Unique chemoselective Strecker-type reaction of acetals with TMSCN catalyzed by MgI2 etherate

Article abstract of DOI:10.1080/00397911.2019.1711413

An efficient and convenient Strecker-type addition of various substituted aromatic acetals, heteroaromatic acetals and α, β-unsaturated acetals with trimethylsilyl cyanide (TMSCN) is achieved catalyzed by 10 mol% of MgI₂ etherate (MgI₂

Full text of DOI:10.1080/00397911.2019.1711413

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Unique chemoselective Strecker-type reaction of
acetals with TMSCN catalyzed by MgI2 etherate
Hua Li, Haokun Pan, Xiangwei Meng & Xingxian Zhang
To cite this article: Hua Li, Haokun Pan, Xiangwei Meng & Xingxian Zhang (2020): Unique
chemoselective Strecker-type reaction of acetals with TMSCN catalyzed by MgI2 etherate,
Synthetic Communications, DOI: 10.1080/00397911.2019.1711413
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https://doi.org/10.1080/00397911.2019.1711413
Unique chemoselective Strecker-type reaction of acetals
with TMSCN catalyzed by MgI2 etherate
Hua Li, Haokun Pan, Xiangwei Meng, and Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 24 July 2019
An efficient and convenient Strecker-type addition of various substi-
tuted aromatic acetals, heteroaromatic acetals and a, b-unsaturated
acetals with trimethylsilyl cyanide (TMSCN) is achieved catalyzed by
10 mol% of MgI2 etherate (MgI2ꢀ(Et2O)n) in a mild, and high chemo-
selective manner with good to excellent yields. A non-coordinating
reaction media (i.e., CH2Cl2) played a vital role in this catalytic pro-
cess.
KEYWORDS
Acetal; MgI2 etherate;
Strecker-type reaction;
trimethylsilyl cyanide
GRAPHICAL ABSTRACT
Introduction
The carbon–carbon bond formation is a fundamental process in organic synthesis and
numerous methods have been developed for achieving it. One of the most powerful
methods is the reaction of the carbonyl groups with a variety of carbon nucleophiles.[1–6]
Acetals are a typical carbonyl protecting group as well as a synthetic equivalent of the
carbonyl group. In general, acetals are stable under strongly basic to neutral conditions
and do not react with nucleophilic reagents, for example, organolithium reagents and
Grignard reagents, under these conditions. However, acetals act as strong electrophiles
toward various nucleophiles under acidic conditions owing to the generation of an oxo-
nium ion intermediate. Many Lewis acids, such as trimethylsilyl triflate (TMSOTf),[7]
TiCl4,[8,9] BiBr3,[10] ZnI2,[11] CoCl2,[12] [Rh(COD)Cl]2,[13] SnBr2,[14] BF3ꢀEt2O[15,16
]
[17,18]
and SnCl2
could promote the cyanation of acetals with trimethylsilyl cyanide
(TMSCN). In addition, tetracyanoethylene (TCNE) also catalyzed the reaction of acetals
with TMSCN.[19] Furthermore, the cyanation of acetals with a-cyanoamine as a cyanat-
ing reagent in the presence of trichlorosilyl triflate was developed by Kotani.[20] Mild
cyanation of acetals with TMSCN in the presence of TESOTf and 2,4,6-collidine or 2,20-
bipyridyl via the pyridinium-type salts has been developed by Fujioka.[21,22] Recently,
CONTACT Xingxian Zhang
zhangxx@zjut.edu.cn
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, Zhejiang, P. R. China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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H. LI ET AL.
Scheme 1. MgI2 etherate-catalyzed Strecker-type reaction of acetals with TMSCN.
Kumamoto’s group has reported high-pressure-promoted uncatalyzed cyanation of ace-
tals using TMSCN in nitromethane.[23]
However, conventional methods using Lewis acids must be carried out under strictly
anhydrous conditions, which are difficult to handle on a particularly large scale.
Therefore, the development of less expensive, environmentally benign, and easily
handled promoters for the synthesis of C–C bond under neutral, mild, and convenient
condition is still highly desirable. Magnesium (II) species are widely applied as Lewis
acid catalysts in various functional transformations and C–C bond-forming reactions
due to the high eletrophilicity of the Mg2þ ion and its tendency to form a multi-coord-
inate (up to 5 or 6) complex.[24] In our previous work,[25–27] we have demonstrated that
MgI2 etherate could efficiently catalyze Strecker of aldehydes, nitrones, and imines with
TMSCN. Herein, we wish to report a mild and efficient Strecker-type addition of
TMSCN to various acetals catalyzed by MgI2 etherate (Scheme 1).
Results and discussion
Initially, the benzaldehyde dimethyl acetal 1a was chosen as a model substrate treated
with TMSCN for investigating the reaction parameters in the Strecker-type reaction,
and the results are summarized in Table 1. The Strecker-type reaction of acetal 1a with
TMSCN was carried out smoothly in the presence of MgI2 etherate. The targeted prod-
uct 2-phenyl-2-methoxyacetonitrile 2a was provided by silica gel flash chromatography.
The best result was observed with 10 mol% of MgI2 etherate using CH2Cl2 as solvent in
3 h time. (Table 1, entry 1–4). Next, the effect of solvent was examined in the presence
of 10 mol% of MgI2 etherate. Among the solvents screened, non-coordinating reaction
media CH2Cl2 and CHCl3 have proven to be the best solvents. Toluene and 1,2-
dichloroethane show good yields as well (Table 1, entries 6–7), while lower yields were
afforded in less polar solvents such as MeCN and tetrahydrofuran (THF). (Table 1,
entries 8–9). No reaction occurred in the polar solvent, MeOH (Table 1, entry 10).
Encouraged by these results, the Strecker-type reactions of various acetals 1 with
TMSCN were investigated using 10 mol% of MgI2 etherate in CH2Cl2 at room tempera-
ture. The results are summarized in Table 2. Aryl aldehyde acetals bearing electron-
donating groups on the benzene ring (i.e., Me, OMe) afforded excellent yields of the
desired products 2b–2d, (Table 2, entries 2–4). Furthermore, good yields were obtained
for aryl aldehyde acetals possessing halo groups (i.e., Cl, Br, F) at the para position on
the benzene ring (Table 2, entries 5–7), while lower yields were observed with 4-nitro-
benzaldehyde acetal and 4-cyanobenzaldehyde acetal (Table 2, entries 9–10). Meanwhile,
heteroaromatic acetals such as 2-thiophenecarboxaldehyde acetal, 2-furanaldehyde acetal
also gave high yields (Table 2, entries 11–12). 1-Naphalenealdehyde acetal, which

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Table 1. Optimization of reaction conditions for MgI2 etherate-catalyzed Strecker-type reactiona.
Entry
MgI2 (mol%)
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
15
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
3
3
24
36
4
4
4
4
4
4
95
95
75
53
94
87
92
69
50
N.A.
1
10
10
10
10
10
10
1,2-dichloroethane
PhMe
MeCN
THF
MeOH
9
10
aThe reaction was carried out by the addition of benzaldehyde dimethyl acetal 1a (1.5 mmol) and TMSCN (1.8 mmol) in
the presence of 10 mol % of MgI2 etherate under the above reaction conditions.
bIsolated yield by silica gel flash chromatography.
contains a highly conjugated plane, seems to be effective and gave the corresponding
adduct in 68% yield (Table 2, entry 13). Moreover, a, b-unsaturated acetal such as cin-
namaldehyde acetal gave the desired product in good yield (Table 2, entry 14).
Unfortunately, very poor yields were observed with ortho-substituted aromatic aldehyde
acetals due to its steric hinderance (Table 2, entries 15–16). However, aliphatic aldehyde
acetals were inert to this silylcyanation under the similar conditions (Table 2,
entries 17–18).
The delicate chemoselectivity of Strecker reaction was evaluated by crossover
experiments of various acetals and its parent aldehydes with TMSCN, respectively.
MgI2 etherate showed high levels of acetals discrimination in the competitive reac-
tions (Table 3). MgI2ꢀ(Et2O)n can uniquely recognize the difference in aromatic ace-
tals and aromatic aldehydes. Benzaldehyde is less reactive than benzaldehyde
dimethyl acetal and the cyanosilylated product of benzaldehyde dimethyl acetal was
predominately afforded (Table 3, entry 1). Similarly, the cyanosilylated product of 4-
methoxy benzaldehyde acetal was exclusively obtained over 4-methoxy benzaldehyde
(Table 3, entry 2). In the crossover experiment of 4-bromobenzaldehyde with 4-bro-
mobenzaldehyde acetal, the reaction exclusively gave the cyanosilylated product of
p-bromobenzaldehyde acetal (Table 3, entry 3). As well, the reactivity of 2- furanal-
dehyde acetal is better than that of its corresponding aldehyde in this MgI2 etherate
catalysis (Table 3, entry 4).
In view of the importance of acetal function as carbonyl equivalent for C–C bond
cross-coupling, we revealed here that a mild Lewis acidic MgI2 etherate could preferen-
tially activate the acetal. The preferential activation of acetal over its parent aldehyde
may be attributed to the fast and irreversible silylation of MgI2 etherate by transient
TMSI to regenerate MgI2 etherate and expel TMSOMe as the thermodynamically
favored by-product as shown in the proposed catalytic cycle (Scheme 2).

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H. LI ET AL.
Table 2. Strecker-type reaction of various acetals catalyzed by MgI2 etheratea.
Enrty
1
Aldehyde
Time (h)
3
Product
Yield (%)b
95
2a
2
3
3
2
2b
2c
94
98
4
5
3
3
1d
2e
92
91
6
3
2f
92
7
3
5
2g
2h
2i
89
91
8
9
12
12
33
10
2j
trace
11
12
13
4
3
6
2k
2l
90
89
68
2m
(continued)

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Table 2. Continued.
Enrty
14
Aldehyde
Time (h)
4
Product
Yield (%)b
92
2n
15
16
24
24
2o
2p
N.R.
trace
17
18
24
24
2q
2r
N.R.
N.R.
aThe reaction was carried out by the addition of acetals (1.5 mmol) and TMSCN (1.8 mmol) in the presence of 10 mol %
of MgI2 etherate in CH2Cl2 at room temperature.
bIsolated yields by silica gel flash chromatography.
Table 3. Crossover cyanosilylation of aldehydes and acetals with TMSCNa.
Entry
1
RCH (OMe)2
RCHO
Ratio (2:4)b
Overall yield (%)c
95
>99/<1
2
3
4
>99/<1
>99/<1
>99/<1
95
92
89
RCH(OMe)2: acetal; RCHO is aldehyde.
aReactions were run with a mixture of 1.5 mmol of aldehyde, 1.5 mmol acetal, 1.5 mmol of TMSCN and 10 mol% of
MgI2ꢀ(Et2O)n in CH2Cl2 at room temperature.
bThe ratio was determined by isolated yields on silica gel.
cIsolated overall yields.

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H. LI ET AL.
Scheme 2. Plausible mechanism for Strecker reaction of acetals with TMSCN catalyzed by
MgI2 etherate.
Conclusion
In conclusion, we have developed a highly efficient Strecker-type reaction of acetals
with TMSCN catalyzed by MgI2 etherate. This magnesium-catalyzed Strecker-type add-
ition is rapid, mild, environmentally friendly and operationally simple. Further studies
on magnesium-catalyzed asymmetric Strecker-type reaction of acetals with TMSCN are
in progress in our laboratory.
Experimental
General
For product purification by flash column chromatography, silica gel (200 ꢁ 300 mesh)
and light petroleum ether (PE, b.p. 60 ꢁ 90 ꢂC) were used. The reactions monitoring
1
was accomplished by TLC on silica gel polygram SILG/UV 254 plates. H NMR spectra
were recorded at 500 MHz in CDCl3 using TMS as internal standard. 13C NMR spectral
measurements were performed at 125 MHz using TMS as an internal standard. All com-
1
pounds were identified by H NMR and are in good agreement with those reported.
HRMS (EI) was determined on a PerkinElmer spectrometer.
General procedure for strecker-type reaction of acetals with TMSCN catalyzed by
MgI2 etherate
To a stirred benzaldehyde dimethyl acetal 1a solution of (15 mmol) was added a freshly
prepared MgI2 etherate (1.5 mmol, 1.0 M in Et2O/PhMe) at room temperature, followed
by addition of trimethylsilyl cyanide (18 mmol). The resulting reaction mixture was
stirred at room temperature for 3.0 h. chromatographic purification of the crude prod-
uct on silica gel gave the 2-phenyl-2-methoxyacetonitrile 2a in 95% yield.
Spectroscopic data for the unknown products
2-(3-methoxyphenyl)-2-methoxyacetonitrile (2d): Colorless transparent liquid; Rf ¼ 0.75
1
(PE:EtOAc ¼ 5:1); H NMR (500 MHz, CDCl3) d 7.34 (t, J ¼ 7.9 Hz, 1H), 7.11–7.03 (m,
2H), 6.96 (dd, J ¼ 2.4, 8.3 Hz, 1H), 5.16 (s, 1H), 3.81 (s, 3H), 3.52 (s, 3H) ppm.
13C NMR (125 MHz, CDCl3) d 159.88, 134.56, 129.89, 119.22, 116.84, 115.32, 112.42,

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77.28, 77.03, 76.77, 71.87, 56.97, 55.13 ppm. HRMS (EI): calcd. for C10H11NO2 [M]þ
177.0790; found 177.0796.
2-(4-fluorophenyl)-2-methoxyacetonitrile (2g): Yellow liquid; Rf ¼ 0.89 (PE:EtOAc ¼
1
5:1); H NMR (500 MHz, CDCl3) d 7.50–7.47 (m, 2H), 7.14–7.11 (m, 2H), 5.18 (s, 1H),
3.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) d 164.36, 162.38, 129.25 (t, J ¼ 8.3 Hz),
116.76, 115.99 (d, J ¼ 22 Hz), 71.49, 57.1 ppm. HRMS (EI): calcd. for C9H8FNO [M]þ
165.0590; found 165.0594.
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