Nitration-Peroxidation of Alkenes: A Selective Approach to β-Peroxyl Nitroalkanes

Article abstract of DOI:10.1021/acs.orglett.9b00266

Nitration-peroxidation of alkenes for the synthesis of β-peroxyl nitroalkanes has been developed by using tert-butyl nitrite and tert-butyl hydroperoxide. The method presents a new and selective difunctionalization of alkenes to introduce a nitro group and a peroxyl group across the double bonds of alkenes under mild conditions. A radical reaction pathway is proposed by experimental and theoretical studies.

Full text of DOI:10.1021/acs.orglett.9b00266

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nitration−Peroxidation of Alkenes: A Selective Approach to
β‑Peroxyl Nitroalkanes
Yuanjin Chen, Yangyang Ma, Liangkui Li, Hao Jiang, and Zhiping Li*
Department of Chemistry, Renmin University of China, Beijing 100872, China
S
* Supporting Information
ABSTRACT: Nitration−peroxidation of alkenes for the synthesis of
β-peroxyl nitroalkanes has been developed by using tert-butyl nitrite
and tert-butyl hydroperoxide. The method presents a new and
selective difunctionalization of alkenes to introduce a nitro group and
a peroxyl group across the double bonds of alkenes under mild
conditions. A radical reaction pathway is proposed by experimental
and theoretical studies.
itration is a fundamental process for the introduction of
we wish to report an efficient and selective three-component
nitration−peroxidation of alkenes with tert-butyl nitrite (t-
BuONO, TBN)10 and tert-butyl hydroperoxide (t-BuOOH,
TBHP) to afford β-peroxy nitro compounds (Scheme 1, eq
3).11,12
We optimized the reaction conditions by the reactions of
TBHP (1), styrene (2a), and NO2 sources (3) (Table 1). The
screening of metal catalysts (entries 1−8) revealed that
Mn(OAc)3·2H2O is the best catalyst and afforded the desired
nitration−peroxidation product 4a in 94% yield (entry 8). The
efficiency of the transformation was reduced when other
solvents were used instead of acetonitrile (entries 9−12).
Notably, a 54% yield of 4a was obtained without a metal
catalyst (entry 13). In addition, other NO2 precursors were
investigated and not applicable for the present transformation
(entries 14−18).
Next, we explored the scope of alkenes 2 in the nitration−
peroxidation of alkenes (Scheme 2). The electronic effect of
the substituents on the phenyl ring of styrenes showed no
obvious influences, and the desired products (4a−4j) were
obtained in good yields. 2,3,4,5,6-Pentafluorostyrene (2k) gave
the desired product (4k) in a slightly lower yield. 2,4,6-
Trimethylstyrene (2l) afforded an 86% yield of 4l.
Furthermore, α-substituted styrenes were well applied to give
the corresponding products (4m−4r). Cyclic alkenes also
delivered the nitration−peroxidation products (4s−4u) with
excellent diastereoselectivity, albeit in moderate yields.
Acrylate derivatives also led to the corresponding nitration−
peroxidation products (4v−4z).13 Allyl methacrylate (2z)
bearing an unconjugated double bonds delivered the
regioselective product (4z) in 34% yield. Notably, the
biologically active compounds, salicylate and estrone deriva-
tives (5a and 5b), were converted to the desired products (6a
and 6b) in 63% and 51% yields, respectively (eq 4). Both E-7
and Z-7 gave 8 with the same diastereoselectivity (eq 5),
1,2
Nthe nitro group (−NO ) into organic molecules.
2
Electrophilic and nucleophilic substitution using a nitronium
+
−
cation (NO2 ) and nitrite anion (NO2 ) are well-established
methods to synthesize nitro compounds. However, these
nitration reactions have drawbacks, such as difficulties in
handling nitration reagents and the limitation of the substrates.
Recently, radical addition of nitrogen dioxide (·NO2) to a
carbon−carbon double bond is growing as a practical strategy
for synthesis of nitroalkenes3 and cyclic nitroalkanes.4,5
Three-component difunctionalization of alkenes is a class of
powerful synthetic reactions.6 Nevertheless, radical difunction-
alization of alkenes to introduce a nitro group and another
different functional group is a distinct challenge due to the
chemo-/regioselectivity of the reactions. To date, only a few
three-component nitration reactions of alkenes have been
reported,7 while the selective reactions are rare. The oxidative
nitration of alkenes using tert-butyl nitrite and molecular
oxygen presents a novel difunctionalization of alkenes, while β-
nitro alcohols and/or their nitrate derivatives were obtained
depending on the structures of alkenes (Scheme 1, eq 1).8
Arguably, the most selective difunctionalization, the halo-
nitration of alkenes, was achieved by using iron(III) nitrate
nonahydrate and halogen salt (Scheme 1, eq 2).9 The method
is well applied for the simple alkenes. However, active alkenes
such as styrenes and acrylates showed lower selectivity. Herein,
Scheme 1. Three-Component Nitration of Alkenes
Received: January 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00266
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Alkenes 2
b
entry
catalyst
FeCl2
FeCl3
CoCl2
AgNO3
CuI
Cu(OAc)2
MnBr2
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
−
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
NO2 source
t-BuONO
solvent
4a (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
36
8
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
Fe(NO3)3·9H2O
(NH4)2Ce(NO3)6
AgNO2
48
70
53
50
76
94
63
60
56
22
54
ND
ND
8
9
10
11
12
13
14
15
16
17
18
DCM
THF
HOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
AgNO3
NaNO2
ND
c
10
a
Reaction conditions: 1 (in decane, 1.5 mmol), 2a (0.5 mmol), 3 (1.0
mmol), catalyst (10 mol %), solvent (2.0 mL), rt, 5 h, under N2,
b
unless otherwise noted. Reported yields were based on 2a and
c
1
determined by H NMR using an internal standard. K2S2O8 (0.65
mol), HOAc (0.5 mL), MeCN (1.5 mL).
a
Reaction conditions: 1 (in decane, 1.5 mmol), 2 (0.5 mmol), 3a (1.0
mmol), Mn(OAc)3·2H2O (10 mol %), MeCN (2.0 mL), rt, 5 h,
b
1
under N2. Reported yields were based on 2 and determined by H
NMR using an internal standard; isolated yields were given in
c
parentheses. d.r. > 20:1.
In addition, the reaction of vinylcyclopropane 9 with 1 and 3a
was performed to afford the ring-opening product 10 (Scheme
3b). These results suggested that the reaction most likely
undergoes a radical pathway. When the reactions were carried
out in the absence of 1 or 3a, the products 113 and 1214 were
obtained (Scheme 3c and 3d). The result indicated that both
nitrogen dioxide (·NO2) and a peroxyl radical (·OOBu-t or
Mn-OOBu-t) could attack the double bond of alkene. In order
to provide an explanation for the chemoselectivity of the
reaction, DFT calculation was carried out (Scheme 4).15 The
results suggested that the attack of ·NO2 to styrene has the
lowest energy. Furthermore, the reaction of 1 and 11 could not
provide the desired product 4a (Scheme 3e). This result
excludes the nitroalkene 11 as an intermediate of the
reaction.16
indicating that peroxidation is most likely the rate-determining
step of the reaction. To our delight, the reaction could be
carried out in gram-scale synthesis without loss of its efficiency
(eq 6).
In order to understand the possible reaction mechanism, the
control experiments were carried out (Scheme 3). The
formation of 4a was suppressed when a radical scavenger,
such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or 2,6-
di-tert-butyl-4-methylphenol (BHT), was added (Scheme 3a).
β-Peroxy nitro products (4) could be converted to the Boc-
protected 2-amino-1-phenylethanols (13) smoothly through
hydrogenation and protection (Scheme 5). In particular, a two-
B
DOI: 10.1021/acs.orglett.9b00266
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Mechanistic Studies
Scheme 6. Tentative Reaction Mechanism
BuONO, 3a)4,5,8,18 and tert-butyl hydroperoxide (t-BuOOH,
1)14 separately (Scheme 6a and 6b). Nitrogen dioxide (·NO2)
adds to alkene (2a) to give the key intermediate A, followed by
the radical coupling with a peroxyl radical (·OOBu-t or Mn-
OOBu-t) to give the final product (4a) (Scheme 6c).
In summary, we have demonstrated the nitration−
peroxidation of alkenes. The protocol provides facile access
to a variety of β-peroxyl nitroalkanes by using readily available
reagents (tert-butyl nitrite and tert-butyl hydroperoxide) and a
range of alkenes under mild conditions. A selective radical
reaction pathway is proposed by experimental and theoretical
studies. Vicinal amino alcohol derivatives could be obtained by
the reduction of the obtained β-peroxyl nitroalkanes.
Scheme 4. DFT Calculation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00266.
Experimental procedures and spectral data for all new
compounds (PDF)
Scheme 5. Examples for Synthesis of 2-Amino-1-
phenylethanols 13
a b c
, ,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhipingli@ruc.edu.cn.
ORCID
Zhiping Li: 0000-0001-7987-279X
Notes
The authors declare no competing financial interest.
a
Reaction conditions: 4 (0.5 mmol), Pd/C (10%), MeOH (2.0 mL),
ACKNOWLEDGMENTS
Financial support from the National Natural Science
Foundation of China (21672259).
b
■
H2 (balloon), rt, 5 h. NaHCO3 (1.0 mol), Boc2O (0.6 mol), MeOH
(2.0 mL), rt, under air, 3 h. Isolated yields.
c
step procedure through hydrogenation and acylation without
intermediate purification provided a 51% yield of tembamide
(14) (eq 7), which exhibits good hypoglycemic activity as well
as anti-HIV activity.17
Based on our results and literature, a possible mechanism for
the nitration-peroxidation of alkenes was proposed (Scheme
6). Nitrogen dioxide (·NO2) and peroxyl radicals (·OOBu-t
and Mn-OOBu-t) are generated from tert-butyl nitrite (t-
REFERENCES
■
(1) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Feuer, H.; Nielsen, T. Nitro compound: Recent
Advances in Synthesis and Chemistry; VCH: New York, 1990.
(2) (a) Ballini, R.; Palmieri, A. Synthetic Procedures for the
Preparation of Nitroalkanes. Adv. Synth. Catal. 2018, 360, 2240−
2266. (b) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods
and Mechanisms; VCH Publishers Inc.: New York, 1989.
C
DOI: 10.1021/acs.orglett.9b00266
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Organic Letters
Letter
(3) (a) Naveen, T.; Maity, S.; Sharma, U.; Maiti, D. A Predictably
Selective Nitration of Olefin with Fe(NO3)3 and TEMPO. J. Org.
Chem. 2013, 78, 5949−5954. (b) Manna, S.; Jana, S.; Saboo, T.; Maji,
A.; Maiti, D. Synthesis of (E)-nitroolefins via decarboxylative nitration
using t-butylnitrite (t-BuONO) and TEMPO. Chem. Commun. 2013,
49, 5286−5288. (c) Maity, S.; Naveen, T.; Sharma, U.; Maiti, D.
Chloride and Acrylic Systems1. J. Am. Chem. Soc. 1952, 74, 3052−
3056.
(8) Taniguchi, T.; Yajima, A.; Ishibashi, H. Oxidative Nitration of
Alkenes with tert-Butyl Nitrite and Oxygen. Adv. Synth. Catal. 2011,
353, 2643−2647.
(9) (a) Taniguchi, T.; Fujii, T.; Ishibashi, H. Iron-Mediated Radical
Halo-Nitration of Alkenes. J. Org. Chem. 2010, 75, 8126−8132.
(b) Taniguchi, T.; Ishibashi, H. Iron-Mediated Radical Nitro-
Cyclization Reaction of 1,6-Dienes. Org. Lett. 2010, 12, 124−126.
(10) (a) Li, P.; Jia, X. tert-Butyl Nitrite (TBN) as a Versatile Reagent
in Organic Synthesis. Synthesis 2018, 50, 711−722. (b) Wei, W.; Zhu,
W.; Wu, Y.; Huang, Y.; Liang, H. Progress in C-N Bonds Formation
Using t-BuONO. Youji Huaxue 2017, 37, 1916−1923.
t
Stereoselective Nitration of Olefins with BuONO and TEMPO:
Direct Access to Nitroolefins under Metal-free Conditions. Org. Lett.
2013, 15, 3384−3387. (d) Maity, S.; Manna, S.; Rana, S.; Naveen, T.;
Mallick, A.; Maiti, D. Efficient and Stereoselective Nitration of Mono-
and Disubstituted Olefins with AgNO2 and TEMPO. J. Am. Chem.
Soc. 2013, 135, 3355−3358.
(4) (a) Shen, T.; Yuan, Y.; Jiao, N. Metal-free nitro-carbocyclization
of activated alkenes: a direct approach to synthesize oxindoles by
cascade C-N and C-C bond formation. Chem. Commun. 2014, 50,
554−556. (b) Li, Y.-M.; Wei, X.-H.; Li, X.-A.; Yang, S.-D. Metal-free
carbonitration of alkenes using K2S2O8. Chem. Commun. 2013, 49,
11701−11703. (c) Li, Y.-M.; Shen, Y.; Chang, K.-J.; Yang, S.-D.
Arylnitration of alkenes by nitration/C-H functionalization cascade
using AgNO3 and HOAc. Tetrahedron Lett. 2014, 55, 2119−2122.
(d) Liu, Y.; Zhang, J.-L.; Song, R.-J.; Qian, P.-C.; Li, J.-H. Cascade
Nitration/Cyclization of 1,7-Enynes with tBuONO and H2O: One-
Pot Self-Assembly of Pyrrolo[4,3,2-de]quinolinones. Angew. Chem.,
Int. Ed. 2014, 53, 9017−9020. (e) Deng, G.-B.; Zhang, J.-L.; Liu, Y.-
L.; Liu, B.; Yang, X.-H.; Li, J.-H. Metal-free nitrative cyclization of N-
aryl imines with tert-butyl nitrite: dehydrogenative access to 3-
nitroindoles. Chem. Commun. 2015, 51, 1886−1888. (f) Wei, W.-T.;
Ying, W.-W.; Bao, W.-H.; Gao, L.-H.; Xu, X.-D.; Wang, Y.-N.; Meng,
X.-X.; Chen, G.-P.; Li, Q. Regioselective Nitrative Cyclization of 1,6-
Enynes with t-BuONO under Metal-Free Conditions. ACS Sustainable
Chem. Eng. 2018, 6, 15301−15305.
(5) For reviews on radical nitration, see: (a) Luo, J.; Wei, W.-T.
Recent Advances in the Construction of C-N Bonds Through
Coupling Reactions between Carbon Radicals and Nitrogen Radicals.
Adv. Synth. Catal. 2018, 360, 2076−2086. (b) Yan, G.; Yang, M.
Recent advances in the synthesis of aromatic nitro compounds. Org.
Biomol. Chem. 2013, 11, 2554−2566. (c) Stepanov, A. V.; Veselovsky,
V. V. Reactions of alkenes with nitrogen oxides and other nitrosating
and nitrating reagents. Russ. Chem. Rev. 2003, 72, 327−341.
(11) For a review on peroxidation of alkenes, see: Gandhi, H.;
O’Reilly, K.; Gupta, M. K.; Horgan, C.; O’Leary, E. M.; O’Sullivan, T.
P. Advances in the synthesis of acyclic peroxides. RSC Adv. 2017, 7,
19506−19556.
(12) Our work on three-component peroxidation of alkenes:
(a) Chen, Y.; Tian, T.; Li, Z. Mn-Catalyzed Azidation-Peroxidation
of Alkenes. Org. Chem. Front. 2019, DOI: 10.1039/C8QO01231H.
(b) Xu, R.; Li, Z. Ag-catalyzed sulfonylation-peroxidation of alkenes
with sulfonyl hydrazides and T-hydro. Tetrahedron Lett. 2018, 59,
3942−3945. (c) Lu, S.; Tian, T.; Xu, R.; Li, Z. Fe- or co-catalyzed
silylation-peroxidation of alkenes with hydrosilanes and T-hydro.
Tetrahedron Lett. 2018, 59, 2604−2606. (d) Chen, Y.; Chen, Y.; Lu,
S.; Li, Z. Copper-catalyzed three-component phosphorylation−
peroxidation of alkenes. Org. Chem. Front. 2018, 5, 972−976.
(e) Lu, S.; Qi, L.; Li, Z. Cobalt-Catalyzed Alkylation-Peroxidation
of Alkenes with 1,3-Dicarbonyl Compounds and T-Hydro. Asian J.
Org. Chem. 2017, 6, 313−321. (f) Zong, Z.; Lu, S.; Wang, W.; Li, Z.
Iron-catalyzed alkoxycarbonylation−peroxidation of alkenes with
carbazates and T-Hydro. Tetrahedron Lett. 2015, 56, 6719−6721.
(g) Liu, K.; Li, Y.; Zheng, X.; Liu, W.; Li, Z. Synthesis of α-ester−β-
keto peroxides via iron-catalyzed carbonylation−peroxidation of α,β-
unsaturated esters. Tetrahedron 2012, 68, 10333−10337. (h) Liu, W.;
Li, Y.; Liu, K.; Li, Z. Iron-Catalyzed Carbonylation-Peroxidation of
Alkenes with Aldehydes and Hydroperoxides. J. Am. Chem. Soc. 2011,
133, 10756−10759.
(13) The optimization of the reaction conditions was provided in
the Supporting Information.
(6) For representative reviews, see: (a) Lan, X.; Wang, N.; Xing, Y.
Recent Advances in Radical Difunctionalization of Simple Alkenes.
Eur. J. Org. Chem. 2017, 2017, 5821−5851. (b) Yi, H.; Zhang, G.;
Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent Advances
in Radical C−H Activation/Radical Cross-Coupling. Chem. Rev. 2017,
117, 9016−9085. (c) Studer, A.; Curran, D. P. Catalysis of Radical
Reactions: A Radical Chemistry Perspective. Angew. Chem., Int. Ed.
2016, 55, 58−102. (d) Kindt, S.; Heinrich, M. R. Recent Advances in
Meerwein Arylation Chemistry. Synthesis 2016, 48, 1597−1606.
(e) Cao, M. Y.; Ren, X.; Lu, Z. Olefin difunctionalizations via visible
light photocatalysis. Tetrahedron Lett. 2015, 56, 3732−3742.
(7) (a) Tang, L.; Yang, Z.; Chang, X.; Zou, G.; Zhou, Y.; Rao, W.;
Ma, X.; Zhao, G. Water-controlled nitro-oximation of alkenes under
catalyst-free conditions. Tetrahedron Lett. 2018, 59, 4272−4275.
(b) Sau, P.; Santra, S. K.; Rakshit, A.; Patel, B. K. tert-Butyl Nitrite-
Mediated Domino Synthesis of Isoxazolines and Isoxazoles from
Terminal Aryl Alkenes and Alkynes. J. Org. Chem. 2017, 82, 6358−
6365. (c) Cao, Q.; Liu, J.; Yu, L.; Gui, Q.; Chen, X.; Tan, Z. Synthesis
of α-Nitro Ketoximes from Styrenes and tert-Butyl Nitrite. Synth.
Commun. 2015, 45, 2181−2187. (d) Grossi, L.; Montevecchi, P. C.;
Strazzari, S. The Chemistry of Peroxynitrite: Involvement of an ET
Process in the Radical Nitration of Unsaturated and Aromatic
Systems. Eur. J. Org. Chem. 2001, 2001, 741−748. (e) Lewis, R. J.;
Moodie, R. B. The nitration of styrenes by nitric acid in
dichloromethane. J. Chem. Soc., Perkin Trans. 2 1997, 2, 563−567.
(f) Suzuki, H.; Mori, T. Side-Chain Nitration of Styrene and Para-
Substituted Derivatives with a Combination of Nitrogen Dioxide and
Ozone. J. Org. Chem. 1997, 62, 6498−6502. (g) Shechter, H.; Conrad,
F.; Daulton, A. L.; Kaplan, R. B. Orientation in Reactions of Nitryl
(14) Terent’ev, A. O.; Sharipov, M. Y.; Krylov, I. B.; Gaidarenko, D.
V.; Nikishin, G. I. Manganese triacetate as an efficient catalyst for
bisperoxidation of styrenes. Org. Biomol. Chem. 2015, 13, 1439−1445.
(15) Shi, E.; Liu, J.; Liu, C.; Shao, Y.; Wang, H.; Lv, Y.; Ji, M.; Bao,
X.; Wan, X. Difunctionalization of Styrenes with Perfluoroalkyl and
tert-Butylperoxy Radicals: Room Temperature Synthesis of (1-(tert-
Butylperoxy)-2-perfluoroalkyl)-ethylbenzene. J. Org. Chem. 2016, 81,
5878−5885.
(16) (a) Lu, X.; Deng, L. Catalytic Asymmetric Peroxidation of α,β-
Unsaturated Nitroalkenes by a Bifunctional Organic Catalyst. Org.
Lett. 2014, 16, 2358−2361. (b) Russo, A.; Lattanzi, A. Catalytic
Asymmetric β-Peroxidation of Nitroalkenes. Adv. Synth. Catal. 2008,
350, 1991−1995.
(17) Cortez, N. A.; Aguirre, G.; Parra-Hake, M.; Somanathan, R.
Synthesis of (R)-tembamide and (R)-aegeline via asymmetric transfer
hydrogenation in water. Tetrahedron: Asymmetry 2013, 24, 1297−
1302.
(18) Lin, Y.; Kong, W.; Song, Q. Palladium-Catalyzed Nitration of
Meyer−Schuster Intermediates with tBuONO as Nitrogen Source at
Ambient Temperature. Org. Lett. 2016, 18, 3702−3705.
D
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