Magnesium chloride (MgCl2) catalyzed highly regioselective C-3 ring opening of 2,3 epoxy alcohols by N-nucleophile

Article abstract of DOI:10.1016/j.tetlet.2021.153013

We herein report Magnesium chloride (MgCl₂) catalyzed first highly C3-selective ring-opening reaction of various 2,3-epoxy alcohols with assorted N-Nucleophiles and sodium azide to furnish 3-amino-1,2 diols and 3-azido-1,2 diols respectively in high yields under mild reaction conditions. This protocol attributes the use of catalytic amount of Magnesium chloride (MgCl₂), simple reaction conditions, practical operation and broad functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2021.153013

Tetrahedron Letters 70 (2021) 153013
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Tetrahedron Letters
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Magnesium chloride (MgCl2) catalyzed highly regioselective C-3 ring
opening of 2,3 epoxy alcohols by N-nucleophile
⇑
Amit Kumar, Gautam Panda
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report Magnesium chloride (MgCl2) catalyzed first highly C3-selective ring-opening reaction of
various 2,3-epoxy alcohols with assorted N-Nucleophiles and sodium azide to furnish 3-amino-1,2 diols
and 3-azido-1,2 diols respectively in high yields under mild reaction conditions. This protocol attributes
the use of catalytic amount of Magnesium chloride (MgCl2), simple reaction conditions, practical opera-
tion and broad functional group tolerance.
Received 11 February 2021
Revised 14 March 2021
Accepted 15 March 2021
Available online 23 March 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Magnesium chloride
Regioselective C-3 ring opening
2, 3 Epoxy alcohols
N-Nucleophile
Azides
Introduction
however many of the reported protocols used stoichiometric
amount of promoters, high temperature and excess use of nucle-
Seebach [1] once expressed his opinion as ‘‘If carbonyl com-
pounds have been said to be ‘virtually the backbone of organic syn-
thesis’, the epoxides correspond to at least ‘one of the main
muscles’.” This message can be very effective for researchers to
understand the importance of epoxides in chemical synthesis [2].
Regioselective and stereospecific ring opening of 2,3-epoxy com-
pounds with various nucleophiles [3] provide a direct access to
versatile chiral building blocks for the synthesis of natural prod-
ucts and synthetic analogues with promising biological activities.
Nucleophilic addition at the C-3 position of 2,3- epoxy alcohols
by amines and azides affords 3-amino 1,2-diols and 3-azido-1,2
diols respectively. 3-amino 1,2-diols can be observed in cardiovas-
cular [4], antibacterial [5], and sedative agents [6] as synthetic
intermediates. However, 3-azido-1,2 diols are used as key interme-
diate for bioactive Dapoxetine [7]. Very less approaches have been
reported for the C-3 regioselective ring opening of 2,3-epoxy alco-
hols using amines [8–12]and azides [13–18] as nucleophiles. Very
recently, Chen J. et al. reported a metal and solvent-free acetic acid-
mediated ring-opening reaction of epoxides with amines [19].
Despite the significant progress achieved in the area of C-3 regios-
elective ring opening of 2,3-epoxy alcohols with amines or azide,
ophiles. Therefore, the development of a catalytic version of this
type of reaction is still highly desirable [20]. Yamamoto H. et al.
reported the first catalytic, highly C3-selective, stereospecific
ring-opening reaction of 2,3-epoxy alcohols with diverse N-nucle-
ophiles using W-salts providing various 3-amino-1,2 diols [21].
Surendra K et al. reported the C-3 selective ring-opening of 2,3-
epoxy alcohols with aromatic amines catalysed by b-cyclodextrin
in water at room temperature to afford the corresponding b-
aminoalcohols in excellent yields with high regioselectivity [22].
Even though, few reports have been published dealing with very
expensive catalyst like W-salts, Et2AlF, and Ti(O-iPr)4) for aminoly-
sis with the amines and azidolysis using azides of 2,3-epoxy alco-
hols. However, to the best of our knowledge, Magnesium chloride
(MgCl2) promoted C-3 ring opening of 2,3 epoxy alcohols with N-
nucleophiles has not been reported so far. Inspired by these well
developed strategies, we sought to investigate whether the less
expensive and easily available Magnesium chloride (MgCl2)
reagent in catalytic amount could be used for the N-nucleophile
addition reaction on 2,3 epoxy alcohols to generate 3-amino-1,2
diols and 3-azido-1,2 diols. Herein, we describe highly efficient
regioselective aminolysis of 2,3-epoxy alcohols with diverse
aromatic as well as aliphatic amines and azidolysis of 2,3-epoxy
alcohols azides using catalytic amount of Magnesium chloride
(MgCl2).Scheme 1.
⇑
Corresponding author.
E-mail
addresses:
gautam.panda@gmail.com,
gautam_panda@cdri.res.in
(G. Panda).
https://doi.org/10.1016/j.tetlet.2021.153013
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
Scheme 1. Ring opening of 2,3 epoxy alchohol.
product (entry 8 and 20 of table 1). Moreover, product yield was
slightly reduced when amount of MgCl2 increased from 15 mol%
to 20 mol%. It indicated that 15 mol% of MgCl2 was found to be suf-
ficient for aminolysis and azidolysis. Next, a brief solvent screening
was undertaken to explore the possibility of using various organic
solvents for the reaction. Thus, the optimization studies were car-
ried out using different organic solvents such as Acetonitrile (ACN),
Dimethyl sulfoxide (DMSO) and Toluene. Among them, except
DMSO, almost all the solvents were found to be admissible. Nota-
bly, the reaction in the presence of toluene and DMF were found to
be most efficient solvents. Moreover, 15 mol% of MgCl2 was found
superior in Azidolysis of trans (3-phenyloxiran-2-yl)methanol (1a)
as compared to known NH4Cl reagent for Azidolysis (entry-19 of
Table 1).
Using the set of optimized reaction conditions, the scope of this
MgCl2 catalyzed ring-opening reaction of various 2,3-epoxy alco-
hols with respect to different kinds of N- nucleophiles was
explored as shown in Table 2. Firstly, disubstituted 2,3-epoxy alco-
hol was introduced with divergent N- nucleophiles under the opti-
mized reaction conditions, and afforded the desired products in
Results and discussion
In order to accomplish our deliberate approach for ring opening
of 2,3-epoxy alcohols with both diverse organic N-Nucleophiles
and sodium azide, we began our investigation using racemic trans
(3-phenyloxiran-2-yl)methanol (1a) and aniline as standard sub-
strates. Initially, the reaction of 1a and aniline in the absence of
MgCl2 was carried out at room temperature for 8 h followed by
heating at 80 °C for another 8 h in DMF as solvent but no ring-
opening reaction occurred. Similarly, azidolysis of racemic trans
(3-phenyloxiran-2-yl)methanol (1a) with sodium azide in absence
of MgCl2 was also not observed. Delightfully, when the reaction
was performed with 10 mol% MgCl2 at room temperature, trans
(3-phenyloxiran-2-yl)methanol (1a) afforded 3-amino-1,2 diol
(50% yield) and 3-azido-1,2 diol (45% yield) with Aniline and
Sodium azide respectively as confirmed by 1H and 13C NMR. In
order to enhance the product yield and rate of reaction, the reac-
tion of trans (3-phenyloxiran-2-yl)methanol (1a) was performed
at 80 °C with 15 mol% of MgCl2 with Aniline and sodium azide sep-
arately which results in drastic change in conversion to desired
2

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
Table 1
Optimization of the Reaction Conditions.
Entry
N-Nucleophile
X
solvent
Temperaturea
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Aniline
Aniline
Sodium azide
Sodium azide
Aniline
Aniline
Aniline
Aniline
Aniline
Sodium azide
Sodium azide
Sodium azide
Aniline
Sodium azide
Aniline
Sodium azide
Aniline
Sodium azide
Sodium azide
–
–
–
–
10
15
15
15
20
10
15
20
15
15
15
15
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
Toluene
Acetonitrile
Acetonitrile
DMSO
DMSO
DMF
rt
80
rt
80
rt
rt
8
8
8
8
3
3
16
0.5
0.5
4
2
2
0.5
2
4
4
4
4
16
NR
NR
NR
NR
50
65
71
93
89
45
90
85
88
84
61
58
35
30
70
rt
80
80
rt
9
10
11
12
13
14
15
16
17
18
19
80
80
80
80
80
80
80
80
80
15
15
NH4Cl (15 mol%)
aTemperature in Degree Celsius; bisolated yield as separated from PTLC; NR = No Reaction.
excellent yields (2aa-2al, 2b and 2c). Notably, the reaction with 4-
(methylthio)aniline, 4-Aminobiphenyl, 3,4-(Methylenedioxy)ani-
line, and aniline provided the respective 3-amino-1,2 diols very
smoothly. Additionally, the reaction was also carried out with
3,4-dimethoxyaniline, 2,6-dimethoxyaniline, 2,5-dimethylaniline,
and benzyl amine to afford the corresponding product in excellent
yields. Pleasingly, the reaction worked well with aniline having
electron withdrawing at para- position and the desired product
(2ag) was isolated in 70% yield. It is worth noting that, the hetero-
aryl 5-bromopyridin-2-amine underwent smooth transformation
leading to product (2ah) in admirable yield (68%). The ring open-
ing was smoothly carried out with most interesting 2-aminophenol
as nucleophile and free hydroxyl group of 2-aminophenol was not
interfering the epxide ring opening. Additionally, Regioselective C-
3 ring opening for resulted compound 2al was confirmed by
13C–1H heteronuclear long-range correlations (Fig. 1). Long-range
correlation between Ha (d = 3.24 ppm), Hb (d = 4.68 ppm), Hc
(d = 5.06 ppm), He (d = 4.48 ppm), Hf (d = 5.48 ppm), and C2
(d = 74.13 ppm) along with the long-range correlation between
Hb (d = 4.68 ppm), Hc (d = 5.06 ppm), Hd (d = 3.88 ppm), and C1
(d = 63.30 ppm) supports the C-3 ring opening of epoxide. Here
In the next phase of our investigation, more sterically hindered
multifarious trisubstituted 2,3 epoxy alcohols were introduced and
examined the scope of various N- nucleophiles under the opti-
mized reaction conditions. It was observed that trisubstituted 2,3
epoxy alcohols (1d-i) underwent smoothly to Azidolysis for 3-
azido-1,2 diols (2d, 2ec, 2fa, 2 g, 2 h and 2i) and Aminolysis for
the 3-azido-1,2 diols (2ea, 2eb and 2fb) in reasonably good to
excellent yields (Table 3). Epoxy ring of (2,3-diphenyloxiran-2-yl)
methanol (1e) was successfully opened with aniline and benzyl
amine as nucleophile through the optimized reaction to furnish
3-amino-1,2 diols (2ea and 2eb) in admirable yields. Similarly, ani-
line opened the ring of more crowded (2-(naphthalen-1-yl)-3-(p-
tolyl)oxiran-2-yl)methanol (1f) very gently to accomplish 2fb in
72% yield.
Finally, the optimized reaction was applied over commercially
available enantiomerically pure (S)-(-) Glycidol. As
a result,
compounds 3 (89%) and 4 (85%) were synthesized successfully by
using sodium azide and Aniline as N-nucleophile respectively
(table 4).
the possibility of regioselctive C-2 ring opening could be ignored
because of observed long-range correlation between Hc
(d = 5.06 ppm), and C1 (d = 63.30 ppm) which would be feasible
only in C-3 ring opening.
Interestingly, electron withdrawing group containing disub-
stited 2,3-epoxy alcohol (1b) was also reacted efficiently with
sodium azide in presence of catalytic amount of MgCl2 to afford
the corresponding 3-azido-1,2 diol (2b) in 84% yield. Moreover,
disubstited 2,3-epoxy alcohol with long aliphatic side chain (1c)
was cleanly reacted with 4-(methylthio)aniline to furnish 2c in
82% of yield.
Plausible Mechanism:
In general, when Lewis acid coordinates with oxirane oxygen, it
was found that Lewis acid induces polarization of the oxirane C–C
bond and enhances the electrophilicity of these two carbon atoms.
In the consequence, nucleophilic [23,24] attack at epoxide ring was
more accessible. In this study, the Mg coordinated with the epox-
ide oxygen [25] and the oxygen of hydroxyl group at C-1 carbon
in a rigid, bidentate manner, which facilitated the ring opening of
2,3-epoxy alcohols with diverse N- Nucleophile (Scheme 2).
3

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
Table 2
Substrate scope for disubstituted 2,3-epoxy alcohols.a,b,c
N-Nucleophile (1 equiv),
MgCl2(15 mol%)
Nu
O
OH
OH
OH
R
R
80°C, DMF,
30 min -16h
1a-c
2aa-2al, 2b and 2c
O
O
N3
NH
OH
NH
OH
OH
NH
OH
OH
2ab
(90%, 2h)
OH
OH
2aa
2ad
2ac OH
(92%, 6h)
(93%, 30 min)
(85%, 16h)
O
O
Br
Br
O
NH
NH
N
NH
NH
O
OH
OH
OH
OH
OH
OH
OH
OH
2ag
(70%, 12h)
2ah
(68%, 12h)
2af
(80%, 16h)
2ae
(88%, 16h)
S
OH
NH
NH
NH
OH
NH
OH
OH
OH
OH
OH
OH
(95%, 2h)
2ai
OH
2al
(91%, 4h)
2aj
(92%, 4h)
2ak
(78%, 8h)
S
N3
OH
OH
NH
2c
OH
OH
F
2b
(84%, 6h)
(82%, 8h)
aReactions were performed on racemic 2,3-epoxy alcohols 1.0 equiv, anilines/sodium azide 1.0 equiv and 15 mol% MgCl2 at 80 °C in DMF MeCN. bYields were calculated after
c
separation through manual column chromatography. One regioisomer could be detected by 1H NMR spectroscopy analysis.
4

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
Hf = 5.48 ppm
Hf
OH
OH
Hf
Hc= 5.06 ppm
N He
O
Hc
N
He
O
Hc
O
C2= 74.13 ppm
Hd= 3.88 ppm
2
2
3
3
C3= 58.75 ppm
He= 4.48 ppm
Hd
Hd
O
1
Ha
Ha
1
Ha
Hb
Hb
Ha
Hb= 4.68 ppm
C1= 63.30 ppm
Ha= 3.24 ppm
B
A
Fig. 1. (A) 13C–1H HMBC correlations of 2al are shown between Hf, Hc, Hb, He and Ha with C2; (B) 13C–1H HMBC correlations of 2al are shown between Hc, Hb and Hd, with C1.
5

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
Table 3
Substrate scope for disubstituted 2,3-epoxy alcohols.a,b,c
N-Nucleophile (1 equiv),
MgCl2(15 mol%)
Nu
R1
O
OH
OH
OH
R
R
R1
80°C, DMF,
30 min -16h
1d-i
2d, 2ea-c, 2fa-b, 2g, 2h,2i
N
N
3OH
3OH
2ec
NH
HO
OH
OH
HN
OH
OH
OH
2d
(75%, 4h)
2ea
(80%, 8h)
(79%, 8h)
2eb
(78%, 8h)
N
N
O
N
3OH
3OH
3OH
NH
OH
F
OH
OH
OH
OH
2h
(64%, 12h)
2fa
(65%,12h)
2g
(60%,16h)
2fb
(72%, 12h)
N
3OH
OH
2i
(69%, 12h)
aReactions were performed on Mixture of Cis/Trans racemic 2,3-epoxy alcohols 1.0 equiv, anilines/sodium azide 1.0 equiv and 15 mol% MgCl2 at 80 °C in DMF MeCN. bYields
were calculated after separation through manual column chromatography. cOne regioisomer could be detected by 1H NMR spectroscopy analysis.
Table 4
Epoxide ring opening (S)-(-) Glycidol by NaN3 and anilinea.
Aniline(1 equiv),
NaN3 (1 equiv),
MgCl2(15 mol%)
MgCl2(15 mol%)
80°C, DMF,
90 min
OH
80°C, DMF,
90 min
OH
OH
H
N
(S)
HO
HO
N3
(R)
O
(R)
(S)-(-)-Glycidol
3
(89%)
4
(85%)
aOne regioisomer could be detected by 1H NMR spectroscopy analysis.
3-amino-1,2 diols and 3-azido-1,2 diols in good to excellent yields.
Interestingly, this strategy was also found suitable for trisubsti-
tuted 2,3 epoxy alcohols to generate quaternary carbon containing
3-amino-1,2 diols. Application of this methodology towards syn-
thesis of natural products having quaternary carbon is underway
and will be reported elsewhere.
Conclusion
In conclusion, we systematically studied the MgCl2 catalyzed
regioselective C-3 ring-opening reactions of various 2,3 epoxy alco-
hols. Only MgCl2 in catalytic amount provides epoxide ring open-
ing by both organic amines and sodium azide for facile access to
6

A. Kumar and G. Panda
Tetrahedron Letters 70 (2021) 153013
MgCl2
O
OH
O
OH
R
OH
R
R
OH
OH
O
H3O
1
3
2
R
Or
R1
Nu R1
Nu R1
Nu R1
HCl
Cl
Mg
O
HCl
R
O
Nu R1
Cl
Mg
O
O
R
R1
Scheme 2. Plausible Mechanism of Epoxide ring opening by N- Nucleophile.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The authors thank Department of Science & Technology (DST;
CRG/2019/000489) for financial support. Instrumental facilities
from SAIF, CDRI are highly appreciated. Amit Kumar thanks CSIR
for providing fellowship (NET-SRF). This has CDRI communication
no 10220.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153013.
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