MgCl2-catalyzed α-amination of α-alkyl-β- ketoesters via oxidative n -acylnitroso aldol reaction with hydroxamic acids

Article abstract of DOI:10.1055/s-0033-1340954

A practical method for α-amination of α-alkyl-β-ketoesters using hydroxamic acids is described. In this protocol, an oxidative N-acylnitroso aldol reaction is catalyzed by magnesium chloride in the presence of the oxidant tert-butyl hydroperoxide. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340954

LETTER
▌A
lMettegr Cl2-Catalyzed α-Amination of α-Alkyl-β-ketoesters via Oxidative N-Acyl-
nitroso Aldol Reaction with Hydroxamic Acids
MgCl2-Catalyzed α-Amination of α-Alkyl-β-ketoesters
Ming-Qiang Liang,a,b Chong-Dao Lu*a
a
The Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics and Chemistry, Chinese 
Academy of Sciences, Urumqi 830011, P. R. of China
Fax +86(991)3838708; E-mail: clu@ms.xjb.ac.cn
b
University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 22.01.2014; Accepted after revision: 17.02.2014
cause it accelerates TBHP-mediated oxidation of
Abstract: A practical method for α-amination of α-alkyl-β-keto-
hydroxamic acids. We carried out this approach in the
esters using hydroxamic acids is described. In this protocol, an oxi-
present study using common bases such as Cs2CO3 or
dative N-acylnitroso aldol reaction is catalyzed by magnesium
Et3N, which promoted the enolization of β-ketoester 1a,
leading to the complete consumption of hydroxamic acid
2a. However, no desired N-acylnitroso aldol product was
observed (Table 1, entry 1). When we replaced the base
with various Lewis acids, we found that catalytic amounts
of magnesium chloride12 facilitated the enolization of 1a
and generated α-amination product 3a in 82% yield (Ta-
ble 1, entry 2). Decreasing the catalyst loading of
Rh2(cap)4 to 0.1 mol% did not affect the reaction, provid-
ing the desired product 3a in 83% yield (Table 1, entry 3).
In fact, comparably high yields were obtained in the ab-
sence of the precious rhodium catalyst: 83% at room tem-
perature and 85% at 40 °C (Table 1, entries 4 and 5).
Therefore we simplified our protocol for the acylnitroso
aldol reaction to involve simply mixing starting materials
with MgCl2/TBHP in a suitable solvent.13 Control experi-
ments confirmed the necessity of each component in this
simplified protocol: in the absence of TBHP,14 no 2a was
consumed; in the absence of MgCl2, the desired reaction
did not occur, even though 2a was oxidized by TBHP.
chloride in the presence of the oxidant tert-butyl hydroperoxide.
Key words: amination, α-alkyl-β-ketoesters, catalysis, magnesium
chloride, acylnitroso
α-Amino-β-ketoesters are potential precursors of β-hy-
droxy-α-amino acids and of nitrogen-containing hetero-
cyclic compounds that serve as important building blocks
in many bioactive agents.1–3 One pathway effective for
constructing this useful scaffold is the direct electrophilic
α-amination of β-ketoesters, and various aminating agents
have been explored in this procedure.4 In particular, ami-
nating agents with nitrogen moieties that can react as
aldol-type or Michael-type acceptors, such as azodi-
carboxylates, have been extensively investigated in the
symmetric and asymmetric versions of this pathway.5
However, few studies have examined acylnitroso species
as aminating agents because they are highly reactive and
usually need to be generated in situ via oxidation.6,7
Read de Alaniz and coworkers recently reported an N-se-
lective acylnitroso aldol reaction that enables α-amination
of α-alkyl-β-ketoesters; this procedure relies on acylnitro-
so intermediates as the electrophilic source of nitrogen.
This one-pot transformation combines copper(II)-cata-
lyzed enolization of β-ketoesters and copper(I)-catalyzed
aerobic oxidation of hydroxamic acids (Scheme 1).8 To
ensure the success of this approach, the acylnitroso inter-
mediates and enolates must be formed under compatible
reaction conditions.8,9 Here we describe a practical meth-
od in which compatible conditions can be ensured, using
magnesium chloride to catalyze enolization and tert-butyl
hydroperoxide (TBHP) for oxidation (Scheme 1).
We then examined the substrate scope of this optimized
protocol for MgCl2-catalyzed α-amination of α-alkyl-
β-ketoesters.15 We tested a wide range of substituted
β-ketoesters and N-hydroxycarbamates, obtaining high or
excellent yields in most cases (Table 2). Various α-meth-
yl-acetoacetates with different ester moieties, such as eth-
yl, benzyl, and tert-butyl, reacted smoothly to give high
yields (3a–c). β-Ketoesters with alkyl substituents (linear
or branched) or aryl substituents (electron-rich or elec-
M
O
O
O
O
R1
OR3
R1
OR3
During initial attempts to develop a new catalyst for the
oxidative N-acylnitroso aldol reaction, we used the rhodi-
um caprolactamate [Rh2(cap)4]/TBHP11 catalytic proto-
col. Our previous studies on the oxidative acylnitroso
hetero-Diels–Alder reaction10 showed that Rh2(cap)4 ac-
celerates the generation of acylnitroso compounds be-
O
O
R2
enolization
oxidation
R2
O
+
R1
OR3
OH
O
R2
N
HN
OH
enolization and oxidation conditions:
OR4
N
OR4
O
OR4
O
ref. 8: Cu(OTf)2 (5 mol%), CuCl (5 mol%), air
this work: MgCl2 (10 mol%), t-BuOOH
SYNLETT 2014, 25, 000A–000D
Advanced online publication: 17.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

Scheme 1 α-Amination of α-alkyl-β-ketoesters using hydroxamic
DOI: 10.1055/s-0033-1340954; Art ID: ST-2014-W0061-L
© Georg Thieme Verlag Stuttgart · New York
acids

B
M.-Q. Liang, C.-D. Lu
LETTER
MnO2,9a which gave 3a in moderate yield without asym-
Table 1 MgCl2-Mediated α-Amination of α-Alkyl-β-ketoestersa
metric induction (conditions 3).
t-BuOOH
Lewis acid
(or base)
O
O
OEt
O
Table 2 Substrate Scope for α-Amination of α-Alkyl-β-ketoesters
O
O
OEt
OH
Using Hydroxamic Acidsa–c
+
MeCN
HN
OH
Ot-Bu
N
O
O
O
O
O
O
MgCl2 (10 mol%)
t-BuOOH (1.2 equiv)
Ot-Bu
R1
OR3
OH
1a
2a
3a
OR4
R1
OR3
+
HN
OH
R2
N
40 °C
R2
Entry Catalytic protocol
Yield (%)b
O
OR4
Rh2(cap)4 (1.0 mol%), base (1.0 equiv)c
0
1
2
3
R1, R2 = Alk, Ar
R3 = Et, Bn, t-Bu, Me
1
2
Rh2(cap)4 (1.0 mol%), MgCl2 (10 mol%)
Rh2(cap)4 (0.1 mol%), MgCl2 (10 mol%)
MgCl2 (10 mol%)
82
R4 = t-Bu, Bn, CCl3CH2, 9-fluorenylmethyl
3
83
Entry
1
Product
Time (h) Yield (%)
4
83
O
O
5d
MgCl2 (10 mol%)
85 (81)e
OEt
OH
Boc
a Reaction conditions: 1a (1.2 equiv), 2a (1.0 equiv), and t-BuOOH in
nonane (1.2 equiv) at r.t., unless otherwise noted.
b Isolated yield of 3a after purification by silica gel chromatography.
The reaction was allowed to continue until 2a was completely con-
sumed based on TLC analysis.
34
85
N
3a N/O ratiod = 13:1
O
O
O
c Base: Cs2CO3 or Et3N; solvent: CH2Cl2.
d Reaction was performed at 40 °C.
OBn
OH
e Preparation of 3a on a 1-gram scale.
N
2
3
4
5
6
7
22
65
20
25
40
49
83
82
80
84
80
96
Boc
tron-deficient) at R1 were effective nucleophilic partners,
generating functionalized N-carbamate hydroxylamines
3a–l in yields of 75–99%. Varying the substituents at the
α-position of the β-ketoesters led to structurally diverse
α-quaternary α-amino-β-ketoesters (3m and 3n), as well
as their cyclic counterparts (3o–q). Even hydroxylamines
protected with the frequently used nitrogen-protecting
groups Cbz, Troc, and Fmoc worked in our reaction, giv-
ing moderate to high yields of the desired products (3r–t).
It is worth noting that we occasionally observed byprod-
ucts derived from the O-selective acylnitroso aldol reac-
tion: 3a, with a ratio of N-aldol product to O-aldol product
of 13:1; 3d, 18:1; 3r, 13:1; and 3s, 16:1.9b
3b
O
Ot-Bu
OH
N
Boc
3c
O
O
Et
OEt
OH
N
Boc
3d N/O ratiod = 18:1
O
O
The reaction was sluggish and low-yielding (<20%) with
β-ketoesters containing hindered substituents at R1 such
as tert-butyl or bulky substituents at R2 such as isopropyl.
When the unsubstituted β-ketoester ethyl acetoacetate
was used, the reaction produced an uncharacterized mix-
ture. This result may reflect electrophilic transformations
of an α-imino β-ketoester intermediate. Read de Alaniz
and coworkers postulated that such an intermediate forms
during the N-aldol reaction when ethyl acetoacetate and
the acylnitroso intermediate couple together, and the
β-hydroxyl group is eliminated.8
Bn
OEt
OH
Boc
N
3e
O
O
i-Pr
OEt
N
OH
Boc
3f
O
O
We then tried to extend this catalytic process to asymmet-
ric catalysis, but our efforts proved fruitless. When we
used MgI2 as catalyst together with a chiral pybox ligand16
in the reaction of 1a and 2a, we obtained α-amination
product 3a as a racemic mixture (Scheme 2, conditions 1
and 2).17 In addition to TBHP, we tested the mild oxidant
OEt
OH
N
Boc
3g
Synlett 2014, 25, A–D
© Georg Thieme Verlag Stuttgart · New York

LETTER
MgCl2-Catalyzed α-Amination of α-Alkyl-β-ketoesters
C
Table 2 Substrate Scope for α-Amination of α-Alkyl-β-ketoesters
Table 2 Substrate Scope for α-Amination of α-Alkyl-β-ketoesters
Using Hydroxamic Acidsa–c (continued)
Using Hydroxamic Acidsa–c (continued)
O
O
O
O
O
O
O
O
O
O
MgCl2 (10 mol%)
MgCl2 (10 mol%)
t-BuOOH (1.2 equiv)
t-BuOOH (1.2 equiv)
R1
OR3
OH
R1
OR3
OH
OR4
HN
OH
OR4
R1
OR3
R1
OR3
+
+
HN
R2
N
R2
N
40 °C
40 °C
R2
R2
OH
O
O
OR4
OR4
1
2
3
1
2
3
R1, R2 = Alk, Ar
R1, R2 = Alk, Ar
R3 = Et, Bn, t-Bu, Me
R3 = Et, Bn, t-Bu, Me
R4 = t-Bu, Bn, CCl3CH2, 9-fluorenylmethyl
R4 = t-Bu, Bn, CCl3CH2, 9-fluorenylmethyl
Entry
8
Product
Time (h) Yield (%)
Entry
16
Product
Time (h) Yield (%)
O
O
O
O
OEt
OMe
78
90
46
91
N
N
OH
OH
Boc
Boc
3p
3h
O
O
O
O
OEt
OH
OMe
OH
N
17
18
19
20
65
57
87
89
41
N
9
10
11
26
46
51
75
97
99
MeO
Boc
Boc
3q
3i
O
O
O
O
OEt
OH
Cbz
OMe
OH
N
8
N
Cl
Boc
3r N/O ratiod = 13:1
3j
O
O
O
O
OEt
OH
Troc
OMe
OH
N
17
90
N
Br
Boc
3s N/O ratiod = 16:1
3k
O
O
O
O
OEt
OH
Fmoc
OMe
OH
N
N
12
13
41
60
97
80
Boc
3t
a Reactions were performed using 1 (1.2 equiv), 3 (1.0 equiv), catalyst
(10 mol%), and oxidant (1.2 equiv) in MeCN at 40 °C. Boc = tert-bu-
toxycarbonyl; Cbz = benzyloxycarbonyl; Troc = (2,2,2-trichloroe-
thoxy)carbonyl; Fmoc = [(9-fluorenylmethyl)oxy]carbonyl.
b Hydroxamic acid was completely consumed after the indicated time.
c Isolated yield of 3 after silica gel chromatography.
3l
O
O
OEt
Et
N
OH
Boc
d The ratio of N-aldol product to O-aldol product (N/O ratio) was de-
termined by 1H NMR analysis of the crude reaction mixture.
3m
O
O
OEt
OH
In summary, we have developed a practical and efficient
catalytic protocol for the α-amination of α-alkyl-β-keto-
esters that relies on an oxidative N-acylnitroso aldol reac-
tion with hydroxamic acids. In this process, the
combination of MgCl2 catalyst and TBHP oxidant simul-
taneously achieves the catalytic enolization of β-ketoester
and oxidation of hydroxamic acid.
Bn
N
14
15
47
70
92
80
Boc
3n
O
N
O
OEt
OH
Boc
3o
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, A–D

D
M.-Q. Liang, C.-D. Lu
LETTER
Yamamoto, H. J. Am. Chem. Soc. 2012, 134, 18566.
(b) Cu(II)-catalyzed enolization–Cu(I)-catalyzed aerobic
oxidation: Frazier, C. P.; Sandoval, D.; Palmer, L. I.; Read
de Alaniz, J. Chem. Sci. 2013, 4, 3857.
(R,R)-(i-Pr-pybox)MgI2 (10 mol%)
3a
1a
2a
+
1) t-BuOOH (1 equiv), MeCN
(83% yield, 0% ee)
(10) Tusun, X.; Lu, C.-D. Synlett 2012, 23, 1801.
(11) For Rh2(cap)4-catalyzed oxidation of tertiary amines to
initiate the Mannich reaction or [3+2] cycloaddition
reaction, see: (a) Catino, A. J.; Nichols, J. M.; Nettles, B. J.;
Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648. (b) Wang,
H.-T.; Lu, C.-D. Tetrahedron Lett. 2013, 54, 3015. For
cascade transformations initiated by catalytic oxidation of
tertiary amines using CuBr2 and TBHP, see: (c) Yu, C.;
Zhang, Y.; Zhang, S.; Li, H.; Wang, W. Chem. Commun.
2011, 1036.
O
O
N
2) t-BuOOH (1 equiv), CCl4
(29% yield, 0% ee)
N
Mg
N
I
I
3) MnO2 (5 equiv), CCl4
4 Å MS
syringe pump addition of 2a over 20 h..
(58% yield, 0% ee)
(R,R)-(i-Pr-pybox)MgI2
Scheme 2 Attempts to extend our protocol to asymmetric catalysis
(12) For the use of magnesium halides as Lewis acids for the
carbonyl-based enolization, see: (a) Evans, D. A.; Tedrow, J.
S.; Shaw, J. T. Downey C. W. J. Am. Chem. Soc. 2002, 124,
392. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow,
J. S. Org. Lett. 2002, 4, 1127. (c) Tirpak, R. E.; Olsen, R. S.;
Rathke, M. W. J. Org. Chem. 1985, 50, 4877.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (21172251 and 21372255), the Young Creative Sci-
Tech Talents Cultivation Project of Xinjiang Uygur Autonomous
Region (2013711017) and the Chinese Academy of Sciences.
(13) For the use of MgCl2/TBHP in allylic oxidation of ionon-like
dienes, see: Yan, M.; Peng, Q.-R.; Lan, J.-B.; Song, G.-F.;
Xie, R.-G. Synlett 2006, 2617.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnouIfproig
(14) Less expensive T-HYDRO® (70 wt% tert-butylhydro-
peroxide in water) can also be used as terminal oxidant in
this reaction; it provides comparable yields to those reported
in the text.
m
iotSrat
ungIiofop
r
t
References and Notes
(15) General Experimental Procedure for the MgCl2-
Catalyzed α-Amination of α-Alkyl-β-ketoesters
TBHP (5–6 M in decane, 0.48 mmol) was added dropwise to
a mixture of β-ketoesters 1 (0.48 mmol), hydroxamic acids 2
(0.40 mmol), and MgCl2 (3.8 mg, 0.040 mmol) in MeCN (2
mL). The reaction was stirred at 40 °C for the indicated time;
reaction completion was confirmed based on the
(1) (a) Nicolaou, K. C.; Boddy, C. N.; Brase, S.; Winssinger, N.
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disappearance of hydroxamic acids (Table 2). Then the
reaction mixture was cooled to r.t., quenched with aq
NaHSO3 solution and extracted with CH2Cl2 three times.
The combined organic layers were dried over anhydrous
Na2SO4, filtered, and then concentrated in vacuo. The
residue was purified by column chromatography to afford
amination product 3. This General Experimental Procedure
was carried out using 1a (69.2 mg, 0.48 mmol) and 2a (53.2
mg, 0.40 mmol). The reaction mixture was stirred for 34 h at
40 °C and purified by silica gel chromatography using PE–
CH2Cl2–EtOAc (4:1:0.75) as eluent to give product 3a (94.3
mg, 85%) as a colorless oil. The structure of 3a was
identified by comparison of its 1H NMR and 13C NMR
spectra with the reported data in ref. 8. See the Supporting
Information for experimental details and characterization
data for all new compounds.
(a) Momiyama, N.; Yamamoto, H. Angew. Chem. Int. Ed.
20002, 41, 2986. (b) Momiyama, N.; Yamamoto, H. J. Am.
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(d) Cheong, P. H.-Y.; Houk, K. N. J. Am. Chem. Soc. 2004,
126, 13912. (e) Akakura, M.; Kawasaki, M.; Yamamoto, H.
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Shagufta Eur. J. Org. Chem. 2012, 6013.
(16) For selected examples of the use of (pybox)MgI2 catalysts in
asymmetric catalysis involving β-dicarbonyl compounds,
see: (a) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J.
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(17) Chiral HPLC analysis conditions for 3a: Chiralcel AD-H
column (0.46 cm × 25 cm), hexanes–i-PrOH (97:3), flow
rate = 1.0 mL/min, λ = 210 nm, tR 1 = 16.4 min, tR 2 = 19.8
min.
(8) Sandoval, D.; Frazier, C. P.; Bugarin, A.; Read de Alaniz, J.
J. Am. Chem. Soc. 2012, 134, 18948.
(9) For O-selective acylnitroso aldol reactions, see: (a) Cu(II)-
catalyzed enolization–MnO2 oxidation with syringe pump
addition of hydroxamic acids: Baidya, M.; Griffin, K. A.;
Synlett 2014, 25, A–D
© Georg Thieme Verlag Stuttgart · New York