Merging aerobic oxidation and enamine catalysis in the asymmetric α-amination of β-ketocarbonyls using N-hydroxycarbamates as nitrogen sources

Article abstract of DOI:10.1002/anie.201400776

We describe herein an unprecedented asymmetric α-amination of β-ketocarbonyls under aerobic conditions. The process is enabled by a simple chiral primary amine through the coupling of a catalytic enamine ester intermediate and a nitrosocarbonyl (generated in situ) derived from N-hydroxycarbamate. The reaction features high chemoselectivity and excellent enantioselectivity for a broad range of substrates. Merging O and N: Enantioselective α-amination of β-ketocarbonyl compounds has been achieved by merging enamine catalysis and Cu^I-catalyzed aerobic oxidation of hydroxycarbamates. Excellent chemoselectivity and enantioselectivity are obtained with the aid of a simple primary/tertiary diamine catalyst. This presents a facile route for the asymmetric synthesis of unnatural amino acids.

Full text of DOI:10.1002/anie.201400776

Angewandte
Chemie
DOI: 10.1002/anie.201400776
a-Amination Very Important Paper
Merging Aerobic Oxidation and Enamine Catalysis in the Asymmetric
a-Amination of b-Ketocarbonyls Using N-Hydroxycarbamates as
Nitrogen Sources**
Changming Xu, Long Zhang, and Sanzhong Luo*
Abstract: We describe herein an unprecedented asymmetric a-
amination of b-ketocarbonyls under aerobic conditions. The
process is enabled by a simple chiral primary amine through
the coupling of a catalytic enamine ester intermediate and
a nitrosocarbonyl (generated in situ) derived from N-hydroxy-
carbamate. The reaction features high chemoselectivity and
excellent enantioselectivity for a broad range of substrates.
in situ by aerobic oxidation. Unfortunately, efforts to render
this process enantioselective have not been successful thus
far, and O-selective aminoxylation products, instead of the
hydroxyamination products, were predominantly formed
[9]
when chiral ligands were applied. During the preparation
of this work, Maruoka et al. reported an asymmetric N-
selective coupling with aldehydes using oxidative nitrosocar-
bonyl chemistry. However, the use of aerobic conditions was
ineffective to deliver the desired products, and the reactions
A
symmetric direct a-amination of carbonyl compounds are
fundamental CÀN bond forming reactions that are of
[10]
required stoichiometric TEMPO and BPO as the oxidants.
significant relevance in the synthesis of chiral materials and
pharmaceuticals. Typically, the reactions are conducted with
electrophilic nitrogen sources coupled with nucleophilic enols
Achieving asymmetric oxidative amination under aerobic
conditions remains elusive in this regard. Herein, we report an
unprecedented asymmetric a-amination of b-ketoesters
under aerobic conditions catalyzed by chiral primary
amines. In this process the enamine catalysis of b-ketoesters
was successfully coupled with aerobic oxidation of N-
hydroxycarbamates to afford the desired amination products
in high yields and with excellent enantioselectivities.
[
1]
[2–4]
or enamines.
Provided with the vast number of readily
accessible amines, the direct coupling of carbonyls and
nucleophilic amines is an appealing and more straightforward
strategy for the synthesis of a-aminocarbonyls. Mechanisti-
cally, such a coupling of two nucleophiles would require
judicious selection of oxidative conditions, and in this regard
oxygen/air is the most economical and an ideal choice of
b-Ketocarbonyls (e.g. ketoesters and 1,3-diketones)
remain a challenging type of substrates in enamine catalysis,
as it is known that amines (mostly primary amines) tend to
form stabilized enamines with b-ketocarbonyls owing to
intramolecular H bonding (Figure 1), and catalytic turnover
[
5]
terminal oxidant. Recently, MacMillan et al. reported an
elegant direct a-amination reaction with simple amines under
aerobic conditions in which an electrophilic a-bromocarbonyl
was generated in situ through an aerobic-oxidation-coupled
[
11]
with enamine carbonyls has thus far not been achieved. In
fact, the resulting enamine carbonyls have been reported to
[
6]
process. In this context, a catalytic asymmetric version
remains to be realized.
[12]
be versatile synthons in asymmetric synthesis, or can act as
[
7]
[13]
Very recently, the groups of Yamamoto and Read de
haptens to induce antibody aldolases.
In addition, the
[
8]
Alaniz have independently reported nitroso-carbonyls oxi-
dized in situ for aminoxylation (i.e. nitroso-aldol) and
hydroxyamination reactions of b-ketoesters, respectively. In
the latter case, aerobic conditions can be successfully used in
the presence of CuCl/Cu(OTf)2 and the overall method
represents a complementary strategy for oxidative a-amina-
tion wherein electrophilic nitrogen sources are generated
oxidative stability of enamines is also of serious concern in
[
*] C. Xu, Dr. L. Zhang, Prof. Dr. S. Luo
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory for Molecular Recognition and Function
Institute of Chemistry, The Chinese Academy of Sciences
Beijing, 100190 (China)
and
Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin, 300071 (China)
E-mail: luosz@iccas.ac.cn
Homepage: http://luosz.iccas.ac.cn
[**] We thank the Natural Science Foundation of China (21390400,
21025208, and 21202171) and the National Basic Research Program
of China (2011CB808600) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400776.
Figure 1. a-Amination of b-ketocarbonyls.
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pursuing oxidative amination, as enamines can be easily
identified as the optimal solvent (Table 1, entries 1 and 12–
16).
[
14]
degraded or cleaved under aerobic conditions.
Bearing
these points in mind, we were quite delighted to find that our
previously developed chiral primary amines 1 were viable
catalysts for the oxidative coupling of acetoacetate 2a and N-
Under the optimized conditions, we then examined the
substrate scope of this aerobically oxidative amination
reaction. As shown in Scheme 1, acetoacetates with variations
[15]
3
hydroxycarbamate 3a under air. Amination product 4a can
be exclusively formed (4a/5a > 20:1) in 97% yield and 96%
ee under the optimized conditions (Table 1, entry 1). Chiral
primary amine 1a, derived from tert-leucine, in concert with
triflic acid (TfOH) and m-nitrobenzoic acid, was identified as
the optimal catalyst (Table 1, entry 1 vs. 2 and 3). In this case,
the addition of weak acid m-nitrobenzoic acid has been found
to significantly improve both the product yield (from 62% in
on the ester moiety (R position), including those with
sterically bulky tert-butyl ester, benzyl, and allyl ester
groups, afford the desired amination adducts in high yields
with excellent enantioselectivities (4a–e). The reactions also
2
tolerate a range of a-substituents on acetoacetates (R
position; 4 f–k). In particular, the reaction with acetoacetates
bearing a-allyl and propargyl substituents proceeded
smoothly to deliver the desired amination adducts with high
6
8 h to 97% in 30 h) and the 4a/5a ratio (from 6:1 to > 20:1;
Table 1, entry 4 vs. 1). This result is consistent with the known
acidic additive effect in promoting enamine turnover, as we
[
15]
previously observed in similar catalysis. Both CuCl and air
have been found to be essential for catalysis, and reactions in
the absence of either CuCl or air showed no activity at all
(
Table 1, entries 5 and 6). The use of other chemical oxidants
such as MnO led to much poorer results (Table 1, entry 7).
2
The screening of other copper salts was also conducted, but
none of them showed activity under the aerobic conditions,
except for CuO (Table 1, entries 8–11). The reaction has also
been optimized in terms of solvents, and acetonitrile was
[
a]
Table 1: Screening and optimization.
[
c]
Entry
Variation from standard
conditions
t [h]
Yield
[%]
4a/5a
ee [%]
[
b]
1
2
3
4
5
6
7
8
9
none
1b
1c
30
60
120
68
30
30
24
30
36
30
30
40
30
36
30
30
97
61
52
62
n.r.
trace
26
n.r.
40
n.r.
n.r.
78
52
65
>20:1
5:1
96
65
83
94
3:1
6:1
without m-NO PhCO H
without CuCl
under Ar
2
2
[
d]
MnO as oxidant
n.d.
3:1
60
58
2
CuCl2
CuO
CuCN
CuI
10
11
12
13
14
15
16
CH Cl2
5:1
4:1
8:1
3:1
n.d.
95
55
86
65
35
2
THF
Et O
2
toluene
MeOH
69
85
[a] Reactions were performed at room temperature in 0.3 mL solvent
with 2a (0.12 mmol), 3a (0.10 mmol), 1-TfOH (20 mol%), m-nitro-
benzoic acid (20 mol%), and copper salts (10 mol%) under air at room
temperature. [b] Yield of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] 5 equiv of MnO . n.d.=not
2
determined, n.r.=no reaction.
Scheme 1. Substrate scope. All reactions were performed at room
temperature in MeCN (0.3 mL) with 2 (0.12 mmol), 3 (0.10 mmol),
1
(
a-TfOH (20 mol%), m-nitrobenzoic acid (20 mol%), and CuCl
10 mol%) under air at room temperature. Yields shown are of
isolated products. [a] CuCl (5 mol%).
4
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yields and enantioselectivities (4j and 4k), and no oxidation
of unsaturated bonds was observed. High N/O regioselectiv-
ities were maintained in all cases, with only trace amino-
xylation products detected by TLC analysis.
1
Variations on the ketone substituent R were next
1
examined. With ethyl ketone (R = Et), the reaction furnished
the major N adduct, 4l (59% yield), along with a minor
O adduct, 5l (19% yield); both products were obtained with
excellent enantioselectivities (95% and 94% ee, respectively;
Scheme 1). The sluggish reaction rate observed in this case
indicates the inhibition of enamine catalysis with large
aliphatic ketones, which are known as difficult substrates for
the stabilizing nature of enamine carbonyls, a stoichiometric
reaction of acetoacetate 2a (or 2c) and chiral primary amine
1a was carried out. In this regard, a catalytic amount of m-
nitrobenzoic acid, the weak acid used in our catalysis, was
found to promote the formation of the expected enamines 8a
and 8c, which can be isolated and purified on a basic alumina
column in 87% and 76% yield, respectively [Eq. (3)]. This
result indicates that the enamine formation should be quite
facile under the catalytic conditions. NMR analysis of
compound 8 clearly showed a NOE between the two methyl
groups, characteristics of the Z enamine configuration, and no
other conformers were detected in the solution phase at room
temperature [Eq. (3)]. We were able to crystalize enamine 8a
in the presence of TfOH (1.0 equiv). The crystal structure of
8a-TfOH, clearly indicates the Z enamine geometry as well as
the H bonding between the enamine NÀH and the ester
[
11]
aminocatalysis. To test the limits of the reaction, a phenyl
1
ketone (R = Ph) was attempted. Although the desired
amination adduct 4m could be obtained in a reasonable
6
2% yield, along with a minor O-selective adduct, 5m, both
products showed rather poor enantioselectivities (< 20% ee;
Scheme 1), which suggests that enamine catalysis is likely not
involved and the reaction may proceed instead through an
unselective enol-based process.
Notably, acyclic 1,3-diketones are also workable sub-
strates under oxidative enamine conditions. Accordingly,
phenylbuta-1,3-dione reacted smoothly to give the major
amination product in 51% yield and 97% ee (4n; Scheme 1).
Most delightfully, aliphatic 1,3-diketones, such as hexane-2,4-
dione and heptane-2,4-dione, can also be applied to give the
desired amination products with excellent enantioselectivities
moiety (Figure 2a). To the best of our knowledge, this
represents the first crystal structure of a catalytically active
[
17]
enamine intermediate derived from a primary amine.
(4o and 4p). In these cases, minor aminoxyl adducts were also
isolated with high enantioselectivities (4n–p). Taken together,
these results highlight the power of enamine catalysis with
primary amines to differentiate the two ketone moieties; the
successes along these lines nicely bypass the difficulties
associated with ketoesters bearing larger ketone moieties
[
16]
(4m vs. 4n).
The reactions worked equally well with cyclic b-ketoesters
The stability and reactivity of enamine 8a was next
examined. Though pure compound 8a is quite stable in stock,
it quickly equilibrates with its parent ketoester 2a in the
to give exclusively N-selective adducts with excellent enan-
tioselectivities (4q–s; Scheme 1). Finally, the reaction was
also found to be compatible with tert-butyl N-hydroxycarba-
mate 3b as the nitrogen source (4t–w), furnishing the desired
amination adducts in slightly reduced yields but with com-
parable enantioselectivities.
presence of one equivalent of H O, when treated with the
2
identified optimal acidic additives TfOH/m-nitrobenzoic acid
[Eq. (4)]. These results suggest catalytic turnover with
enamine esters turns out to be a quite facile process by the
aid of the acidic additive under our conditions. Stoichiometric
The obtained amination adducts can be selectively
reduced to reveal the free amino group in the presence of
Raney Ni under H . Accordingly, the hydrogenation of Cbz-
2
protected adduct 4b produced the syn amino alcohol 6 with
high stereoselectivity; both the NÀOH and ketone carbonyl
groups were reduced under these conditions [Eq. (1)]. On the
other hand, the hydrogenation of the Boc-protected 4v
occurred selectively on the N-OH moiety to give the amino-
ketone product 7 [Eq. (2)]. A free amino group, generated
in situ through hydrogenative Cbz deprotection, seems essen-
tial for directing the further reduction of the ketone moiety.
Preliminary studies have been carried out to understand
the mechanistic details of this reaction. Taking advantage of
Figure 2. a) X-ray crystal structure of 8a-TfOH. H atoms are omitted
for clarity. Thermal ellipsoids set at 30%. b) Proposed transition state.
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reactions of enamine 8a with N-hydroxycarbamate 3a have
also been conducted. Under the aerobic conditions, the
reaction smoothly gave the amination adduct 4a in 85% yield
and 97% ee, with the same configuration obtained under
catalytic conditions, thus unequivocally verifying the enamine
catalytic nature of this reaction. The critical role of acids in
tuning reactivity and selectivity is also quite evident, as the
reactions led to poor outcome in the absence of either of the
acids, and was completely shut down when no acids were
added [Eq. (5)].
Keywords: aerobic oxidation · a-amination · b-ketocarbonyls ·
enamine catalysis · organocatalysis
.
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Received: January 24, 2014
Published online: March 12, 2014
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