Highly efficient and chemoselective direct aldol reaction of acyldiazomethane with aldehydes promoted by MgI2 etherate

Article abstract of DOI:10.1016/j.cclet.2017.04.019

Direct aldol condensation of various aromatic, heteroaromatic, α,β-unsaturated aldehydes and aliphatic aldehydes with acyldiazomethane was realized using MgI₂ etherate (MgI₂·(Et₂O)_n) as a promoter in the presence of diisopropyl amine (DIPEA) in excellent yields in a short time under mild conditions with high chemoselectivity. Iodide counterion, and a non-coordinating less ploar reaction media (i.e., CH₂Cl₂) are among the critical factors for this unique reactivity.

Full text of DOI:10.1016/j.cclet.2017.04.019

Accepted Manuscript
Title: Highly efficient and chemoselective direct aldol reaction
of acyldiazomethane with aldehydes promoted by MgI2
etherate
Authors: Weipeng Qi, Xiaoqiang Xie, Tengjiang Zhong,
Xingxian Zhang
PII:
S1001-8417(17)30148-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.04.019
CCLET 4055
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
1-2-2017
13-4-2017
17-4-2017
Please cite this article as: Weipeng Qi, Xiaoqiang Xie, Tengjiang Zhong,
Xingxian Zhang, Highly efficient and chemoselective direct aldol reaction of
acyldiazomethane with aldehydes promoted by MgI2 etherate, Chinese Chemical
Lettershttp://dx.doi.org/10.1016/j.cclet.2017.04.019
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Communication
Highly efficient and chemoselective direct aldol reaction of acyldiazomethane with
aldehydes promoted by MgI2 etherate
*
Weipeng Qi, Xiaoqiang Xie, Tengjiang Zhong, Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032, China
 Corresponding author.
E-mail address: zhangxx@zjut.edu.cn.
Graphical Abstract
MgI2·(Et2O)n –promoted aldol condensation of various aldehydes with acyldiazomethane was described in the presence of
DIPEA in good to excellent yields under mild conditions with high chemoselectivity.
ABSTRACT
Direct aldol condensation of various aromatic, heteroaromatic, α,β-unsaturated aldehydes and aliphatic aldehydes with acyldiazomethane was realized
using MgI2 etherate (MgI2(Et2O)n) as a promoter in the presence of diisopropyl amine (DIPEA) in excellent yields in a short time under mild
conditions with high chemoselectivity. Iodide counterion, and a non-coordinating less ploar reaction media (i.e. CH2Cl2) are among the critical factors
for this unique reactivity .
Keywords: Chemoselective; Aldehyde ; Acyldiazomethane ; Direct aldol reaction ; MgI2 etherate
α-Diazo carbonyl compounds [1] are a potential source of amino alcohols and acids. α-Diazo carbonyl compounds are generally
prepared by the azido transfer reaction of carbonyl compounds [2]. Recently the synthesis of α-diazo carbonyl compounds has been
widely explored, such as α-diazo-β-hydroxy esters which are involved in many reactions in organic chemistry. The most
straightforward synthesis of α-diazo carbonyl compounds involves the condensation of aldehydes and acyldiazomethanes. This is
generally carried out by using strong bases, such as butylithium [3], lithium diisopropylamide (LDA) [4], sodium hydride (NaH) [5],
potassium hydroxide (KOH) [6], t-BuOK [7], TBAOH [8], DBU [9], Mg/La mixed oxide [10], NAP-MgO [11], Bu2Mg [12]. As well,
some acids, such as ZnEt2 [13], ZnMe2 [14], PhCOOH [15], Ti(OiPr)4 [16], Zr(OtBu)4 [2d], Sc(OTf)3 [17] are utilized into this coupling
as catalysts. However, some of these methods involve the use of very strong bases, expensive catalysts, prolonged reaction time and
vigorous reaction conditions, which afford the low yields of the products. Moreover, the use of strong bases may not be compatible
with certain functional groups in the substrates. From the viewpoints above, the development of less expensive, environmentally
benign, and easily handled promoters for aldol reaction of acyldiazomethane with aldehydes to form α-diazo-β-hydroxy esters is still
highly desirable.
Magnesium (II) species is widely used as Lewis acid promoter in various functional transformations and C-C bond-forming
reactions due to the high electrophilicity of Mg2+ ion and its good coordination to Lewis basic oxygen and nitrogen atom [18]. Among
them, magnesium halides are most frequently used. Herein, in the continuation of our research field [19], we will wish to report an
efficient and facile method for the synthesis of α-diazo-β-hydroxy esters by the coupling of aldehydes with acyldiazomethane
promoted by MgI2·(Et2O)n in the presence of DIPEA in CH2Cl2 at room temperature (Scheme 1).
We initiated to optimize the reaction conditions by the condensation of benzaldehyde with ethyl diazoacetate (EDA) as a model
reaction and the results are summarized in Table 1. No product formation was observed by using the sole MgI2·(Et2O)n or Et3N,
respectively. The reaction stoichiometry was checked by varying the amounts of MgI2·(Et2O)n used. As shown in Table 1, the yields of
ethyl 3-hydroxy-2-diazo-3-phenyl propionate are improved by increasing the amount of MgI2·(Et2O)n (Table 1, entries 2-7) and 1.0
equiv. of MgI2·(Et2O)n was sufficient. In addition, the amount of Et3N has also effects on the reaction conversion and yield. 2.0 equiv.
of Et3N was enough although good yield was also afforded with 3.0 equiv. of Et3N (Table 1, entries 7-9). Furthermore, we explored the

use of a range of solvents. It is evident that the excellent yield was given using CH2Cl2 as solvent and good yields are afforded in
CHCl3 and toluene, respectively (Table 1, entries 10, 11). Moderate yields of the product were isolated in THF and Et2O (Table 1,
entries 12, 13), while low yields were given in CH3CN and DMSO (Table 1, entries 14, 15). No reactions were occured in DMF and
MeOH (Table 1, entries 16, 17). As well, a variety of Lewis acids, such as ZnCl2, ZnI2, Al(OiPr)3, TiCl4, FeCl3, Mg(ClO4)2, MgCl2 and
MgBr2 were compared under parallel reaction conditions (100 mol% of Lewis acid and 200 mol% of Et3N) in the condensation of
benzaldehyde with EDA in CH2Cl2. Only ZnCl2 as a promoter could give the desired product in moderate yield (71%). ZnI2, Al(OiPr)3,
TiCl4, FeCl3, Mg(ClO4)2, MgCl2 and MgBr2 are practically inert to this aldol reaction.
Of various the bases screened, DIPEA, Et3N and iPr2NH gave the excellent yields, respectively (Table 2, entries 1-3). Good yield
was obtained in the presence of TMG (Table 2, entry 4). 2, 6-Lutidine gave very low yield. It is worthy to be noted that the desired
aldol product was yielded in the presence of N, N-diethyl aniline and N-methylmorpholine, respectively, which was accompanied by
formation of ethyl 3-phenyloxirane-2-carboxylate (Table 2, entries 6, 7). Furthermore, ethyl 3-phenyloxirane-2-carboxylate was
exclusively afforded in the presence of morpholine and DMAP, respectively (Table 2, entries 8, 9). No reactions occurred using iPrNH2,
and pyrrolidine (Table 2, entries 10, 11). So DIPEA was chosen to be the optimal base due to its more stability and convenient workup.
Encouraged by this optimizing reaction conditions, we chose a variety of structurally divergent aldehydes possessing a wide range of
functional groups to understand the scope and generality of this MgI2·(Et2O)n-promoted aldol-type condensation to form β-hydroxy-α-
diazo carbonyl compounds. The detailed procedures are deposited in Supporting information. The results are summarized in Table 3. A
variety of substrates, including aromatic, heteroaromatic and aliphatic aldehydes, smoothly underwent condensation with EDA to
afford the corresponding β-hydroxy-α-diazo carbonyl compounds in a short time (15-30 min). Nearly quantitative yields were obtained
with aromatic aldehydes possessing electron-withdrawing groups at the para position (Table 3, entries 2-6) and excellent yields were
afforded with ortho- and meta-substituted aromatic aldehydes (Table 3, entries 7-10). Aromatic aldehydes with electron-donating
groups also afforded high yields of the desired products (Table 3, entries 11-14), in contrast to TABOH [6], DBU [8], Mg/La mixed
oxide [9], and NAP-MgO [10] reported earlier which gave poor yields. 1-Naphthaldehyde, which contains a highly conjugated plane,
seems to be effective, and gave the corresponding aldol adduct in 93% yield (Table 3, entry 15). Moreover, α, β-unsaturated aldehyde
such as cinnamaldehyde also gave good yield of 1,2-addition product in a short time (Table 3, entry 16). Heteroaromatic aldehydes
such as pyridine-3-carboxaldehyde, thiophene-2-carboxaldehyde gave high yields (Table 3, entries 17, 18). As well, the aliphatic
aldehydes with the bulkier substituents such as tert-butyl and cyclohexyl groups gave good yields (Table 3, entries 19, 20).
Gratifyingly, the reactivity of benzoyldiazomethane (R = Ph) toward the aldehydes bearing electron-withdrawing groups and electron-
donating groups is similar compared to that of EDA under the identical condition (Table 3, entries 21-23), which afforded the desired
products in excellent yields. However, the condensation of aliphatic and aromatic ketones, such as cyclohexanone and acetophenone,
with EDA were also found to be unsuccessful. All the characterization of products and copies of 1H NMR and 13C NMR spectra are put
in Supporting information.
Next, we investigated the reaction of dicarboxaldehyde with EDA. In this reaction, 2.5 equivalents of EDA were required in order to
have a complete conversion of dicarboxaldehyde. Aromatic dicarboxaldehyde such as 1,4-phthalaldehyde was examined. The reaction
exclusively produced bis-aldol adduct 1x in 91% yield (Eq.1).
The delicate chemoselectivity of aldol-type condensation was evaluated by crossover experiments of various aldehydes with EDA.
MgI2·(Et2O)n shows high levels of aromatic aldehydes discrimination in the competitive reactions with EDA (Table 4). Firstly,
MgI2·(Et2O)n can uniquely recognize the delicate difference in electronic effect involved in aromatic aldehydes. p-Anisaldehyde is less
reactive than benzaldehyde and the aldol product of benzaldehyde was predominately afforded (Table 4, entry 1). Similarly, the aldol
product of 4-nitrobenzaldehyde was mainly obtained over benzaldehyde. In crossover reactions of p-anisaldehyde with 4-
nitrobenzaldehyde, 4-chlorobenzaldehyde or 4-trifluoromethylbenzaldehyde, respectively, the reaction exclusively gave the aldol
product of 4-nitrobenzaldehyde, 4-chlorobenzaldehyde or 4-trifluoromethyl-benzaldehyde (Table 4, entries 3-5). More significantly,
MgI2·(Et2O)n shows the remarkable preference for benzaldehyde over pivalaldehyde (Table 4, entry 7). These results suggest that the
relative reactivity of aromatic aldehydes in the MgI2·(Et2O)n-promoted process is determined almost solely by eletrophilicity of
carbonyl group of aromatic aldehydes.
In summary, we have developed a facile and efficient method for the direct ester aldol condensation between acyldiazomethanes and
aromatic, heteroaromatic, aliphatic, and αβ-unsaturated aldehydes promoted by MgI2·(Et2O)n at room temperature. The broad substrate
scope, simple operation, high chemoselectivity, and mild condition make this a powerful method. This methodology may find
widespread use in organic synthesis for the preparation of β-hydroxy-α-diazo carbonyl compounds. Further investigation is in progress

in our laboratories to study stereoselectivity, and to attempt the preparation of chiral units which might function as important synthetic
targets in drugs and natural products.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos. 21372203 and 21272076) for the financial support.
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O
OH
O
MgI2
(Et2O)n
H
R2
R1CHO
+
R1
R2
DIPEA, CH2Cl2, r.t.
N2
N2
Scheme 1. MgI2·(Et2O)n-promoted aldol reaction of acyldiazomethane with various aldehydes.
Table 1
Screening the reaction parameters for the condensation of benzaldehyde with EDA. a
MgI2·(Et2O)n Et3N
Yield
(%) c
16
31
46
59
71
82
95
85
94
92
87
78
74
60
Entry
Solvent
Time (h)
(mol%) b
15
(mol%) b
1
2
3
4
5
6
7
8
200
200
200
200
200
200
200
100
300
200
200
200
200
200
200
200
200
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Toluene
THF
8
8
3
3
2
1
0.25
1
0.25
5
4
7
7
12
12
12
12
30
50
60
70
80
100
100
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
16
17
Et2O
CH3CN
DMSO
DMF
61
NRd
NR
MeOH
a To a solution of benzaldehyde (1.0 mmol) and EDA (1.2 mmol) in solvents was added MgI2·(Et2O)n and Et3N at room temperature.
b Relative to the benzaldehyde.
c Yields after silica gel column chromatography purification.
d NR = no reaction.
Table 2
Optimization of base in the condensation of benzaldehyde with EDA catalyzed by MgI2·(Et2O)n.a
Entry Base
Time (h) Yield (%) b
1
DIPEA
0.25
96
2
i-Pr2NH
0.25
91
3
4
Et3N
TMG
0.25
4
95
86
5
6
7
8
2,6-lutidine
C6H5NEt2
N-Methylmorpholine
Morpholine
DMAP
4
4
4
4
4
4
4
34
41 (44 c)
48 (26 c)
NA (50 c)
NA (45 c)
NR
9
10
11
i-PrNH2
Pyrrolidine
NR
a To a solution of benzaldehyde (1.0 mmol) and EDA (1.2 mmol) in CH2Cl2 was added 1.0 mmol of MgI2·(Et2O)n and 2.0 mmol of base at room temperature and
the mixture was stirred for various times.
b Yields after silica gel column chromatography purification.
c Yield of ethyl 3-phenyloxirane-2-carboxylate.
Table 3
MgI2·(Et2O)n-promoted aldol condensation of acyldiazomethane to aldehydes.a
O
O
OH
O
MgI2 (Et2O)
n , DIPEA
H
R2
+
R1
H
R1
R2
CH2Cl2, r.t.
N2
N2
Time
(min)
20
15
15
15
15
15
15
15
Yield
(%) b
96
97
96
96
99
98
95
Entry
R1
R2
Product
1
2
3
4
5
6
7
8
C6H5-
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
1a
1b
1c
1d
1e
1f
4-ClC6H4-
4-FC6H4-
4-BrC6H4-
4-NO2C6H4-
4-CF3C6H4-
3,4-F2C6H3-
2-ClC6H4-
1g
1h
94

9
3-NO2C6H4-
3-MeOC6H4-
4-MeOC6H4-
2-MeC6H4-
3,4-Me2C6H3-
Piperonal
OEt
OEt
OEt
OEt
OEt
OEt
OEt
15
15
30
30
30
30
15
15
15
15
20
20
30
45
20
93
93
92
93
90
91
93
89
93
92
90
92
94
91
98
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1-C10H7-
C6H5CH=CH- OEt
2-Thienyl-
3-Pyridyl-
t-Bu-
Cyclohexanal
C6H5-
OEt
OEt
OEt
OEt
C6H5-
C6H5-
C6H5-
1t
1u
1v
1w
4-MeOC6H4-
4-NO2C6H4-
a The conditions are same as that in Table 2.
b Yields after silica gel column chromatography purification.
Table 4
Crossover aldol reaction of aldehydes with EDA.a
Ratio
Overall yield
Entry
R
R'
(1/1')b
(%)c
94
97
97
95
97
92
95
1
2
3
4
5
6
7
C6H5-
C6H5-
4-MeOC6H4-
4-NO2C6H4-
4-MeOC6H4-
4-MeOC6H4-
4-MeOC6H4-
2-MeC6H4-
t-Bu-
78 / 22
27 / 73
> 99 / 1
> 99 / 1
> 99 / 1
> 99 / 1
> 99 / 1
4-NO2C6H4-
4-ClC6H4-
4-CF3C6H4-
2-ClC6H4-
C6H5-
a Reactions were run with a mixture of 1.0 mmol of each aldehyde, 1.0 mmol of EDA and 1.0 mmo of MgI2·(Et2O)n in the presence of 2.0 mmol of DIPEA in
CH2Cl2 at room temperature.
b The ratio was determined by flash column chromatography.
c Isolated overall yields.