Efficient and mild Strecker-type reaction of nitrones catalyzed by MgI2 etherate

Article abstract of DOI:10.1080/00397911.2017.1350276

An efficient Strecker-type reaction of nitrones with trimethylsilyl cyanide (TMSCN) catalyzed by MgI₂ etherate has been achieved in a short time under mild condition. The condensations of aromatic nitrones, heterocyclic nitrones, and aliphatic

Full text of DOI:10.1080/00397911.2017.1350276

Synthetic Communications
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An Efficient and Mild Strecker-Type Reaction of
Nitrones Catalyzed by MgI2 Etherate
Zhili Chen, Xinyu Zhou, Xiaoqiang Xie & Xingxian Zhang
To cite this article: Zhili Chen, Xinyu Zhou, Xiaoqiang Xie & Xingxian Zhang (2017): An
Efficient and Mild Strecker-Type Reaction of Nitrones Catalyzed by MgI2 Etherate, Synthetic
Communications, DOI: 10.1080/00397911.2017.1350276
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Date: 10 July 2017, At: 20:14

An Efficient and Mild Strecker-Type Reaction of Nitrones Catalyzed by MgI2
Etherate
Zhili Chen1, Xinyu Zhou1, Xiaoqiang Xie1, Xingxian Zhang1
1College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou,
Zhejiang, P. R. China
Abstract
An efficient Strecker-type reaction of nitrones with TMSCN catalyzed by MgI2 etherate
has been achieved in a short time under mild condition. The condensations of aromatic
nitrones, heterocylic nitrones and aliphatic nitrones with TMSCN are carried out in good
to excellent yields. Further dehydration of -cyanohydroxylamine smoothly produced
the -imine nitrile in good yields by hydrolysis with treatment of 2.0 mol/L HCl in
methanol.
Graphical Abstract
KEYWORDS: Strecker-type reaction; nitrones; TMSCN; α-cyanohydroxylamines; MgI2
etherate
INTRODUCTION
1

The Strecker reaction is a process for the preparation of α-amino nitriles, which are
versatile intermediates for the synthesis of amino acids via hydrolysis of the nitrile. [1] In
recent years, there are many studies on Strecker reaction of aldehydes, ketones and
imines, while little attention has been drawn to nitrones. Among organic nitrogen
compounds bearing a carbon-nitrogen double bond, nitrones are a particularly interesting
class of compounds by virtue of their utility in organic synthesis. They possess
electronegative oxygen, which can coordinate strongly to metals[2] and polarizes a
carbon-nitrogen double bond to effectively enhance the electrophilic reactivety[3]. They
are readily available to form aldehydes and ketones, and they are excellent electrophilic
substrates capable of reacting with a variety of nucleophiles showing a higher reactivity
and stability than imines. The nitrones are reactive starting materials in a large amount of
1,3-dipolar cycloadditions[4] and act as electrophiles with a variety of both carbon and
heteronucleophiles[5].
It occurred to us that the reaction of trimethylsilyl cyanide (TMSCN) with nitrones would
give rise to -cyanohydroxylamine derivatives, which is also a useful way to give natural
or unnatural amino acids sequentially undergoing hydrolysis and catalytic hydrogenation.
Accordingly, this work was undertaken to synthesize and investigate the chemistry of
-cyanohydroxylamine.
2

To date there are few catalysts to be extended to the Strecker-type reaction of nitrones,
such as TMSOTf[6], Et2AlCl[6], thiourea[7]. Recently, Ukaji’s group has reported
Strecker-type reaction of nitrones with acetone cyanohydrins in the presence of
n-BuMgCl-catalysis.[8] Therefore, the development of less expensive, environmentally
benign, and easily handled promoters for the synthesis of -cyanohydroxylamine by
Strecker condensation 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 Mg2+ ion and its tendency to form a multi-coordinate (up to 5 or 6) complex.[9] In
our previous work,[10] we have demonstrated that MgI2 etherate could efficiently catalyze
Strecker addition of aldehydes and imines with TMSCN. Herein, we wish to report a mild
and efficient Strecker-type addition of TMSCN to various nitrones catalyzed by MgI2
etherate.
RESULTS AND DISCUSSION
Initially, the (Z)-benzylideneaniline N-oxide (1a) was chosen as the 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
(Z)-benzylideneaniline N-oxide 1a with TMSCN was carried out using Mg(II) catalysts.
The targeted product α-cyanohydroxylamine 2a was provided by treatment with 2.0
mol/L HCl in methanol. As shown in Table 1, the reaction proceeded very sluggishly and
3

gave the desired adduct in a low yield in CH2Cl2 without any catalysts. MgCl2 and MgBr2
etherate were less effective to this reaction and gave the product in 53% and 67% yield,
respectively. The best result was observed with 5.0 mol% of MgI2 etherate using CH2Cl2
as solvent in a very short time, while Mg(ClO4)2 also showed good yield. (Table 1, entries
1-4). Next the effect of solvent was examined in the presence of 5.0 mol% of MgI2
etherate. Among the solvents screened, non-coordinating reaction media CH2Cl2 and
CHCl3 are proven to be the best solvents (Table 1, entries 5-6). Less polar solvents,
MeCN, THF and Et2O, showed good yields as well (Table 1, entries 7-9), while moderate
yield was given in toluene (Table 1, entry 10). Lower yields were afforded in polar
solvents, MeOH, acetone and DMF (Table 1, entries 11-13).
Encouraged by these results, the Strecker-type reaction of various nitrones 1 with
TMSCN was investigated using 5.0 mol% of MgI2 etherate in CH2Cl2 at room
temperature. The results are summarized in Table 2. The reaction of 4-methyl and
4-methoxy substituted nitrones on aromatic ring 1b and 1c gave the
α-cyanohydroxylamine 2b and 2c in excellent yields in very short time (Table 2, entries 2
and 3). As well, the nitrone bearing electron-withdrawing groups on aromatic ring also
provided the corresponding products in good yields (Table 2, entries 4 and 5). In the case
of heteroaromatic nitrone 1f the Strecker-type reaction proceeded well to produce 2f in 95%
yield (Table 2, entry 6). However, in the case of nitrones 1g derived from
4

3-methyl-2-thiophene aldehyde, α-cyano-O-trimethylsilyl hydroxylamine as a stable
product was obtained in near quantitatively yield without affording α-cyanohydroxyl
amine due to its instability (Table 2, entry 7). Furthermore, the Strecker-type reaction of
nitrones 1h, prepared from cinnamaldehyde and nitrobenzene, with TMSCN exclusively
occurred 1,2-addition and gave the stable O-trimethylsilyl derivative in moderate yield
(Table 2, entry 8). Next, the influence of the substituents on the nitrogen atom of the
nitrones was examined. As shown in Table 2, the Strecker-type reactions of N-benzyl
nitrone 1i-1o were carried out in good to excellent yields in terms of various nitrones
bearing electron-withdrawing groups and electron-donating groups on aromatic ring
(Table 2, entries 10-14). It was worthy to be noted that the more sterically hindered
nitrone 1l also gave an excellent yield (Table 2, entry 12). In addition, the Strecker
reaction of the aliphatic nitrones 1p and 1q, which are derived from the oxidation of its
corresponding secondary amine,[11] also proceeded smoothly and afforded the desired
product in 96% and 94%, respectively (Table 2, entries 16 and 17). Furthermore, MgI2
etherate could effectively catalyze Strecker-type reaction of chiral nitrone 1r (Table 1,
entry 18). The cyanation afforded the unseparable diastereomer in the excellent yield with
moderate stereoselectivity. Apparently, the substituents on the nitrogen atom of nitrone
did not affect the reaction.
Interestingly, cyanation of N-phenyl nitrones with 4-chloro, 4-bromo, 4-trifluromethyl
substituents on aromatic ring proceeded well and gave a dehydrated cyanoimine 3a-3c in
5

good to excellent yield, respectively (Table 3, entries 1-3). In terms of nitrone derived
from furfuryl aldehyde, the reaction gave a dehydrated cyanoimine 3d exclusively (Table
3, entry 4). Especially, the cyanation of a cyclic nitrone, 3,4-dihydroisoquinoline N-oxide,
also carried out smoothly and gave a dehydrated imine 3e in good yield (Table 3, entry 5),
which is much better than that of the cyanation catalyzed by n-BuMgCl reported by Ukaji
[8]
.
The possible mechanism for the formation of α-cyanohydroxylamine catalyzed by MgI2
etherate is shown in Scheme 1. The uniqueness of MgI2 etherate is attributed to the
dissociative character of iodide counterion, which is cooperation with coordination of
Lewis basic oxygen atom of nitrone 1 with Mg (Ⅱ) leading to a more Lewis acidic
cationic Mg-coordinate 4. It is feasible to promote a nucleophilic addition of TMSCN to
form an intermediate 5. The irreversible silylation of intermediate 5 by transient TMSI to
regenerate MgI2 etherate catalyst and produce the desired product 6 as shown in the
proposed catalytic cycle. Then α-cyanohydroxylamine was obtained by acidification.
CONCLUSION
In conclusion, we have developed a highly efficient Strecker-type reaction of nitrones
with TMSCN catalyzed by MgI2 etherate. This magnesium-catalyzed Strecker-type
addition is rapid, mild, environmentally friendly and operationally simple. We have
demonstrated that iodide counterion, weakly coordinating peripheral ethereal ligands for
6

Mg(II), and a non-coordinating reaction media are critical factors for the unique
reactivity of this catalytic system. Further studies on magnesium-catalyzed asymmetric
Strecker-type reaction of nitrones 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 oC) were used. The reactions monitoring was
accomplished by TLC on silica gel polygram SILG/UV 254 plates. Melting points were
performed on X-4B microscopic melting point meter. 1H 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 compounds were
identified by 1H NMR and are in good agreement with those reported. EI-MS were
determined on a PerkinElmer spectrometer. HRMS (ESI) were determined on a Therm
LCQ TM Deca XP plus spectromer. HRMS (TOF-EI) were determined on GCT premier
spectrometer. IR spectroscopy was performed on a Nicolet 6700 infrared spectrometer.
General Procedure For Strecker-Type Reaction Of Nitrones.
To a solution of the corresponding nitrones 1 (1.0 mmol) in CH2Cl2 (5 mL) was added
trimethylsilyl cyanide (1.5 mmol) and a freshly prepared MgI2 etherate [12] (0.05 mmol,
1.0 mol/L in Et2O/toluene 1:1, 5.0 mol %). The reaction mixture was stirred at room
temperature for 10 to 15 minutes. The solvent was evaporated after completion of
7

reaction, and the resulting mixture was treated with 2.0 mol/L HCl/MeOH (2 mL).
Saturated NaHCO3 aqueous was added and the resulting mixture was extracted with
dichloromethane (3 20 mL). The combined organic phase was washed with brine and
concentrated. The residue was purified by flash column chromatography on a silica gel to
give the cyanated product.
ACKNOWLEDGMENTS
We acknowledge the financial support from National Natural Science Foundation of
China (21372203, 21272076) and the Scientific Innovation Program for University
Students in Zhejiang Province.
REFERENCES
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(c) Khan, N. U. H.; Kureshy, R. I.; Abdi, S. H. R.; Agrawal, S.; Jasra, R. V. Coordin.
Chem. Rev. 2008, 252, 593.
[2] Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Cerreira, E. M. Acc. Chem. Res. 2000, 33,
373.
[3] (a) Tsuge, O.; Urano, S.; Iwasaki, T. Bull. Chem. Soc. Jpn. 1980, 53, 485; (b) Padwa,
A.; Koehler, K. F. J. Chem. Soc., Chem. Commun. 1986, 789.
[4] (a) Aurich, H. G.; Frenzen, G.; Gentes, C. Eur. J. Inorg. Chem. 1993, 126, 787; (b)
Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1; (c) Xie, L.; Bai, H.; Li, J.; Yu, X.;
8

Zhang, Z.; Fu, B. Tetrahedron, 2017,73, 2920; (d) Zhao, H.; Liu, Y.; Zhao, Y.; Pang, H.;
Chen, X.; Song, X.; Tian, T.; Li, B.; Yang, Z.; Du, J.; Feng, N. Org. Lett. 2017, 19, 26; (e)
Tamura, O.; Shiro, T., Ogasawara, M.; Toyao, A.; Ishibashi, H. J. Org. Chem., 2005, 70,
4569; (f) Gothelf, K. V. In Methods and Applications of Cycloaddition Reactions in
Organic Syntheses; Nishiwaki, N. Ed.; Wiley & Sons, Inc.: New Jersey, 2014. Chapter. 6.
[5] (a) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229. (b) Reznikov, V. A.;
Vishnivetskaya, L. A.; Volodarskii, L. B. Russ. Chem. Bull. 1993, 42, 889.
[6] Merino, P.; Tejero, T.; Revuelta, J.; Romero, P.; Cicchi, S.; Mannucci, V. ; Brandi, A.;
Goti, A. Tetrahedron: Asymmetry 2003, 14, 367.
[7] Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44, 2817.
[8] Sakai, T.; Soeta, T.; Inomata, K.; Ukaji, Y. Bull. Chem. Soc. Jpn. 2012, 85, 231.
[9] For review see: Zhang, X.; Li, W. Chin. J. Org. Chem. 2003, 23, 1185.
[10](a) Lu, Y.; Wang, Y.; Zhang, X. J. Chem. Res. 2013, 11, 709; (b) Wang, Y.; Feng, M.;
Liu, Y.; Zhang, X. J. Chem. Res. 2012, 10, 566.
[11] Murahashi, S.; Shiota, T.; Imada, Y. Org. Synth. 1991, 70, 265.
[12] Arkley, V.; Attenburrow, J.; Gregory, G. I.; Walker, T. J. Chem. Soc. 1962, 1260.
9

Table 1. Optimization of reaction conditions for MgX2-catalyzed Strecker-type reactiona
Entry Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
THF
Time (min) Yields (%)b
1
None
MgCl2
MgBr2
Mg(ClO4)2
MgI2
180
30
30
15
10
15
10
15
15
15
30
30
30
38
53
67
81
92
90
85
80
76
66
31
18
29
2
3
4
5
6
MgI2
7
MgI2
8
MgI2
9
MgI2
Et2O
10
11
12
13
MgI2
Toluene
Acetone
MeOH
DMF
MgI2
MgI2
MgI2
aThe reaction was carried out by the addition of (Z)-benzylideneaniline N-oxide (1.0
mmol) and TMSCN (1.5 mmol) in the presence of 5.0 mol % of MgX2 under the above
reaction conditions, followed by hydrolysis with treatment of 2.0 mol/L HCl in methanol.
bIsolated yield by silica gel flash chromatography.
10

Table 2. Strecker-type reaction of various nitrones catalyzed by MgI2 ethreratea
Entry
R1
R2
Time
(min)
10
Prod. Yield (%)b
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
92
95
96
80
81
95
99
71
80
99
95
94
91
94
88
2a
2b
2c
2d
2e
2f
2
4-MeC6H4
4-MeOC6H4
2-ClC6H4
2-FC6H4
2- Thienyl
10
3
10
4
10
5
10
6
10
2gc
2hc
2i
7
3-Me-2-thienyl 10
8
Cinnamyl
Ph
10
15
15
15
15
15
15
15
9
10
11
12
13
14
15
4-MeOC6H4
2-MeOC6H4
2,6-Me2C6H3
4-ClC6H4
2-ClC6H4
2-Thienyl
2j
2k
2l
2m
2n
2o
11

16
17
18
tert-Bu
n-Bu
Ph
10
10
15
96
2p
2q
2r
n-Pr
94
(R)-C6H5CH(CH3) Ph
87
(dr 37:63)d
a The reaction was carried out by addition of nitrones (1.0 mmol) and trimethylsilyl
cyanide (1.5 mmol) in the presence of 5.0 mol % of MgI2 etherate in CH2Cl2 at room
temperature, followed by hydrolysis with treatment of 2.0 mol/L HCl in methanol.
b Isolated yields by silica gel flash chromatography.
c The desired product is O-trimethylsilyl derivative.
d The ratio of dr value was determined by 1H NMR analysis.
12

Table 3. The preparation of cyanoimines by dehydration from α-cyanohydroxylamines
Entry
R1
Ph
Ph
Ph
Ph
R2
Product
3a
Yield (%)a
4-BrC6H4
4-ClC6H4
4-CF3C6H4
2-Furfuryl
81
76
97
89
82
1
2
3
4
5
3b
3c
3d
3e
aIsolated yields by silica gel flash chromatography.
13

Scheme 1. MgI2 etherate-catalyzed Strecker-type reaction of nitrones with TMSCN.
14

Scheme2. The proposed mechanism of MgI2 etherate-catalyzed Strecker-type reaction of
nitrone.
15