives complex B. When thermal energy is applied, the
amino–copper(II) intermediate B[14] is in equilibrium with
the nitrogen radical C and copper(I) complex D. If an excel-
lent radical acceptor (e.g., 1,1-diarylalkene 2b) is present,
the nitrogen radical can add to the alkene, generating inter-
mediate E. Under oxidizing conditions, the benzylic radical
À
is oxidized to the carbocation and elimination ensues to give
cal intermediates. The C H aminations reported herein use
low-cost metal catalysts and oxidants, and the reaction
I
À
C H amination product 6, whereas the Cu complex D is
oxidized back to CuII by MnO2.
mechanism is largely distinct from that of other alkene C H
À
Typically, nitrogen-centered radicals are generated from
already functionalized amines,[15] such as aminohalides, that
decompose in the presence of light or heat. In this case, the
metals work in concert to oxidize the N-arylsulfonamide.
Based on the reactive substrates in Tables 2 and 3 and the
unreactive substrates (alkyl sulfonamides, see below), only
aminyl radicals stabilized by two aryl substituents, or one
aryl and one sulfonyl substituent, form to any extent in the
reaction.[16k] N-Sulfonylhydroxylamines 10 also likely gener-
ate aminyl radicals that subsequently decompose to sulfonyl
radical intermediates (Table 2, entries 16 and 17).
amination processes, making it likely to serve as a comple-
ment to other reported procedures. The method for genera-
tion of nitrogen radicals described in this procedure, in gen-
eral, appears to be more simple and safe than methods that
use N-halogenated amines or peroxycarbamates and is com-
plementary with respect to substrate scope to reactions in-
volving other catalysts and promoters.[3,6] The nitrogen-radi-
cal-generating method disclosed herein could serve as inspi-
ration for the rational design of additional coupling reac-
tions.
The pathway in which MnO2 is promoting the reaction in-
dependent of CuII involves the oxidation of the amine by
MnO2. This oxidation is less common, but not unknown[13]
and is thought to occur via one electron oxidation, perhaps
associative. Thus, MnO2 can generate the aminyl radical,
and the radical can then continue through the cycle as inter-
mediate C in Scheme 3. Based on the optimization Table 1
trend, it appears that reactivity generally tracts with metal
coordination ability in the order [Cu(bisoxazoline)]ACTHNUTRGNEUNG(OTf)2 >
Cu(2-ethylhexanoate)2 >MnO2. This supports an associative,
inner-sphere amine-oxidation process.
As a final probe of nitrogen radical reactivity, 1-(1-cyclo-
propylvinyl)benzene (2h) was subjected to the intermolecu-
Experimental Section
Synthesis of N-(2,2-Bis(4-methoxyphenyl)vinyl)-4-methyl-N-phenylbenze-
nesulfonamide (6a): Conditions A: An oven-dried pressure tube equip-
ped with a magnetic stir bar was put under an Ar atmosphere and charg-
ed with CuACHTUNGTRNE(NUG OTf)2 (15 mg, 0.0404 mmol), bis(oxazoline) 7 (9 mg,
0.0505 mmol), and CH3Ph (1 mL) and stirred at 608C for 2 h. The mix-
ture was treated with N-phenyltosylamide 5a (50 mg, 0.202 mmol), MnO2
(53 mg, 0.606 mmol), 4-MeO-DPE 2b (146 mg, 0.606 mmol), and the re-
maining CH3Ph (1.02 mL, 0.1m). Molecular sieves (4 ꢁ; 41 mg) were
flame dried for 2 min and added directly to the reaction mixture. The
pressure tube was purged with argon for 2 min, sealed, heated to 1208C,
and stirred for 24 h. Filtration of the cooled reaction mixture through a
pad of SiO2 and subsequent evaporation of the solvent in vacuo gave
crude mixtures. Flash chromatography of the resulting crude mixture on
À
lar C H amination conditions (Eq. [1]).
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Copper-Catalyzed Oxidative Amination
FULL PAPER
silica gel (0–40% EtOAc in hexanes gradient) gave 6a (88 mg, 90%) as
a light yellow solid. M.p. 130–1318C; 1H NMR (400 MHz, CDCl3): d=
7.51 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H),
7.02–6.99 (m, 3H), 6.85 (d, J=9.2 Hz, 2H), 6.80–6.78 (m, 5H), 6.63 (d,
J=9.2 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.44 ppm (s, 3H); 13C NMR
(75 Hz, CDCl3): d=159.5, 158.7, 143.8, 140.8, 137.5, 134.8, 133.2, 131.2,
130.2, 129.5, 128.9, 128.2, 127.8, 127.8, 126.6, 123.7, 113.6, 113.2, 55.3,
55.2, 21.6 ppm; IR (neat): u˜ =3036, 2932, 2836, 1605, 1512, 1354, 1294,
1247, 1165, 1090, 1032, 814, 694 cmÀ1; HRMS (ESI): m/z calcd for
[M+Na]+ C29H27O4NNaS: 508.1553, found: 508.1556.
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Acknowledgements
We thank Mr. Garrick Zebrig for Table 2, entry 3, and for exploring
some less reactive substrates in the intermolecular C H amination reac-
tion. We thank the National Institutes of Health, NIGMS (GM-078383)
for funding this research.
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ACHTUNGTRENNUNGphenyl-
AHCTUNGTRENNUNG
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S. R. Chemler and T. W. Liwosz
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Received: May 10, 2013
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!