One-pot Mukaiyama–Mannich reaction of aldehydes, amines and silyl enol diazoacetate catalyzed by MgI2 etherate

Article abstract of DOI:10.1080/10426507.2019.1633322

Three-component Mukaiyama–Mannich reaction of aldehydes, amines, and silyl enol diazoacetoacetate was efficiently carried out to afford δ-amino substituted-α-diazoacetoacetate derivatives catalyzed by 5 mol% of MgI₂ etherate (MgI₂?(OEt₂)_n) under mild and neutral reaction conditions in good to excellent yields.

Full text of DOI:10.1080/10426507.2019.1633322

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
One-pot Mukaiyama–Mannich reaction of
aldehydes, amines and silyl enol diazoacetate
catalyzed by MgI2 etherate
Nengju Mi, Xiangwei Meng, Haokun Pan, Kailun He & Xingxian Zhang
To cite this article: Nengju Mi, Xiangwei Meng, Haokun Pan, Kailun He & Xingxian Zhang
(2019): One-pot Mukaiyama–Mannich reaction of aldehydes, amines and silyl enol diazoacetate
catalyzed by MgI2 etherate, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2019.1633322
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1633322
One-pot Mukaiyama–Mannich reaction of aldehydes, amines and silyl enol
diazoacetate catalyzed by MgI2 etherate
Nengju Mi, Xiangwei Meng, Haokun Pan, Kailun He, and Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 18 March 2019
Accepted 14 June 2019
Three-component Mukaiyama–Mannich reaction of aldehydes, amines, and silyl enol diazoacetoa-
cetate was efficiently carried out to afford d-amino substituted-a-diazoacetoacetate derivatives cat-
alyzed by 5 mol% of MgI2 etherate (MgI2ꢀ(OEt2)n) under mild and neutral reaction conditions in
good to excellent yields.
KEYWORDS
Three-component; silyl enol
diazoacetoacetate;
Mukaiyama–Mannich reac-
tion; MgI2 etherate
GRAPHICAL ABSTRACT
Introduction
TiCl4-promoted Mukaiyama–Mannich addition of a-diazo-
b-ketoester or a-diazo-b-ketoketone and aromatic and ali-
phatic N-tosylaldimines to give d-N-tosylamino-substituted
b-keto diazocarbonyl compounds. In addition, the asymmetric
Mukaiyama–Mannich type reaction of silyl enol diazoacetoa-
cetate with chiral N-(benzylidene)-p-toluene was investigated
in the presence of Lewis acids, such as BF3ꢀEt2O, TiCl4,
Cu(OTf)2, La(OTf)3 and TBSOTf. However, only TBSOTf
provided a low yield of the desired adduct.[12,13] To the best of
our knowledge, few reports of one-pot Mukaiyama–Mannich
addition of aldehydes, amines and silyl enol ether of diazo
compounds were reported.[15]
We have recently reported an efficient and facile method
for the synthesis of a-diazo-b- hydroxy esters by the cou-
pling of aldehydes with ethyl diazoacetate (EDA) promoted
by MgI2 etherate (MgI2ꢀ(OEt2)n) in the presence of DIPEA
(diisopropyl ethyl amine) at room temperature.[16] In con-
tinuation of our interest on the catalytic applications of
MgI2 etherate for various organic transformation, we herein
wish to describe a facile and efficient protocol for one-pot
Mukaiyama–Mannich addition of ethyl 3-(tert-butyldime-
thylsilanoxy)-2-diazobut-3-enoate 1a with aldehydes, amines
catalyzed by MgI2 etherate under mild reaction conditions.
Diazoacetoacetates are widely used reactants for metal carbene
transformations in the synthesis of natural products and com-
pounds of pharmaceutical interest.[1–3] Diazoacetoacetates
exhibit higher thermal and acid stability than do their diazoa-
cetate counterparts, and they often offer greater reaction con-
trol in transformations following diazo decomposition.[4]
Catalytic reactions of diazoacetoacetate involving addition,
insertion and association that produce cyclopropanes, cycloal-
kanone structures and b-lactams are well documented.[5–8]
Chemical modifications with diazocarbonyl compounds have
been of long-standing interest and both acid or base promoted
aldol reactions have been developed for this purpose.
However, these reactions generally result in the loss of the
diazo functionality.[9] Typically, the addition product was
obtained by nucleophilic addition of the diazoacetoacetate
enolate with imine in the presence of a strong base LiHMDS
[lithium bis(trimethylsilyl)-amide] in good yields.[14]
Although the anionic species thus generated can efficiently
add to carbonyl compounds and imines, some of these meth-
ods clearly require stoichiometric strong bases or Lewis acids,
low temperature and anhydrous conditions. Silyl enol ether, as
an equivalent of the corresponding enolate anion, has been
well applied in organic synthesis due to its good stability and
high selectivity, Doyle’s group[10] firstly reported
scandium(III) triflate-catalyzed Mukaiyama–Mannich add-
ition of methyl 3-(tert-butyldimethylsilanoxy)-2-diazobut-3-
Results and discussion
We investigated one-pot Mukaiyama–Mannich addition of a
enoate with imines catalyzed by. Wang et al.[11] reported variety of aldehydes, such as aromatic, heteroaromatic, and
CONTACT Xingxian Zhang
zhangxx@zjut.edu.cn
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P. R. China.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1633322.
ß 2019 Taylor & Francis Group, LLC

2
N. MI ET AL.
Table 1. One-pot Mukaiyama–Mannich addition of aldehydes, amines with
silyl enol diazoacetoacetate 1a-1c catalyzed by MgI2ꢀ(OEt2)na.
butyl a-diazoacetoacetate (1c), respectively (Table 1, entries
17–21). We have observed that the use of an aromatic amine
gave, in general, good results whereas an aliphatic amine did
not yield any product even prolonging the reaction time in
the presence of MgI2 etherate. (Table 1, entry 20).
Entry
R1
R2
R
Time(h) Product Yield(%)b
C6H5
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-ClC6H4
4-NO2C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
2
10
1
2
1
1
0.5
1
1
5
5
5
10
1
2
2
2
2
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
90
73
94
93
95
91
97
94
93
89
87
88
77
90
88
87
90
92
90
89
88
NRc
Compound 2l was obtained as a yellow powder with a
molecular formula of C20H20N4O6 as established by the HR-
ESI-TOF-MS m/z at 435.1286 [M þ Na]þ (calcd. for
C20H20N4NaO6: 435.1275). The IR spectrum indicated the
presence of an amino group (3375 cmꢁ1), a diazo group
(2137 cmꢁ1), an ester group (1714 cmꢁ1) and a carbonyl
group (1645 cmꢁ1). The 1H-NMR (see Supplemental
Materials) of compound 2l showed eight aromatic proton
signals at dH 6.46 (dd, J ¼ 1.9, 7.4 Hz, 2H), 6.88 (dd, J ¼ 2.0,
6.8 Hz, 2H), 7.30 (dd, J ¼ 1.8, 6.8 Hz, 2H) and 7.99 (dd,
J ¼ 1.7, 7.4 Hz, 2H), which were characteristic of a 1,4-sub-
stituted phenyl ring; an amino proton signal at dH 5.72 (d,
J ¼ 6.3 Hz, 1H), a benzyl proton signal at dH 4.91-4.95 (m,
1H), a methylene signal at dH 4.35 (q, J ¼ 7.2 Hz, 2H), a
methoxy group at dH 3.79 (s, 3H), a methylene signal at dH
3.35 (dd, J ¼ 4.7, 14.6 Hz, 1H) and 3.40 (dd, J ¼ 8.8, 14.6 Hz,
1H), and a typical methyl signal at dH 1.35 (t, J ¼ 7.2 Hz,
3H). The 13C NMR spectroscopic data (see Supplemental
Materials) revealed that compound 2l contained 16 carbon
resonances. Among them, signals at dc 161.49 and 190.36
indicated that there was a ketone carbonyl and an ester car-
bonyl group. Signals at dc 14.31 was assignable to a methyl
group. Signals at dc 29.67 was assignable to a tertiary carbon
of CN2 group. Signals at dc 55.25, 61.90 and 46.88 were
assignable to an oxygenated methylene, a methoxy, and a
methylene group, respectively. Signals at dc 54.31 was
assignable to a benzyl carbon. Signals at dc 112.10 (2C),
114.36 (2C), 126.12 (2C), 127.24 (2C), 132.72, 138.30,
152.12, 159.15 were sp2 carbons on aromatic ring.
4-MeOC6H4 OEt
4-MeOC6H4 OEt
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
2-MeOC6H4 OEt
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
PhCH2
C6H5
C6H5
C6H5
OEt
OEt
OEt
OEt
4-MeOC6H4
C6H5
trans-PhCH ¼ CH
2-thienyl
2-furyl
OEt
OEt
OEt
OMe
OMe
OMe
OtBu
OtBu
OEt
C6H5
4-ClC6H4
2-thienyl
C6H5
2-thienyl
C6H5
2s
2t
4
4
12
2u
NAc
aThe reaction was carried out by addition of aldehyde (1.0 mmol), amine
(1.0 mmol) in CH3CN, followed by addition of silyl enol diazoacetoacetate
1a–1c (1.2 mmol) and 5 mol% of MgI2ꢀ(Et2O)n. The reaction mixture was
stirred at room temperature for various time.
bIsolated yields on silica gel column chromatography.
cNA ¼ not available, NR ¼ no reaction.
a,b-unsaturated aldehydes, with aniline, 4-methoxyaniline,
4-toluidine, 4-nitroaniline, 4-chloroaniline. The results were
summarized in Table 1. The good to excellent yields
strongly suggest that MgI2ꢀ(OEt2)n is an efficient Lewis acid
catalyst for the three-component Mukaiyama–Mannich add-
ition of aldehydes, amines and silyl enol a-diazoacetoacetate
1a–1c. The reaction proved to be general and proceeded
smoothly under very mild conditions at room temperature
in a short period.
There is no need to exclude moisture and oxygen from
the reaction system. The aromatic aldehydes bearing elec-
tron-donating and electron-withdrawing groups in para-sub-
stituted aromatic ring reacted smoothly to afford the desired
d-amino substituted-a-diazoacetoacetate derivatives in excel-
lent yields (Table 1, entries 3–6). Anilines bearing an elec-
tron-donating group in para-substituted aromatic ring (i.e.
OMe, Me) reacted faster than anilines bearing an electron-
withdrawing group (i.e. NO2, Cl) and afforded the corre-
sponding Mannich adduct in better yields (Table 1, entries
7–12). Due to the steric hindrance, Mukaiyama–Mannich
addition of o-methoxybenzlaldehyde or o-methoxyaniline
with ethyl silyl enol diazoacetoacetate 1a proceeded slug-
gishly and gave a mild yield, respectively (Table 1, entries 2
and 13). Vinyl aldehydes such as cinnamaldehyde reacted
The interesting chemoselectivity was evaluated by cross-
over experiments (Table 2) of silyl enol diazoacetoacetate 1a
with
aldimines
and
its
parent
aldehydes.
Mukaiyama–Mannich addition of aldimines with silyl enol
diazoacetoacetate 1a was carried out prior to its parent aro-
matic aldehydes in the competitive reactions. The reactivity
of aldimines is better than that of aldehydes in this MgI2
etherate catalysis. No Mukaiyama aldol adduct was observed
in the one-pot Mukaiyama–Mannich addition of aldehydes,
amines and silyl enol diazoacetoacetate 1a under the same
reaction conditions, which is attributed to the rapid forma-
tion and activation of imines in the presence of MgI2 ether-
ate. The unique reactivity of MgI2 etherate is attributed to
the dissociative character of iodide counterion.[17,18]
with aniline to afford the Mannich adduct in good yield Experimental
under the similar reaction conditions (Table 1, entry 14).
Especially, MgI2 etherate worked well with acid sensitive
General
electron-rich heterocyclic aldehydes such as furfural, thio-
phene-2-carbaldehyde, which provided the corresponding
products in high yields. (Table 1, entries 15 and 16). As
well, MgI2 etherate could efficiently catalyze one-pot
Mukaiyama–Mannich addition of silyl enol a-diazoacetoace-
For product purification by flash column chromatography,
silica gel (200 ꢂ 300 mesh) and light petroleum ether (PE,
1
b.p. 60 ꢂ 90oC) were used. H NMR spectra were taken on a
Bruker AM-500 spectrometer with TMS as an internal
standard and CDCl3 as solvent. 13C NMR spectral measure-
tate derived from methyl a-diazoacetoacetate (1b) and tert- ments were performed at 125 MHz using TMS as an internal

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
a
Table 2. Crossover Mukaiyama–Mannich addition of aldimines with its parent aldehydes catalyzed by MgI2ꢀ(OEt2)n
.
Entry
1
Aldimine
Aldehyde
Overall yield(%)
90
Ratio (2:3)b
99 > 1
2
3
4
94
95
86
99 > 1
99 > 1
99 > 1
aThe reaction was carried out by addition of aldehyde (1.0 mmol), imine (1.0 mmol) with silyl enol diazoacetoacetate 1a (1.0 mmol) catalyzed by 5 mol %
MgI2ꢀ(OEt2)n in untreated CH3CN at room temperature.
bRatio was determined by isolated yields on silica gel column chromatography.
standard. IR spectroscopy was performed on a Nicolet 6700 of various aldehydes including aromatic aldehydes, hetero-
infrared spectrometer. HRMS were determined on a GCT aromatic aldehydes, vinyl aldehydes, and amines with silyl
enol diazoacetoacetate. In this context, MgI2 etherate, as a
mild Lewis acid, demonstrates a remarkable catalytic per-
formance. This magnesium-catalyzed Mukaiyama–Mannich
addition has some advantages of simplicity, efficiency, mild
reaction conditions and high yields. Further investigation on
the asymmetric Mukaiyama–Mannich coupling catalyzed by
chiral Mg(II)-complex is ongoing in our lab.
Premier spectrometer. The reaction monitoring was accom-
plished by TLC on silica gel polygram SILG/UV 254 plates.
The Supplemental Materials contains sample 1H and 13C
NMR spectra of products 2 (Figures S1–S35).
The representative one-pot Mukaiyama–Mannich reac-
tion—To a stirred solution of benzaldehyde (1.0 mmol) and
aniline (1.0 mmol) in CH3CN (5 mL) was added a freshly pre-
pared MgI2 etherate (0.05 mmol) at room temperature,
followed by addition of ethyl 3-(tert-butyldimethylsilanoxy)-
2-diazobut-3-enoate 1a (1.2 mmol). The resulting homoge-
neous mixture was stirred at room temperature for 2.0 h and
quenched by saturated NaHCO3 aqueous solution. Extractive
workup with ethyl acetate and chromatographic purification
of the crude product on silica gel gave ethyl 2-diazo-3-oxo-5-
phenyl-5-(phenylamino)pentanoate 2a in 90% yield.
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4
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