Aza-Rubottom Oxidation: Synthetic Access to Primary α-Aminoketones

Article abstract of DOI:10.1021/jacs.8b13818

An aza analogue of the Rubottom oxidation is reported. This facile transformation takes place at ambient temperature and directly converts silyl enol ethers to the corresponding primary α-aminoketones. The use of hexafluoroisopropanol (HFIP) as the solven

Full text of DOI:10.1021/jacs.8b13818

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Communication
Aza-Rubottom Oxidation: Synthetic Access to Primary #-Aminoketones
Zhe Zhou, Qing-Qing Cheng, and László Kürti
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2019
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Aza-Rubottom Oxidation: Synthetic Access to Primary α-
Aminoketones
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Zhe Zhou, Qing-Qing Cheng and László Kürti*
Department of Chemistry, Rice UniversityꢀBioScience Research Collaborativeꢀ6500 Main Street, Houston, TX
77030 (USA) E-mail: kurti.laszlo@rice.edu
Supporting Information Placeholder
O-phosphinylhydroxylamine) are usually very volatile and
their use is limited due to safety concerns (i.e., toxicity). One
unique approach developed by the Wirth group uses a hy-
pervalent iodine reagent to facilitate an intramolecular um-
polung reaction to access α-aminoketones, although the
amino group must be fully substituted.7 Other noteworthy
approaches to access secondary and tertiary α-amino car-
bonyl compounds include several types of copper-catalyzed
coupling reactions.8
ABSTRACT: An aza analogue of the Rubottom oxidation is
reported. This facile transformation takes place at ambient
temperature and directly converts silyl enol ethers to the
corresponding primary α-aminoketones. The use of hex-
afluoro isopropanol (HFIP) as the solvent is essential for the
success of this reaction. Overall this process is well-suited for
the aza-functionalization and derivatization of complex or-
ganic molecules.
A. Typical Two-Step Approaches to Primary α-Amino Ketones
O
H2/Pd/BaSO4
R3
R1
The alpha-aminoketone moiety is commonly found in bio-
logical molecules, natural products and active pharmaceuti-
cal ingredients. Despite their apparent importance, synthetic
access to these compounds is not always straightforward.1
This is especially evident when the desired amino ketones
have a primary amino group attached to a fully substituted
α-carbon atom. The most common strategy for synthesizing
these compounds involves a two-step approach, in which
either an azido,2 a nitro,3 or a hydroxylamino group4 is first
installed at the α-position. A subsequent hydrogenation,
usually catalyzed by a transition metal such as Pd, Pt or
Raney Ni, is then carried out to obtain the corresponding
primary α-aminoketone (Figure 1, A). Aside from the added
steps, this approach also has limitations such as the lack of
chemoselectivity during the reduction and the potential in-
stability of the azido- or nitro- intermediates.
N3
R2
O
O
O
O
R3
H
Zn/HOAc
Raney Ni
R3
NO2
R3
R1
R1
R1
NH2
R2
R2
R2
R3
R1
NOH
Cbz
R2
B. Asymmetric Synthesis of Primary α-Amino Ketones
Boc
N
O
O
O
N
R3
NBoc
NHBoc
TFA
H2, Raney Ni
MeOH, sonication
Boc
R3
H
R3
NH2
R1
R1
R1
*
*
R2
R2
R2
Chiral Catalyst
DCM
C. The Rubottom Oxidation and the Proposed “Aza-Rubottom Oxidation”
R3
R3
O
O
DMDO or mCPBA
Aminating Reagent
O
R
R
O
O
R3
OH
Rubottom
Oxidation
R2
R
R
O
R1
Si
R
R2
Si
R
R1
R2
R1
R3
R3
HN
Significant efforts have been devoted into making α-
hydrazinyl compounds from ketones and azodicarbonyl
compounds such as DEAD under basic or organocatalytic
R3
NH2
Aza-Rubottom
Oxidation
R
R
R
R
O
R1
R2
R2
Si
R
Si
R
R2
R1
R1
conditions (Figure 1, B).5
Although this type of α-
hydrazination reaction is generally high-yielding and can be
rendered enantioselective, it is far from trivial to cleave the
N-N bond and reveal the desired primary amino ketones. An
ideal reaction should be able to directly install the primary
amino group without the need to perform an additional re-
duction or N-deprotection. A few such examples have been
reported in the literature.6 The common strategy is to trap
the enolates generated from the corresponding ketones with
an electrophilic nitrogen source. However, good yields can
only be obtained with ketones that can form stable enolates,
such as malonates, phenyl acetates and phenylacetonitriles.
Moreover, the required aminating reagents (i.e. chloramine,
Figure 1. Existing methods for the synthesis of α-amino-
ketones and the proposed “aza-Rubottom oxidation”
Contrary to the generally difficult α-amination reactions, the
α-hydroxylation of ketones is a well-established transfor-
mation that today is considered to be trivial. Two general
approaches are available, namely the trapping of an in-situ
generated enolate with Davis oxaziridine9 and the Rubottom
oxidation in which silyl enol ethers are oxidized with either
peroxyacids, peroxides or dioxiranes.10 These two approaches
have wide applicability, and both have been successfully used
numerous times, even in the synthesis of extremely complex
natural products.11
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While limited attempts have been made to mimic the first
During our ongoing studies of developing enantioselective
NH-aziridination reactions, we were surprised to discover
that when HFIP is used as the solvent, a noticeable back-
ground reaction is present when the olefin substrates are
very electron rich. This is especially evident when a tetra-
substituted olefin is used, which can be fully converted to the
corresponding NH-aziridine with no transition metal cata-
lyst, albeit at a significantly slower rate. We ruled out the
possibility of trace metal contamination in the HFIP by con-
ducting a control experiment using redistilled HFIP, which
gave the same result. This background reaction is negligible
unless the olefins are very electron-rich (i.e., tetra-alkyl sub-
stituted).
1
2
3
4
5
6
7
8
approach (i.e. the aforementioned trapping of enolates with
chloramine or O-phosphinylhydroxylamine), to the best of
our knowledge, no systematic studies have been dedicated to
developing an amino analogue of the Rubottom oxidation
(AKA “Aza-Rubottom oxidation”). Herein, we report our
findings in the development of such a transformation.
The Rubottom oxidation of silyl enol ethers goes through an
epoxide intermediate.10b Presumably, an aza-Rubottom oxi-
dation will go through the corresponding (NH)-aziridine
intermediate (Figure 1, C). 12,13 While catalyst-free epoxidation
of olefins can be easily achieved with either peracids or diox-
iranes, the prevailing wisdom is that NH-aziridination of
olefins requires the presence of a transition metal (TM) cata-
lyst.14
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Realizing that silyl enol ethers are even more electron-rich
than fully carbon-substituted olefins, we were curious to see
whether they could be aziridinated and in-situ converted to
the corresponding α-amino ketones without the use of a
transition metal catalyst.15
Table 1. Optimization of Reaction Conditions.
O
O
aminating reagent (XONH2)
catalyst/additive
TBSO
Ph
Me
Me
NH2 HCl
HCl
NH2
Ph
Ph
We started our investigation using silyl enol ether 1 and sev-
eral aminating reagents (Table 1, 2-6) to determine the opti-
mal reaction conditions (Table 1). Unsurprisingly, the reac-
tion could proceed under virtually the same conditions used
in the NH-aziridination reaction14b and give the desired α-
aminoketone 1a in good yield (Table 1, entry 1).
Me Me
1b
solvent, rt, 16 h
Et2O
Me Me
1a
1
Aminating Reagent (XONH2)
O2N
O
O
NH
O
S
H2N
NH2
TfOH
O
OH
O
NO2
R
O
H2N
O
4 R = C6H5
5 R = p-NO2C6H4
6
2 (HOSA)
3 (DPH)
To facilitate the characterization and isolation of the prod-
uct, we converted the free amine to an HCl salt 1b, which was
found to be more stable. The aminating reaction did not pro-
ceed when the Rh catalyst was removed (Table 1, entry 2).
This is likely due to the desilylation of 1 caused by the acidic
reaction mixture of HOSA and HFIP which outcompetes the
amination reaction in the absence of a catalyst. Indeed, when
a stronger base was used, a decent yield of 1b was obtained
(Table 1, entry 4).
Entry[a]
1
XONH2
Catalyst
Additive
Solvent Yield (%)
2 (1.2 equiv) Rh2(esp)2 pyridine (1.2 equiv)
HFIP
HFIP
HFIP
HFIP
TFE
66%
0b
2
2 (2 equiv)
2 (2 equiv)
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
pyridine (4 equiv)
K3PO4 (2 equiv)
Cs2CO3 (3 equiv)
Cs2CO3 (3 equiv)
Cs2CO3 (3 equiv)
Cs2CO3 (3 equiv)
none
3
Traceb
41%
Trace
0
4
2 (1.5 equiv)
2 (1.5 equiv)
2 (1.5 equiv)
2 (1.5 equiv)
3 (1.5 equiv)
3 (1.2 equiv)
2 (1.2 equiv)
4 (1.5 equiv)
5 (1.5 equiv)
6 (1.2 equiv)
3 (1.2 equiv)
3 (1.2 equiv)
3 (1.2 equiv)
Next, we examined several different electrophilic aminating
reagents. Aminating reagents 2-5 can be considered as the
nitrogen analogues of peracids, and we hypothesized that
NH-oxaziridine 6, the aza analogue of dioxiranes, may be-
have like an aminating agent and would transfer the NH
unit. The results showed that DPH (3) is the best aminating
reagent (Table 1, entry 9), and it gives a better yield than the
Rh-catalyzed reaction (Table 1, entry 9 vs 1). Buffering with a
base is necessary to minimize desilylation and increase the
yield of the desired product (Table 1, entry 9 vs entry 8). NH-
Oxaziridine 6 failed to react (Table 1, entry 13), indicating
that the analogy between an NH-oxaziridine and the corre-
sponding dioxirane is merely structural and is not reflected
in their reactivity. We also noticed an extreme case of solvent
effect in this reaction: HFIP is absolutely essential for the
success of this reaction (Table 1, entry 5-7, 14-16), and the
mixing of co-solvents is detrimental to the success of this
transformation.
5
6
MeCN
DCM
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
7
0
8
47%
85%
Trace
17%
10%
0
9
iPr2NEt (1.5 equiv)
iPr2NEt (1.5 equiv)
iPr2NEt (3 equiv)
iPr2NEt (3 equiv)
iPr2NEt (1.5 equiv)
iPr2NEt (1.5 equiv)
iPr2NEt (1.5 equiv)
iPr2NEt (1.5 equiv)
10
11
12
13
14
15
16
Trace
0
MeCN
DCM
Next, we explored the scope of the reaction (Scheme 1). Sub-
strates bearing one phenyl group and various alkyl substitu-
ents gave good yields under the optimized conditions
(Scheme 1, 1b, 7b-9b). It should be noted that an allyl group
was unaffected under the reaction conditions (Scheme 1, 7b),
demonstrating the reaction’s chemoselectivity, in which a
more electron-rich π bond is preferentially oxidized. When R1
was a substituted phenyl group, we observed a noticeable
electronic effect in which electron-rich substrates gave high-
er yields than electron-poor ones (Scheme 1, 10b vs 12b).
0
[a] Optimization reactions were conducted on a 0.2 mmol
scale. Aminating reagent and additives were mixed in 1 mL
solvent and stirred at rt for 10 min before the silyl enol ether
was added to the mixture. Reactions were stopped after 16 h,
and the amine product was converted to its HCl salt after
isolation. [b] The silyl ether 1 decomposed to the ketone.
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Heterocycles were tolerated in these reactions and substrates
Scheme 2. Transition Metal-Catalyzed Aza-Rubottom
Oxidation.
1
2
3
4
5
6
7
8
bearing thiophene, imidazole, and benzofuran rings gave
satisfactory yields (Scheme 1, 13b-15b). The reaction also
worked well when R1, R2 and R3 are all alkyl groups (Scheme
1, 17b and 18b). Finally, an indomethacin-derived substrate 19
was successfully aminated to furnish 19b, demonstrating this
transformation’s remarkable functional group tolerance and
its potential application in late-stage functionalization of
medicinal chemistry intermediates. It should be emphasized
that most of these products have been previously unknown.
Catalyst
HOSA (1.2 equiv.)
Pyridine (2.4 equiv.)
O
O
R2
R3
TBSO
R1
HCl
NH2
R2 R3
NH2 HCl
R2 R3
R1
R1
Et2O
HFIP, rt, 6 h
20b-24b
20-24
20a-24a
1 mmol scale
Structures of α-Amino Ketones
Compound #[a]: Isolated Yield (%), Catalyst
9
O
O
O
Me
Me
Scheme 1. Transition Metal-Free Aza-Rubottom Oxi-
dation.
NH2 HCl
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
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42
43
44
45
46
47
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49
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59
60
CO2Et
Me NH2 HCl
Me CO2Et
Br
NH2 2HCl
N
O
O
DPH (1.2 equiv.)
iPr2NEt (1.5 equiv.)
20b
21b
22b
R2
R3
TBSO
R1
HCl
NH2
R2 R3
NH2 HCl
R2 R3
49% [5 mol% CuTC]
82% [1 mol% Rh2(esp)2]
40% [5 mol% CuTC]
55% [1 mol% Rh2(esp)2]
R1
R1
Et2O
HFIP, rt, 16 h
1b, 7b-19b
1, 7-19
1 mmol scale
1a, 7a-19a
O
O
HCl
CO2Et
NH2
NH2
CO2Et
HCl
Structures of α-Amino Ketones
Compound #[a]: Isolated Yield (%)
F
23b
73% [1 mol% Rh2(esp)2]
24b
75% [1 mol% Rh2(esp)2]
O
O
O
O
NH2 HCl
HCl
NH2 HCl
NH2
Me
Ph
HCl
Me Me
Me NH2
[a] Reactions were conducted on a 1 mmol scale. HOSA (1.2
equiv), pyridine (2.4 equiv) were dissolved in 5 mL of HFIP.
The silyl enol ether was added at room temperature with
rigorous stirring, followed by the metal catalyst. The purified
free amines were treated with a solution of HCl in diethyl
ether to obtain the corresponding HCl salts.
1b: 82%
7b: 65%
8b: 65%
O
9b: 69%
OMe O
O
O
NH2 HCl
Me
NH2
HCl
NH2
MeO
NH2
HCl
S
HCl
Me Me
Me Me
Me Me
F
10b: 79%
11b: 57%
12b: 56%
13b: 73%
O
Me NH2
HCl
O
O
We hypothesized that in the case of less reactive silyl enol
ethers, a more reactive nitrogen source is needed. Naturally,
we decided to use transition metal catalysis, hoping that the
more reactive metal-nitrenoid complexes can overcome the
energy barrier and will aminate even these less electron-rich
substrates.
Me
O
Me
NH2 HCl
HCl
Me NH2
N
Me
N
14b: 54%
15b: 53%
16a: 55%
16b: 29%[b]
Cl
O
Me
NH2
O
O
HCl
O
HCl
NH2
Me
Me
Me
Me
The reactions worked as predicted, and primary α-
aminoketones bearing electron-withdrawing substituents
were obtained in good to excellent yields (Scheme 2).
Me
N
HCl
NH2
O
O
MeO
19b: 21% (78% brsm)
17b: 54%
18b: 69%
Both Cu- and Rh-complexes can catalyze this transformation,
although Rh is significantly more efficient (Scheme 2, 21b).
Silyl enol ethers with carboxylate substituents (Scheme 2,
23b and 24b) as well as electron-deficient heterocycles
(Scheme 2, 22b) were successfully aminated with the addi-
tion of only 1 mol% Rh2(esp)2 catalyst, and the reaction
reaches completion within 6 h at room temperature. It
should be noted that very recently, Professor E. J. Corey and
coworker reported a similar Rh-catalyzed reaction in the
context of the synthesis of ketamine analogues.17
Substrates that failed to react
OTBS
Me
OTBS
OTBS
CO2Et
CO2Et
Me
Me
Me
Br
N
20 (E/Z mixture)
21 (E/Z mixture)
22 (E/Z mixture)
[a] Reactions were conducted on a 1 mmol scale. DPH (1.2
equiv), diisopropylethylamine (1.5 equiv) were dissolved in 5
mL of HFIP. The silyl enol ether was added at room tempera-
ture with rigorous stirring. The purified free amines were
treated with a solution of HCl in diethyl ether to obtain the
corresponding HCl salts. [b] The free amine rapidly decom-
poses when concentrated.
Like the un-catalyzed reaction, the transition metal-
catalyzed aza-Rubottom oxidation also requires the use of
HFIP as the solvent for effective conversion. Moreover, the
reaction becomes sluggish with the addition of a co-solvent.
This echoes the significant rate acceleration effect by fluori-
nated solvents that we have observed in Rh-catalyzed NH-
aziridination of unactivated olefins. Intrigued by this obser-
vation, we decided to search the literature for some insights
on the mechanism of this transformation.
However, when more strongly electron-withdrawing substit-
uents are present in the silyl enol ethers (20-22), the reac-
tions failed to proceed. For example, an ester group is suffi-
cient to suppress the amination of silyl enol ether via either
the inductive effect (20) or conjugation (21). In the case of 22,
we suspect the in-situ protonation of the pyridinyl nitrogen
in HFIP (pKa ~ 9.3) severely reduced the reactivity of the silyl
enol ether to prevent the reaction from taking place. We also
found that the less stable silyl ketene acetals will undergo
fast desilylation under the reaction conditions, which severe-
ly reduce the yield.16
Although the consensus agrees that the rate acceleration by
HFIP is most likely caused by hydrogen bond interactions,18
to the best of our knowledge no detailed mechanistic studies
have been carried out on the effect of fluorinated solvents in
olefin aziridination reactions. However, an outstanding study
on the rate acceleration by HFIP in the context of olefin
epoxidation was reported by the Berkessel group in 2006.19 In
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this study, it is reported that HFIP enables the epoxidation of
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
olefins by hydrogen peroxide in the absence of additional
catalysts. In the subsequent quantum-chemical investigation,
Berkessel et. al. proposed that higher-order aggregates of
HFIP molecules are responsible for the rate acceleration.
L.K. gratefully acknowledges the generous financial support
of Rice University, National Institutes of Health (R01 GM-
114609-04), National Science Foundation (CAREER:SusChEM
CHE-1546097), the Robert A. Welch Foundation (Grant C-
1764), that are greatly appreciated. The authors also thank
Professor E. J. Corey for helpful discussions.
Scheme 3. Mechanistic Hypothesis.
OTBS
CF3
R1
F3C
H
OTBS
H
R3
O
O
R2
R3
R1
HN
TBSO
R1
N
O
H
R2
DPH
HFIP
NH2
R2 R3
R1
9
REFERENCES
H
R3
O
R2
F3C
10
11
12
13
14
15
16
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19
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23
24
25
26
27
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43
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47
48
49
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53
54
55
56
57
58
59
60
O2N
CF3
1. (a) Erdik, E., Electrophilic α-amination of carbonyl compounds.
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amination of carbanions, enolates, and their surrogates. Organic
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4. (a) Momiyama, N.; Yamamoto, H., Enantioselective O- and N-
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NO2
A similar mechanism is likely involved in the aza-Rubottom
oxidation, in which higher-order solvent aggregates formed
from multiple HFIP molecules activates the hydroxylamine-
derived aminating reagent via cooperative hydrogen-bonding
interactions (Scheme 3). This explains the detrimental effect
caused by a co-solvent, since it will exponentially affect the
concentration of the active HFIP aggregates.
An intriguing implication based on this hypothesis is that an
enantioselective version of this reaction can be potentially
achieved with a chiral nonracemic hydrogen-bond donor
catalyst that activates achiral hydroxylamines. This could be
analogous to what has been reported for asymmetric epoxi-
dation catalyzed by organocatalysts.20
In summary, we have developed two sets of conditions for
the synthesis of primary α-aminoketones from silyl enol
ethers. Electron-rich substrates can be α-aminated without
transition metal catalysis, while substrates bearing electron-
withdrawing substituents can undergo α-amination with the
help of Rh or Cu catalysts. Solvent aggregates formed from
multiple HFIP molecules are likely responsible for the ob-
served reactivity. We hope these aza-Rubottom reactions will
become valuble synthetic tools for organic synthesis.
Amination
Reaction
of
β-Ketoesters
Using
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Hydroxycarbamates: Merging Aerobic Oxidation and Lewis Acid
Catalysis. J. Am. Chem. Soc. 2012, 134, 18948-18951; (d) Xu, C.;
Zhang, L.; Luo, S., Merging aerobic oxidation and enamine
catalysis in the asymmetric alpha-amination of beta-
ketocarbonyls using N-hydroxycarbamates as nitrogen sources.
Angew. Chem. Int. Ed. 2014, 53, 4149-4153; (e) Sandoval, D.;
Samoshin, A. V.; Read de Alaniz, J., Asymmetric Electrophilic
alpha-Amination of Silyl Enol Ether Derivatives via the
Nitrosocarbonyl Hetero-ene Reaction. Org. Lett. 2015, 17, 4514-
4517.
ASSOCIATED CONTENT
Supporting Information
5. (a) Evans, D. A.; Nelson, S. G., Chiral Magnesium
Bis(sulfonamide) Complexes as Catalysts for the Merged
Enolization
and
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Acyloxazolidinones. A Catalytic Approach to the Synthesis of
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Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.;
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Amination of Ketones. J. Am. Chem. Soc. 2002, 124, 6254-6255; (c)
Janey, J. M., Recent advances in catalytic, enantioselective alpha
aminations and alpha oxygenations of carbonyl compounds.
Angew. Chem. Int. Ed. 2005, 44, 4292-4300; (d) Marigo, M.;
Jørgensen, K. A., Organocatalytic direct asymmetric α-
heteroatom functionalization of aldehydes and ketones. Chem.
Commun. 2006, 2001-2011; (e) Yang, X.; Toste, F. D., Direct
asymmetric amination of alpha-branched cyclic ketones
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The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, characterizations of compounds and
NMR spectra. (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: kurti.laszlo@rice.edu
Notes
The authors declare no competing financial interests.
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It should be noted that like many aromatic nitro compounds,
DPH can potentially undergo highly energetic self-
decomposition when heated above 100 ºC in the presence of a
strong base at high concentration. Although we have not
observed any such incident, it is important to use all appro-
priate PPEs and safety precautions when carrying out reac-
tions with DPH and avoid using strong base and/or tempera-
ture above 50 ºC.
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8. (a) Zhao, B.; Du, H.; Shi, Y., A Cu(I)-Catalyzed C−H α-Amination
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12. An early example of this type of reactivity was reported by the
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no groups are fully substituted (i.e. tertiary amino group): (a)
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