An efficient hydrocyanation of α, β-unsaturated diesters with TMSCN catalyzed by MgI2 etherate

Article abstract of DOI:10.1080/10426507.2019.1700377

A mild, efficient and highly regioselective addition of trimethylsilyl cyanide (TMSCN) to α,β-unsaturated diesters has been achieved by using MgI₂ etherate as catalyst under solvent-free conditions. This protocol provides the corresponding β-cy

Full text of DOI:10.1080/10426507.2019.1700377

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
An efficient hydrocyanation of α, β-unsaturated
diesters with TMSCN catalyzed by MgI2 etherate
Haokun Pan, Hua Li, Huijun Liu & Xingxian Zhang
To cite this article: Haokun Pan, Hua Li, Huijun Liu & Xingxian Zhang (2019): An efficient
hydrocyanation of α, β-unsaturated diesters with TMSCN catalyzed by MgI2 etherate, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2019.1700377
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1700377
An efficient hydrocyanation of a, b-unsaturated diesters with TMSCN catalyzed
by MgI2 etherate
Haokun Pan, Hua Li, Huijun Liu, and Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 15 September 2019
Accepted 29 November 2019
A
mild, efficient and highly regioselective addition of trimethylsilyl cyanide (TMSCN) to
a,b-unsaturated diesters has been achieved by using MgI2 etherate as catalyst under solvent-free
conditions. This protocol provides the corresponding b-cyano esters in high yields.
KEYWORDS
a,b-Unsaturated diester;
TMSCN; hydrocyanation;
MgI2 etherate
GRAPHICAL ABSTRACT
Introduction
condensation of aldehydes or ketones, amines and TMSCN
catalyzed by MgI2 etherate under solvent-free conditions.[16]
In continuation of our research field, we will report a highly
regioselective hydrocyanation of TMSCN with diethyl alkyli-
denemalonates in the presence of 10 mol% MgI2 etherate
under solvent-free conditions.
As one of the most general and versatile methods for C–C
bond formation, the conjugate addition to a,b-unsaturated
carbonyl compounds has received much attention.[1]
Hydrocyanation of a,b-unsaturated carbonyl compounds usu-
ally provides a practical method for the synthesis of b-cyano
carbonyl derivatives. The conjugate addition of cyanide ion to
a,b-unsaturated ketones has been studied using different types
of cyanide sources such as acetone cyanohydrin,[2] potassium
hexacyanoferrate(II),[3] tributylsilyl cyanide[4] and trimethyl-
silyl cyanide (TMSCN).[5] Several catalytic systems have been
used to promote this process, including quinidinium salt-
s,[2a,2b] metal complexes,[2c,4,5a,5b,5d,5h,6] CsF,[5c,5g] and
potassium carbonate,[7] as well as KOH.[8] Recently, Bronsted
basic ionic liquid as catalytic and reusable media for conjugate
cyanation of CF3-substituted alkylidenemalonates using acet-
one cyanohydrin.[9] Moreover, organic nitriles (R-CN) are
common and important intermediates that can be trans-
formed into different classes of molecules such as amines,[10]
carboxylic acids,[11] esters,[12] and heterocycles.[13] Many
drugs containing a nitrile functionality show important
pharmacological activities.[14] To the best of our knowledge,
there is only a few reports on the 1,4-hydrocyanation of
a,b-unsaturated esters.[15] Therefore, the development of less
expensive, environmentally friendly, and easily handled pro-
moters for the addition of TMSCN to a,b-unsaturated esters
is still highly desirable.
Results and discussion
We optimized the reaction conditions by the hydrocyanation
of diethyl n-butylidenemalonate 1a with TMSCN as a model
reaction and the results are summarized in Table 1. We
firstly explored the effect of solvents on this addition. It is
evident that 1,4-hydrocyanation was carried out smoothly in
various solvents in the presence of 10 mol% MgI2ꢀ(Et2O)n at
room temperature. Among them, an excellent yield was
formed using MeCN as a solvent (Table 1, entry 3).
Interestingly, a nearly quantitative yield was afforded under
solvent-free conditions (Table 1, entry 7). The reaction stoi-
chiometry was checked by varying the amounts of
MgI2ꢀ(Et2O)n under solvent-free conditions. The yields of
ethyl 2-carbethoxy-3-cyano-3-butylpropionate 2a are
improved by increasing the amount of MgI2ꢀ(Et2O)n (Table
1, entries 7–10). 10 mol% of MgI2ꢀ(Et2O)n was sufficient. To
examine the effect of other catalysts, a variety of Lewis acids,
such as MgCl2, Mg(ClO4)2, MgBr2, TiCl4, SnCl4, ZnI2 and
ZnCl2 were compared under parallel reaction conditions
(Table 1, entries 11–17). TiCl4, Mg(ClO4)2, MgCl2 and
In our previous paper, we have demonstrated that MgI2
etherate could efficiently promote one-pot three-component MgBr2 could give the desired product in moderate to good
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/10.1080/10426507.2019.1700377.
ß 2019 Taylor & Francis Group, LLC

2
H. PAN ET AL.
Table 1. Optimization of reaction conditions.a
Entry
Lewis acid (mol%)
Solvent
Cyanide source
t (h)
Yield (%)
1
2
3
4
5
6
7
8
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (10)
MgI2ꢀ(Et2O)n (20)
MgI2ꢀ(Et2O)n (5)
MgI2ꢀ(Et2O)n (3)
MgCl2(10)
Mg(ClO4)2(10)
MgBr2(10)
TiCl4(10)
ZnI2(10)
SnCl4(10)
CH2Cl2
CHCl3
MeCN
THF
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
CNCOOMe
CNCOOEt
K4Fe(CN)6
CuCN
4.5
4.5
4.5
5.0
7.5
4.5
5.0
4.5
12.0
12.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
83
85
95
88
85
70
97
97
69
35
82
76
75
80
55
25
12
35
37
N.R.
N.R.
toluene
MeOH
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
9
10
11
12
13
14
15
16
17
18
19
20
21
ZnCl2(10)
MgI2ꢀ(Et2O)n(10)
MgI2ꢀ(Et2O)n(10)
MgI2ꢀ(Et2O)n(10)
MgI2ꢀ(Et2O)n(10)
aTo a solution of diethyl 2-butylidenepropanedioate (2.0 mmol) and cyanide source (2.4 mmol) in solvents (10 mL) was added
(0.2 mmol) Lewis acid at room temperature.
Table 2. MgI2ꢀ(Et2O)n-catalyzed 1,4-hydrocyanation of TMSCN to diesters.a
Encouraged by these optimized reaction conditions, we
chose a variety of structurally diversified diethyl alkylidene-
malonates and arylidenemalonates possessing a wide range
of functional groups to understand the scope and generality
of this MgI2ꢀ(Et2O)n-catalyzed 1,4-hydrocyanation. The
results are summarized in Table 2. A variety of substrates,
including alkylidenemalonates, arylidenemalonates, and het-
eroarylidene malonates underwent addition with TMSCN to
afford the corresponding b-cyano propionate derivatives.
Diethyl alkylidene-malonates (1a–1c), especially with a bulk-
ier substituent such as a cyclohexyl group, gave excellent
yields (Table 2, entries 1–3). As well, excellent yields were
afforded with diethyl arylidenemalonates possessing halogen
groups (Table 2, entries 5–9). Moreover, diethyl arylidene-
malonates with electron-donating groups afforded good
yields of the desired products (Table 2, entries 10–13).
Nearly quantitative yields were obtained with diethyl arylide-
nemalonate possessing electron-withdrawing groups (Table
2, entries 14–16). In addition, diethyl arylidenemalonate 1q
derived from 1-naphthaldehyde, which contains a highly
conjugated plane, seems to be effective, and gave the desired
adduct in 95% yield (Table 2, entry 17). Furthermore,
diethyl heteroarylidenemalonates, derived from pyridine-3-
carboxaldehyde, furane-2-carboxaldehyde and indol-3- car-
boxaldehyde, also provided high yields (Table 2,
entries 18–20).
Entry
R
Time (h)
Product
Yield(%)b
1
2
3
4
5
6
7
8
n-Pr
Et
c-hexyl
Ph
2-FPh
2-ClPh
2-BrPh
4-ClPh
4-BrPh
4-MePh
2-MeOPh
3-MeOPh
4-MeOPh
2-NO2Ph
3-NO2Ph
4-NO2Ph
1-naphthyl
2-furanyl
3-pyridyl
3-indolyl
5.0
5.0
6.0
5.0
7.0
7.0
7.0
5.0
5.0
7.0
7.0
6.0
6.0
3.0
3.0
2.0
8.0
3.0
4.0
3.0
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
97
95
94
96
92
93
94
94
95
89
85
87
84
99
99
99
95
93
96
94
9
10
11
12
13
14
15
16
17
18
19
20
2s
2t
aReaction conditions: TMSCN (2.4 mmol), MgI2ꢀ(Et2O)n (0.2 mmol), diethyl aryli-
dene-, heteroarylidene- or alkylidene-malonates 1a–1t (2.0 mmol) were
stirred at room temperature under solvent-free conditions.
bIsolated yields after silica gel column chromatographic purification.
yield. ZnI2 produced a low yield. SnCl4 and ZnCl2 were
almost inactive in terms of substrate conversion and yield.
Furthermore, various types of cyanide sources were
screened, respectively (Table 1, entries 18 to 21). Low yields
were given by using CNCOOEt or CNCOOMe as cyanide
source. No reaction was observed by using K4Fe(CN)6 or
Experimental
General
All reagents were commercially available and directly used
CuCN as cyanide source in the presence of MgI2 etherate, without further treatment. H NMR and 13C NMR spectra
1
respectively.
were recorded at 500 MHz in CDCl3 using TMS as internal

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
standard. 13C NMR spectral measurements were performed
at 125 MHz using as an internal standard. FTIR were
recorded on a Bruker Tensor 27 spectrometer. EI-MS were
determined on a Perkin Elmer spectrometer. HRMS(ESI)
were determined on a Therm LCQ TM Deca XP plus spec-
trometer. For product purification by flash column chroma-
tography, silica gel (200 ꢁ 300 mesh) and light petroleum
ether (PE, b.p. 60 ꢁ 90 ꢂC) were used.
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The representative procedure for the synthesis of b-cyano
diesters —To a stirred mixture solution of a,b-unsaturated
diesters 1a–1t (2.0 mmol) and TMSCN (198 mg, 2.4 mmol)
was added a freshly prepared MgI2 etherate (0.2 mL,
1.0 mol/L PhMe/Et2O) at room temperature. The resulting
reaction mixture was stirred at room temperature for several
hours and quenched with saturated aqueous NaHSO3.
Extractive workup with ethyl acetate and chromatographic
purification of the crude product on silica gel gave the
desired adduct.
Spectroscopic data for the products (Table 2, entries
2a–2t) is provided in Supplemental Materials file.
Conclusions
We have disclosed a highly efficient 1,4-hydrocyanation of
alkylidenemalonates and arylidenemalonates with TMSCN
catalyzed by MgI2 etherate at room temperature under solv-
ent-free conditions. The broad substrate scope, simple oper-
ation, high regioselectivity, and mild condition make this a
powerful method. Further investigation is in progress in our
laboratories to study stereoselectivity, and to attempt the
preparation of chiral units which might function as import-
ant synthetic targets in drugs and natural products.
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ORCID
Xingxian Zhang
http://orcid.org/0000-0003-4474-7600
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