Direct Catalytic Chemoselective α-Amination of Acylpyrazoles: A Concise Route to Unnatural α-Amino Acid Derivatives

Article abstract of DOI:10.1021/jacs.5b11773

A direct copper-catalyzed highly chemoselective α-amination is described. Acylpyrazole proved to be a highly efficient enolate precursor of a carboxylic acid oxidation state substrate, while preactivation by a stoichiometric amount of strong base has been used in catalytic α-aminations. The simultaneous activation of both coupling partners, enolization and metal nitrenoid formation, was crucial for obtaining the product, and wide functional group compatibility highlighted the mildness of the present catalysis. The bidentate coordination mode was amenable to highly chemoselective activation over ketone and much more acidic nitroalkyl functionality. Deuterium exchange experiments clearly demonstrated that exclusive enolization of acylpyrazole was achieved without the formation of a nitronate. The present catalysis was applied to late-stage α-amination, allowing for concise access to highly versatile α-amino acid derivatives. The product could be transformed into variety of useful building blocks.

Full text of DOI:10.1021/jacs.5b11773

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Article
Direct Catalytic Chemoselective #-Amination of Acylpyrazoles:
A Concise Route to Unnatural #-Amino Acid Derivatives
Keisuke Tokumasu, Ryo Yazaki, and Takashi Ohshima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11773 • Publication Date (Web): 09 Feb 2016
Downloaded from http://pubs.acs.org on February 9, 2016
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Journal of the American Chemical Society
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α
Direct Catalytic Chemoselective -Amination of Acylpyrazoles:
α
A Concise Route to Unnatural -Amino Acid Derivatives
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Keisuke Tokumasu, Ryo Yazaki,* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582 Japan
ABSTRACT: A direct copper-catalyzed highly chemoselective α-amination is described. Acylpyrazole proved to be a highly effi-
cient enolate precursor of a carboxylic acid oxidation state substrate, while pre-activation by a stoichiometric amount of strong base
has been used in catalytic α-aminations. The simultaneous activation of both coupling partners, enolization and metal nitrenoid
formation, was crucial for obtaining the product and wide functional group compatibility highlighted the mildness of the present
catalysis. The bidentate coordination mode was amenable to highly chemoselective activation over ketone and much more acidic
nitroalkyl functionality. Deuterium exchange experiments clearly demonstrated that exclusive enolization of acylpyrazole was
achieved without the formation of a nitronate. The present catalysis was applied to late-stage α-amination, allowing for concise
access to highly versatile α-amino acid derivatives. The product could be transformed into variety of useful building blocks.
Introduction
catalytic α-aminations (Scheme 1-b). Attachment of an aryl
group at the α-position was unavoidable for efficient enoliza-
tion and a general and complementary catalytic α-amination of
carboxylic acid oxidation state pronucleophiles has not been
reported. Herein we disclose catalytic α-amination of car-
boxylic acid oxidation state pronucleophile, allowing for ex-
tremely high chemoselectivity and late-stage α-amino acid
synthesis through simultaneous activation of both coupling
partners (enolization/metal nitrenoid formation) (Scheme 1-c).
α-Amino acids are widely used as biologically active mole-
cules and building blocks in synthetic organic chemistry. Pep-
tide-based drugs have attracted increased attention due to their
low number of side effects, and replacement of natural α-
amino acid residues with unnatural residues improves their
pharmacokinetics and bioactivity.1 Therefore, extensive efforts
are focused on developing an efficient synthesis of unnatural
α-amino acids.2 Most of the earlier methodologies, however,
rely on carbon-carbon bond formation, as exemplified by the
Strecker type reaction3 and alkylation of glycine derivatives.4
Alternatively, α-amination of carboxylic acid oxidation state
substrates is considered a straightforward method.5 Especially,
a carbon framework construction followed by late-stage α-
amination is advantageous for highly complex α-amino acid
synthesis.6 While catalytic α-amination reactions have been
investigated for decades, readily enolizable lower oxidation
state substrates, such as aldehydes and ketones, are mostly
used as carbonyl donors.
Scheme 1. Catalytic
dation State Substrates
α
-Amination of Carboxylic Acid Oxi-
a) Catalytic α-Amination of Pre-Activated Ketene Silyl Acetals7a-e
O
R23Si
catalyst
O
R
+
"N"
R1O
R
R1O
[N]
ketene silyl acetals
"N" = aminating agent
Catalytic deprotonative activation of carboxylic acid oxida-
tion state pronucleophiles and subsequent coupling with elec-
trophiles remains a particularly formidable task due to the
intrinsic low acidity of α-protons. Consequently, pre-
activation strategies with ketene silyl acetals are generally
used. Even when using ketene silyl acetals, however, catalytic
α-amination is fairly rare despite a number of precedents of
nucleophilic addition to polar electrophiles, such as aldehydes,
imines and electron-deficient olefins (Scheme 1-a). Although
the pre-activation strategy is highly efficient for synthesizing
simple α-amino acids, late-stage α-amination of complex
molecules possessing carboxylic acid equivalents has never
been applied.8 Moreover, the use of more than a stoichiometric
amount of a strong base limits functional group compatibility,
particularly acidic functionalities. Recently, only a few car-
boxylic acid oxidation state pronucleophiles were applied to
b) Catalytic α-Amination of α-Aryl Ester Derivatives7f-h
O
O
catalyst
Ar
Ar
+
"N"
R3
R3
H
acyloxazolidinones, esters
[N]
"N" = aminating agent
c) Chemoselective and Late-Stage α-Amination of Acylpyrazoles (This work)
O
O
catalyst
R4
R4
N
N
+
PhI NTs
N
N
NHTs
H
acylpyrazoles
(R4 ≠ Ar)
■ Highly chemoselective
■ Late-stage α-aminaiton
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Results and discussion
product in low yield; instead, decomposition of starting mate-
1
2
3
4
5
6
7
8
rial was observed (4). In addition, bulker 3,5-diisopropyl sub-
stituents almost completely terminated the catalysis, presuma-
bly because the coordination to the catalyst was disturbed by
bulky substituents (5). Other carboxylate donors, acylpyrrole
and acylimidazole, which acidity of α-proton would be similar
to that of acylpyrazole, were not effective, suggesting that
bidentate coordination mode of acylpyrazole was essential (6
and 7). Propiophenone did not afford the desired product (8).
Moreover, bidentate coordinative acyloxazolidione and thia-
zolidinethione also gave unsatisfactory results (9 and 10).
Our strategy for catalytic chemoselective α-amiantion was
depicted in Scheme 2. We selected acylpyrazole9 for chemose-
lective α-amination as a carboxylic acid oxidation state pronu-
cleophile because 1) acylation of commercially available py-
razole proceeds under mild conditions by conventional meth-
ods (acid chloride, condensation reagent, etc.) without requir-
ing a strong base;10 2) a weak amide conjugation and bidentate
coordination mode enables chemoselective enolization over
readily enolizable ketones, allowing for broad functional
group compatibility and late-stage α-amination;11 and 3)
acylpyrazole can be easily transformed into diverse functional
groups. As an aminating agent, iminoiodinane12 was selected
because iminoiodinane does not generate a nucleophilic co-
product, which would cause an undesired substitution reaction
on the carbonyl group of acylpyrazole.13 Moreover, transition
metals generate highly reactive metal nitrenoide species using
iminoiodinane, as exemplified by aziridination and C–H ami-
nation.14
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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40
41
42
43
44
45
46
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49
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51
52
53
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55
56
57
58
59
60
Table 1. Initial Catalyst Screeninga
catalyst
O
O
(10 mol%)
Me
Me
N
N
+
PhI NTs
N
N
MS 4A
CH2Cl2
NHTs
0 °C, 24 h
1a
2
3a
yield
(%)
yield
(%)
entry
entry
catalyst
catalyst
CuOTf
Scheme 2. Simultaneous Activation Strategy for Chemose-
Cu(OTf)2
AgOTf
0
68
0
7 c
8 d
37
43
27
lective
α
-Amination
1
Cu(ClO4)2
2b
3
0
9 d
10
Cu(OCOCF3)2
Cu(OAc)2
Cu(acac)2
CuCl2
simultaneous
activation
Rh2(OAc)4
Zn(OTf)2
Sc(OTf)3
TfOH
0
trace
trace
trace
43
O
O
catalyst: [M]
R
R
N
N
+
PhI NTs
N
N
4
6
11
12
H
NHTs
5b
6b
0
enolate
precursor
nitrenoid
precursor
CF3COOH
0
13e CuCl2 + AgOTf
aConditions: 1 (0.4 mmol), 2 (0.2 mmol). Yields were deter-
mined by 1H-NMR analysis using 2-methoxynaphthalene as an
internal standard. b5 mol% catalysts were used. cToluene complex
[M]
O
[M]
N
transient aziridine
formation
[M]=NTs
or
d
e
O
was used. Hydrated metal catalysts were used. 10 mol% CuCl2
and 10 mol% AgOTf were used.
R
R
+
N
N
N
N
[M] NTs
Ts
chemoselective
enolization
Scheme 3. Evaluation of Carboxylic Acid Oxidation State
Pronucleophiles
Based on the above strategy, we first evaluated various cata-
lysts in the reaction of acylpyrazole 1a with iminoiodinane 2
(Table 1). Among them, cationic copper(II) triflate was a
competent catalyst for the α-amination reaction (entry 0).15
This reaction did not require an external base. Less Lewis
acidic transition metals were not effective (entries 1 and 2).
Lewis acids without an empty d orbital for metal nitrenoid
formation gave unsatisfactory results (entries 3 and 4). In addi-
tion, Brønsted acid catalysts did not give 3a at all (entries 5
and 6), indicating that highly electrophilic metal nitrenoid
formation is crucial for obtaining the product. A variety of
copper catalysts were evaluated next. While cationic copper
catalysts gave a moderate yield (entries 7-9), less Lewis acidic
copper catalysts did not afford 3a (entries 10-12). Combined
use of CuCl2 with AgOTf, which in situ generates cationic
copper species, increased the catalytic activity (entry 13). The-
se results suggested that proper Lewis acidity is also important
to efficiently promote the reaction.
Cu(OTf)2
(10 mol%)
O
O
Me
+
PhI NTs
Me
O
X
MS 4A
CH2Cl2
0 °C, 24 h
X
NHTs
2
O
N
O
Me
N
Me
N
Me
N
iPr
N
N
NHTs
NHTs
NHTs
iPr
1a: 68% yield
4: 7% yield
5: trace
O
O
O
Me
Me
NHTs
Me
NHTs
7: 0% yield
N
N
N
NHTs
8: 0% yield
6: 0% yield
O
S
O
O
Me
Me
NHTs
10: 0% yield
We also evaluated various carboxylic acid oxidation state
pronucleophiles (Scheme 3). The substituents on pyrazole
were turned out to be crucial for high yield. Acylpyrazole
without 3,5-dimethy substituents on pyrazole provided the
O
N
S
N
NHTs
9: 0% yield
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We next investigated the substrate scope of acylpyrazoles
To demonstrate the chemoselective nature of the present
catalysis, deuterium exchange experiments were conducted
(Scheme 4). We selected a substrate with a nitroalkyl func-
tionality, 1t, as a model substrate. When 1t was treated with a
catalytic amount of mildly basic triethylamine in D2O/THF,
we exclusively obtained a di-deuterated product at the α-
position of nitro functionality (Scheme 4-a).17 This result
clearly indicated that the α-proton of the nitroalkyl function-
ality was inherently more acidic than the corresponding
acylpyrazole, and nitronate was exclusively formed under
even mildly basic conditions.18 In sharp contrast, the amination
proceeded chemoselectively at the α-position of acylpyrazole
over the nitroalkyl functionality under our standard conditions
(Scheme 4-b). Moreover, when deuterated 1t(d2) was subject-
ed to the standard conditions, 3t(d2) was observed without a
decrease in the deuterium ratio of the nitroalkyl functionality,
suggesting that exclusive enolization of acylpyrazole was
achieved under the standard conditions without the formation
of a nitronate.11 This is the first catalytic chemoselective
deprotonative activation method of a carboxylic acid oxidation
state pronucleophile over a highly acidic nitroalkyl functional-
ity.
using copper(II) triflate as an optimal catalyst (Table 2).16
Under the optimized conditions, we observed wide functional
group tolerance. The present catalysis could be run in gram
scale without a significant loss of yield (3a). A variety of alkyl
chains could be incorporated (3b – 3f). Homophenylalanine
derivatives were obtained in high yield with benzylic position
intact (3g–3i).15 Notably, terminal alkene, a suitable substrate
for aziridination, survived the present catalysis (3j).7a Alkyl
halide, ether, phthalimide, and boronate ester functionalities
were incorporated without significant detrimental effects to
the chemical yield (3l–3q), thus highlighting the wide func-
tional group compatibility of the present α-amination reaction.
A bis-acylpyrazole substrate selectively provided a mono-
aminated product (3r). A readily enolizable malonate deriva-
tive could be converted in high yield into 3s, which is amena-
ble to further differential elaboration of acylpyrazole and ester
functionalities.
1
2
3
4
5
6
7
8
9
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
Table 2. Substrate Scope of Acylpyrazolea
Cu(OTf)2
(10 mol%)
O
O
R
R
N
N
+
PhI NTs
N
N
Scheme 4. Chemoselective Enolization of Acylpyrazole
over Highly Reactive Nitroalkyl Functionality
MS 4A
CH2Cl2
0 °C, 48 h
NHTs
1
2
3
O
O
Et3N
(20 mol%)
H
H
D
D
O
O
O
N
N
N
N
Me
Me
Me
(a)
(b)
(c)
N
N
N
NO2
N
NO2
7
7
X
X
X
6
D2O/THF
H
H
H H
NHTs
NHTs
3b: 76%
NHTsMe
3a: 76%, 64%b
1t
1t(d2): 76% yield
(>95 atom%D)
3c: 63%
O
O
O
Cu(OTf)2
(10 mol%)
PhI=NTs 2
X
X
X
O
O
H
H
H
H
NHTs
NHTs
NHTs
N
NO2
N
NO2
7
7
3d: 63%
3e: 60%
3f: 72%
MS 4A
CH2Cl2
H
H
H NHTs
Y
O
O
O
1t
3t: 56% yield
X
X
6
X
NHTs
NHTs
NHTs
Cu(OTf)2
(10 mol%)
PhI=NTs 2
3g: 78%
3j: 58%
3h (Y = Br): 72%
3i (Y = OMe): 69%
O
O
D
D
D D
N
NO2
N
NO2
7
7
MS 4A
CH2Cl2
H
H
H NHTs
O
O
O
1t(d2)
(>95 atom%D)
3t(d2): 56% yield
(>95 atom%D)
X
X
Br
X
CF3
6
NHTs
NHTs
NHTs
3k: 61%
3l: 73%
3m: 75%
O
O
O
O
Acylpyrazole, having an aryl ketone and other electron
withdrawing functionalities, was then subjected to the opti-
mized conditions to further demonstrate the chemoselective
nature of the present catalysis (Table 3). When keto-
acylpyrazoles 1u and 1v were used, the amination reaction
proceeded exclusively at the α-position of acylpyrazole and
the corresponding products (3u and 3v) were isolated in high
yield.19 Chemoselective α-amination also proceeded with
acylpyrazole 1w derived from levulinic acid, whereas levulinic
acid derivatives commonly afforded β/δ-aminated product via
bromination.20 Other electron-withdrawing groups were also
applicable and the desired products were obtained chemose-
lectively (3y and 3z). Highly coordinative phosphate substrate
N
X
OTBDPS
X
OEt
X
3
NHTs
NHTs
3o: 83%
O
O
NHTs
3p: 65%
3n: 63%
O
O
O
O
N
X
N
3
X
Bpin
X
OMe
NHTs
NHTs
3q: 60%
NHTs
3r: 60%
3s: 70%
aConditions: 1 (0.4 mmol), 2 (0.2 mmol). Isolated yields are
shown. bGram scale synthesis (5.31 mmol scale). X stands for 3,5-
dimethylpyrazolyl group.
1 afforded the product 3 in moderate yield, presumably
α α
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because the competitive coordination of phosphate functionali-
ty disturbs the efficient enolization of acylpyrazole
Scheme 6. Divergent Transformation of the Product
1
2
3
4
O
O
a,b,c
Me
N
Me
N
MeO
Table 3. Substrate Scope for Chemoselective
α
-Aminationa
NHTs
NHBoc
5
6
7
8
Cu(OTf)2
(10 mol%)
O
O
3a
11a
R
R
N
N
+
PhI NTs
N
N
MS 4A
CH2Cl2
0 °C, 48 h
O
O
NHTs
f
Me
d
a
Me
HO
Ph
1
2
3
9
NHTs
NHTs
O
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
12a
15a
O
O
O
O
Y
X
Me
X
OEt
O
N
O
O
X
g
NHTs
O
NHTs
Me
N
Me
Me
NHTs
EtO
H
NHTs
3w: 45%b
3x: 72%
NHTs
13a
NHTs
16a
3u (Y = Me): 70%
3v (Y = Et): 72%
3a
O
O
O
O
O
O
Me
NHTs
17a
CN
S
OEt
OEt
MeO
Me
NHTs
HO
X
X
Ph
X
P
7
N
H
e
h
NHTs
NHTs
NHTs
O
O
14a
3y: 75%
3z: 71%
3α: 33%
Reaction conditions: (a) NaOEt, EtOH, rt, 99% yield. (b)
(Boc)2O, DMAP, Et3N, DCM, 0 °C, quant. (c) Mg, MeOH, soni-
cation, rt, 99% yield. (d) NaOH, H2O/MeOH, rt, 97% yield. (e) H-
Gly-OMe HCl, NEt3, toluene, 50 °C, quant. (f) PhMgBr, Et2O,
0 °C to rt, 94% yield. (g) LiAlH4, THF, –40 °C, 83% yield. (h)
NaBH4, H2O/THF, rt, quant.
aConditions: 1 (0.4 mmol), 2 (0.2 mmol). Isolated yields are
shown. 20 mol% Cu(OTf)2. X stands for 3,5-dimethylpyrazolyl
group.
b
Our catalytic α-amination was applied to late-stage α-
amination (Scheme 5). TBS-protected lithocholic acid deriva-
was converted into the corresponding α-amino acid
ina synthetically useful yield in the presence
of 20 mol% catalyst, indicating that the present catalysis was
tive 1
β
derivative 3
β
To gain preliminary mechanistic insight, we performed sev-
eral control experiments. Addition of 1,1-diphenylethylene
(18) to the standard conditions completely terminated the reac-
tion; instead, 2,2-diphenylaziridine 19 was obtained as a by-
product, suggesting the generation of highly reactive copper
nitrenoid (Scheme 7).22,23 This finding was also consistent with
the poor results obtained Lewis acid (Zn, Sc: Table 1, entries 3
and 4) or Brønsted acid (Table 1, entries 5 and 6) as a cata-
lyst.24
applicable to late-stage α-amination of complex molecules.
Scheme 5. Late-Stage
Derivative
α
-Amination of Lithocholic Acid
O
O
Me
Me
X
X
H
H
Me
H
Me
NH
Cu(OTf)2
(20 mol%)
Ts
H
Me
H
Me
MS4A
CH2Cl2
0°C, 48 h
H
H
Scheme 7. Confirmation of Copper Nitrenoid Formation
+
H
H
O
H
H
PhI=NTs 2
OTBS
X = 3,5-dimethylpyrazolyl
OTBS
Me
N
1β
3β
54% yield
(dr = ca.1/1)
N
Cu(OTf)2
(10 mol%)
PhI=NTs 2
O
1a
+
Ph
NTs
Me
N
N
MS 4A
CH2Cl2
0 °C, 48 h
Deprotection of the tosyl group of 3a was achieved, and the
corresponding N-Boc protected amino ester 11a was obtained
in high yield (Scheme 6), while, in previous catalytic α-
amination of α-aryl pronucleophiles, further elaboration of the
products into primary amines seemed to be difficult.7f-7h In
addition, the acylpyrazole functionality was transformed into
various functional groups, such as carboxylic acid, ester, ke-
tone, aldehyde, and alcohol in high yield.9b It is noteworthy
that direct peptide coupling was also achieved by treatment
with glycine ester without any condensation reagent (14a).21
Ph
Ph
19: 37% yield
NHTs
Ph
3a: not obserbed
18
To confirm whether the reaction involved an α-carbon radi-
cal intermediate, substrate 1 having a terminal olefin at the 5-
exo position was subjected to the standard conditions (Scheme
8-a). In this reaction, only the usual α-aminated product 3
was observed and no cyclized product was detected in the
crude reaction mixture.25 When α-cyclopropyl substrate 1
was subjected to the standard conditions, we detected no ring-
opened products (Scheme 8-b).25,26 These findings indicated
that an α-radical intermediate was not involved in the present
catalysis.
γ
γ
δ
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Corresponding Author
Scheme 8. Radical Clock Experiments with 1
γ
and 1
δ
1
2
3
4
5
6
7
yazaki@phar.kyushu-u.ac.jp
ohshima@phar.kyushu-u.ac.jp
Cu(OTf)2
(10 mol%)
PhI=NTs 2
O
O
O
NHTs
N
N
N
N
N
N
(a)
MS 4A
CH2Cl2
0 °C, 48 h
Notes
R
1γ
3γ: 58% yield
The authors declare no competing financial interest.
R = H, NHTs
not observed
8
O
9
Ph
Ph
N
N
ACKNOWLEDGMENT
10
11
12
13
14
15
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60
Cu(OTf)2
(10 mol%)
NHTs
O
This work was financially supported by Grant-in-Aid for
Scientific Research (B) (#24390004), Young Scientists (B)
(#26860012), Exploratory Research (#15K14930), Scien-
tific Research on Innovative Area 2707 Middle molecular
strategy and Platform for Drug Discovery, Informatics, and
Structural Life Science from MEXT. R.Y thanks Ube In-
dustries, Ltd. Award in Synthetic Organic Chemistry, Japan,
Shorai Fundation for Science and Technology and The So-
ciety of Iodine Science. We are grateful to Dr. Kensuke
Kiyokawa at Osaka University and Dr. Akira Yoshimura at
University of Minnesota Duluth for fruitful discussion re-
garding iminoiodinane synthesis.
PhI=NTs 2
Ph
Ph
3δ: not observed
Ph
N
(b)
N
MS 4A
CH2Cl2
0 °C, 48 h
O
X
Ph
1δ
X = 3,5-dimethylpyrazoly, OH
not observed
On the other hand, the intermediacy of the radical species
was supported by radical scavenger addition experiments
(Scheme 9). The desired α-aminations were completely termi-
nated by adding
a stoichiometric amount of BHT or
TEMPO.27 We speculated that copper nitrenoid species with a
radical character would be generated, followed by stepwise
transient aziridine formation.28-30
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Scheme 9. Addition of Radical Scavengers
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O
Me
N
N
Cu(OTf)2
(10 mol%)
PhI=NTs 2
O
1a
+
Me
N
N
OH
MS 4A
CH2Cl2
O
N
tBu
tBu
NHTs
0 °C, 48 h
or
3a: not observed
Me
BHT
TEMPO
Conclusion
In conclusion, we developed a Lewis acidic copper cata-
lyzed chemoselective α-amination by combining acylpyrazole
and iminoiodinane. Noteworthy is that α-amination of acylpy-
razole exclusively proceeded over much more acidic nitroalkyl
functionalities, which could be easily activated even by a cata-
lytic amount of mild base. Our method offers concise access to
previously untouched unnatural α-amino acids through late-
stage α-amination. Further applications of acylpyrazole as a
carboxylic acid oxidation state pronucleophile for late-stage
functionalization and the development of enantioselective
variants are in progress.31
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectroscopic data for all new com-
pounds. The Supporting Information is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
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Tanaka, M.; Kurosaki, Y.; Washio, T.; Anada, M.; Hashimoto, S.
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1
2
3
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9
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copper nitrenoid.
10
11
12
13
14
15
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17
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19
20
21
22
23
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inferior results were obtained.
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(29) The possibility of inhibition of enolization by radical scaven-
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52, 413.
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1
2
3
simultaneous
activation
4
5
O
O
catalyst
R
R
N
N
+
PhI NTs
N
N
6
H
NHTs
7
8
enolate
precursor
nitrenoid
precursor
up to 83% yield
• Highly chemoselective
9
• Late-stage α-aminaiton
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