mCPBA-mediated dioxygenation of unactivated alkenes for the synthesis of 5-imino-2-tetrahydrofuranyl methanol derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.152620

A mCPBA-mediated, metal-free, intramolecular dioxygenation reaction of unactivated alkenes is reported. In the presence of m-chlorobenzoic peracid, different unsaturated amide substrates could be cyclized via epoxide intermediates, producing the corresponding 5-imino-2-tetrahydrofuranyl methanol products in up to 94% yield at room temperature.

Full text of DOI:10.1016/j.tetlet.2020.152620

Journal Pre-proofs
mCPBA-mediated Dioxygenation of Unactivated Alkenes for the Synthesis of
5-Imino-2-tetrahydrofuranyl Methanol Derivatives
Xiaojun Deng, Luwen Zhang, Huixia Liu, Yu Bai, Wei He
PII:
S0040-4039(20)31123-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152620
TETL 152620
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 June 2020
27 October 2020
28 October 2020
Please cite this article as: Deng, X., Zhang, L., Liu, H., Bai, Y., He, W., mCPBA-mediated Dioxygenation of
Unactivated Alkenes for the Synthesis of 5-Imino-2-tetrahydrofuranyl Methanol Derivatives, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152620
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1
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
mCPBA-mediated Dioxygenation of Unactivated Alkenes for the Synthesis of
5-Imino-2-tetrahydrofuranyl Methanol Derivatives
Xiaojun Deng, Luwen Zhang, Huixia Liu, Yu Bai, Wei He*
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mCPBA-mediated, metal-free, intramolecular dioxygenation reaction of unactivated
alkenes is reported. In the presence of m-chlorobenzoic peracid, different unsaturated
amide substrates could be cyclized via epoxide intermediates, producing the
corresponding 5-imino-2-tetrahydrofuranyl methanol products in up to 94% yield at
room temperature.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
metal-free, mCPBA,
1,2-Diol, dioxygenation,
pentenamides
Introduction
For example, aryliodine compounds have been shown to
catalysis the diacetylation of alkenes,11 and when an
The 1,2-diol structures are important skeletons,
ubiquitously found in pharmaceuticals and their
intermediates, such as the glycoprotein processing inhibitor
swainsonine,1 the anticancer agent anisomycin,2 the
immunomodulator cytoxazone,3 and other bioactive molecules4
(Figure. 1). Since the pioneering work reported by Sharpless,5 a
number of useful strategies for alkene dioxygenation have
been developed for the preparation of such compounds, the
majority of these methods are based on catalysis by
transition metals, such as osmium,6 iron,7 palladium,8
rhodium,9 and others10 (Scheme 1, a). Despite the synthetic
utility, the toxicity and high cost of transition metals limit its
application. Therefore, the developing of new processes in
metal-free manner for dioxygenation of alkenes has become
a hot issue for chemists.
appropriate chiral hypervalent iodine catalyst was used, an
asymmetric reaction could also be achieved (Scheme 1, a).12
In another example, Moriyama13 has described a catalysis
diacetylation by organic selenium compounds, in which in
situ-generated peroxyseleninic acid oxidized C=C double
bonds to epoxides (Scheme 1, b). In addition, Tomkinson has
reported that malonoyl peroxides can mediate alkene
dihydroxylation via
a dioxonium or oxiranium ion
intermediate (Scheme 1, c).14 Finally, in the presence of an
O-centered radical reagent, alkene dihydroxylation can also
proceed in a radical reaction pathway (Scheme 1, d) 15
. Among
the various metal-free methods for dioxygenation of alkenes
mentioned above, substrate adaptability and atomic economy
problems are still exists.
OR3 R1
I
R3O
R1
[O]
- ArI
O
O
ArI(OR3)2
(a)
Ar
OAc
R2
[O]
O
R1
R2
R2
HO
HN
OH
OAc
OH
OMe
H
[O] = -OH, OAc, OSOPh...
O
OH
OH
OH
N
N
H2O
OH
R2
OH
MeO
H
O
R2
RSe(O)OOH
R1
or
R1
(b)
anisomycin
swainsonine
cytoxazone
R1
R2
1,2 diol product
R2
OH
O
R1
HO
HO
N
H
O
HO2C
H2N
HO
O
6
5
OH
Malonoyl
peroxides
O
O
OH
hydrolysis
R1
O
R2 (c)
OH
OH
Ph
R1
O
myriocin
castanospermine
O
OH
O
Ph
R2
R1
O
Figure. 1 Biologically active compounds containing 1,2-diols
O-centered
radical regent
R2
structures.
R4
R2
OR4
(d)
R3
O
R1
O R3
Scheme. 1 Metal-free strategies used for dioxygenation of alkenes.

2
Results and discussion
showed that the mCPBA/HNTs2/HFIP system was optimal
for 1a dioxygenation.
Inspired by the works aboat mCPBA-mediated alkene
aminohydroxylation reactions.16-17 We reasoned that the
cyclohydroxylation may be generated through a tandem
epoxidation and epoxide ring-opening sequence. Compared
with aryliodine or selenium catalyzed methods, the
mCPBA-mediated process is more simple and effective. In
Table 1 Optimization of reaction conditions.a
Z
N
O
Me
Me
Conditions
O
NHZ
Me Me
OH
1a
2a
the
initial
investigation,
Oxidant
2a
Entry
Solvent
Additive (equiv.)
N-phenyl-2,2-dimethyl-4-pentenamide 1a was chosen as a
model substrate. The reaction parameters including the
oxidants, additives, and solvents, were examined to
determine the optimal reaction conditions, and the results
are summarized in Table 1. The reaction could be carried
out at room temperature in hexafluoroisopropanol (HFIP),
and HNTs2 was essential for the transformation, as a low
yield was obtained in the absence of HNTs2 (entry 2). Then,
several acid additives were tested, which resulted in reduced
isolated yields (entries 3-6). The solvent screening
(equiv.)
Yield%
1
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
DCM
CH3CN
THF
iPrOH
HFIP
HFIP
HFIP
HFIP
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
mCPBA (1.5)
HNTs2 (1.5)
-
78
8
2
3
TFA (1.0)
60
65
60
16
15
10
-
4
TfOH (1.0)
BF3OEt2 (1.0)
PhCOOH (1.0)
HNTs2 (1.0)
HNTs2 (1.0)
HNTs2 (1.0)
HNTs2 (1.0 )
HNTs2 (1.0)
HNTs2 (1.0)
HNTs2 (1.0)
HNTs2 (1.0)
5
6
7
8
9
10
11
12
13
14
-
determined
that
hexafluoroisopropanol
remarkably
mCPBA (2.0)
DDQ (2.0)
83
-
promoted the transformation, while the use of DCM,
CH3CN, THF or iPrOH as the solvent led to a low reactivity
or not achieving the conversion (entries 7-10). Increasing
the amount of mCPBA to 2.0 equivalents further increased
the yield of 2a to 83% (entry 11). Among the different
oxidants tested, DDQ, AcOOH, and H2O2 were ineffective
for the transformation (entries 12–14). These results clearly
AcOOH (5.0)
H2O2 (5.0)
-
-
aThe reactions were conducted on 0.2 mmol 1a as substrates for 15 h, and
isolated yields are given.
Table 2 Substrate scope.a,
Z
N
R3
O
mCPBA
HNTs2
R1
O
R2
R5
NHZ
R4
OH
HFIP, r.t.
R2 R1
R4
R3
R5
1
2
Substrate
product
Entry
Substrate
Yieldb
Entry
21
Yieldb
Product
2a
, 83%
, 84%
1a
Z = Ph,
Ph
Ph
N Ph
1
2
3
4
5
6
7
Ph Ph
O
Z
2b
1b
1c
1d
1e
1f
1g
Z = p-CH3C6H4,
H
c
N
2u
, 88%, d.r.= 1:1.2
b
N
1u
1v
Z = o-ClC6H4,
Z = m-ClC6H4,
Z = p-ClC6H4,
Z = p-NO2C6H4,
Z = p-CF3C6H4,
2c
2d
2e
, 72%
O
H
Ph
b
N
O
, 65%
Z
b
, 76%
OH
O
OH
b
2f
, 73%
Me
Et
N
Ph
2g
, 80%
d
2v
Et Me
O
, 85%, d,r.= 1:1.2
H
N
O
22
Ph
1h
1i
1j
1k
1l
1m
2h
Z = p-MeC6H4,
, 76%
, 77%
8
9
Z
Z = p-FC6H4,
Z = o-ClC6H4,
Z = m-ClC6H4,
Z = p-ClC6H4,
Z = p-BrC6H4,
N
2i
2j
Ph Ph
OH
H
Ph
Ph
b
10
11
12
13
14
15
, 54%
N
O
Z
b
R
N
Ph
R
R
H
2k
, 51%
R
N
23
24
O
b
2w
1w
1x
, 87%
R= Ph,
R= Et,
2l
, 60%
Ph
OH
O
b
2x
2m
, 83%
, 64%
O
1n
b
Z = OMe,
2n
, 57%
, 75%
OH
1o
Z = Bn,
b
2o
Ph
Ph Ph
Ph
Ph
Ph
N
O
H
N
N
2y
, 85% (1.7 g in 76%)
n
1y
25
H
N
16
17
18
1p
1q
1r
2p
2q
2r
n = 1,
n = 3,
n = 4,
, 84%
, 81%
, 64%
Cl
n
O
Ph
Ph
O
OH
O
Ph
Cl
OH
Ph
Ph
O
N
N
O
Ph
Ph
H
N
Ph Ph
1s
2s
, 73%
d
H
O
1z
2z
, 94% yield,d.r.= 5:1
26
Me
R
N
19
20
O
Ph
O
OH
Ph
O
O
OH
Me
Ph
N
N
Me Me
O
NHPh
1aa
27
28
29
R=H,
R=Cl, 1ab
1ac
2aa
2ab
2ac
H
N
, 85% (2.0 g in 83%)
, 89%
, 78%
R
Me
Me
1t
2t
, 83 %, d,r.=
1:1.4c
O
O
Ph
R=CH3,
OH
OH
aThe reactions were conducted on 0.2 mmol 1 as substrate with HNTs2 (1.0 equiv.) and mCPBA (2.0 equiv.) at room temperature for 15 h, isolated
yield. bReaction time extended to 24 h. cd.r. = diastereoselectivity, as determined by isolated yield. dAs determined by 1H NMR spectrum.

3
With the optimized conditions in hand, various substituted were also compatible with the reaction, generating the
pentenamides were examined. The effects of substituents on the corresponding tetrahydrofuranyl methanol products 2w and 2x
N-phenyl group of 2,2-dimethylpentenamide were initially with quaternary carbon centers in 87% and 83% yields,
tested. The results showed that both electron-rich and respectively. Furthermore, the 2,2,4-triphenyl pentenamide was
electron-deficient
substrates
were
suitable
for
the also applicable to this transiformation, giving 2y in 85% yield,
transiformation, affording the desired five-membered ring and gram-level reaction got a slightly lower yield. Notably, the
dioxygenation products (2a-g) in good yields (65%–84%). internal olefin substrate of 2,2-diphenyl-5-methylpentenamide 1z
Interestingly, compared with the 2,2-dimethyl substituted exhibited better reactivity than the other substrates, giving 2z in
pentenamides, the more highly sterically hindered 2,2-diphenyl up to 94% yield with 5:1 diastereoselectivity. This result further
substrates, giving the corresponding tetrahydrofuranyl indicated that the substituent on the double bond promoted the
methanamine derivatives 2h-m in slightly lower yields (51%– reaction. This promotion is possibly because the methyl
77%). These results indicated that the Thorpe-Ingold effect had substituent stabilized the ethylene oxide intermediate. In
less impact on this transformation, even though the addition, the substituted vinylbenzamide substrates were also
Thorpe-Ingold effect has been observed in a number of catalytic suitable for the dioxygenation (1aa–1ac), and the gram-level
difunctionalizations of alkenes.18 The 2,2-diphenylpentenamides reaction for the synthesis of 2aa was tested, giving 2aa in 85%
with N-methoxyl and N-benzyl protecting groups were found to yield. The electron-withdrawing effect of a chlorine atom
function as suitable substrates for the reaction, giving 2n and 2o substituent was beneficial to obtain a higher yield (2ab, 89%),
in 57% and 75% yields, respectively. Furthermore, substrates while the methyl-substituted product gave a slightly lower yield
with different alkyl ring sizes could also be applied to the (2ac, 78%). This result was possible because the strong
reaction under the standard conditions, giving the corresponding electron-withdrawing chlorine atom substitution on the benzene
spiro-tetrahydrofuranyl methanamine products (2p–r) in 64%– ring increased the nucleophilicity of the carbonyl oxygen.
84% yields. It is noteworthy that a substrate bearing a
heterocycle was also suitable, affording the corresponding
oxybicyclo 2s in good yield. To further investigate the substrate
scope, various unsaturated amides with more complex
substitutions were examined. In these trials, the 2,2,3-trimethyl
pentenamide 1t and 2,2-diphenyl-3-methyl pentenamides 1u
were also tolerated, giving 2t and 2u in good yields with
moderate diastereoselectivity. Furthermore, a substrate bearing a
quaternary carbon center also worked well under the standard
conditions, giving the dioxygenation product 2v in 85% yield
On the basis of these data, a possible reaction mechanism
was developed (Scheme 2). This transformation proceeds via
oxidation of the unsatured amide, which transform into an in
situ-generated epoxide intermediate (Int. 1). Then, the epoxide
intermediate subsequently attacked by the oxygen through TsA,
while the TsB transition state involving an attack by a nitrogen is
unfavorable, because the nitrogen atom in an amide moiety is
usually less nucleophilic than a carbonyl oxygen atom.19 In the
presence of an excess of HNTs2, the cyclization product remains
protonated. Finally, a proton can be abstracted from Int. 2 by
treatment with NaOH to give the neutral product 2z.
with
1:1.2
diastereoselectivity.
Moreover,
N-phenyl-2,2-disubstituted-4-methyl pentenamides 1w and 1x
H
Ph
O
H
Ph
O
NTs2
NaOH (aq.)
PhN
O
N
N
Ph
Ph
Ph
Ph
Ph
Ph
HNTs2
OH
O
OH
Ph Ph
H
Me
2z
Me
Int. 2
Me
TsA
Me
N
Ph Ph
H
Ph
- H2O
Me
N
O
Ph
O
1z
O
O
O
O
H
Ph
Ph
O
H
Int. 1
N
(mCPBA)
Cl
Ph
H
O
Me
TsB, unfavorable
Scheme 2 Plausible reaction mechanism.
In conclusion, we have demonstrated a simple and (2019ZDLSF03-03) and the National Major and
effective mCPBA-mediated dioxygenation of unactivated Technology Projects of China on “Key New Drug Creation
alkenes to afford various 5-imino-2-tetrahydrofuranyl and
Development
Program”
(Project
No.
methanol derivatives, which are important motifs in 2014ZX09J14104-06C). And we also would like to give our
compounds for drug development and biological studies. great thanks to professor Shengyong Zhang for valuable
Notably, the present reaction was conducted at room discussion.
temperature with inexpensive materials, and was tolerated
by a broad range of substrates with good regioselectivity.
Supplementary Material
Acknowledgments
Supplementary data associated this article provided as a
separate electronic file.
We are grateful for the financial support from the Shaanxi
Province Key Research and Development Program

4
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5
Declaration of Interest Statement
We declare that we have no financial and personal
relationships with other people or organizations that can
inappropriately influence our work, there is no
professional or other personal interest of any nature or
kind in any product, service and/or company that could be
construed as influencing the position presented in, or the
review of, the manuscript entitled.
W
2
ei He
020-10-23
Highlights
1. mCPBA-mediated Dioxygenation of unactivated
alkenes
2. High selectivity for 5-imino-2-tetrahydrofuranyl
methanol skeletons
3. Mild reaction conditions and broad substrate
scope
Graphical Abstract
mCPBA-mediated dioxygenation of Unactivated Alkenes for the Synthesis of 5-Imino-2-tetrahydrofuranyl
Methanol Derivatives
Xiaojun Deng, Luwen Zhang, Huixia Liu, Yu Bai, Wei He*
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
Z
N
R3
mCPBA
HNTs2
R1
R2
O
O
R4
OH
R5
NHZ
R2 R1
R4
HFIP, r.t.
R3
R5
Alkene dioxygenation with mild conditions
High selectivity for tetrahydrofuranyl methanol
29 examples, up to 94% yield