Iron-Mediated Azidomethylation or Azidotrideuteromethylation of Active Alkenes with Azidotrimethylsilane and Dimethyl Sulfoxide

Article abstract of DOI:10.1002/adsc.201800078

A radical azidomethylation of various alkenes with azidotrimethylsilane and dimethyl sulfoxide has been achieved under mild reaction conditions, and the method efficiently introduces common and valuable azide and methyl groups into organic compounds. It offers a convenient method for preparing organic azides, which can be easily transformed into related amine derivatives and N-heterocycles. Control experiments such as capturing of the intermediate and gram-scale reactions of the developed system as well as further transformations of the products of the reaction are presented. And a free radical is involved in the reaction process. (Figure presented.).

Full text of DOI:10.1002/adsc.201800078

Title: Iron-Mediated Azidomethylation or Azidotrideuteromethylation of
Active Alkenes with Azidotrimethylsilane and Dimethyl Sulfoxide
Authors: Rui Zhang, Haifei Yu, Zejiang Li, Qinqin Yan, Pan Li, Jilai Wu,
Jing Qi, Menglu Jiang, and Lixian Sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800078
Link to VoR: http://dx.doi.org/10.1002/adsc.201800078

10.1002/adsc.201800078
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iron-Mediated Azidomethylation or
Azidotrideuteromethylation of Active Alkenes with
Azidotrimethylsilane and Dimethyl Sulfoxide
Rui Zhang,a Haifei Yu,a Zejiang Li,*a,b Qinqin Yan,a Pan Li,a Jilai Wu,a Jing Qi,*a
Menglu Jiang,a and Lixian Suna
a
College of Chemistry & Environmental Science, Hebei University, Baoding, Hebei, 071002, P. R. China, email:
lizejiang898@126.com; qijinghbu2013@126.com.
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University,
b
Baoding, Hebei 071002, P. R. China
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
methylation of N-arylacrylamides with dimethyl
Abstract. A radical azidomethylation of various alkenes
with azidotrimethylsilane and dimethyl sulfoxide has been sulfoxide.[16] A key research focus of our group is the
achieved under mild reaction conditions, and the method
efficiently introduces common and valuable azide and
methyl groups into organic compounds. Control experiments
such as capturing of the intermediate and gram-scale
reactions of the developed system as well as further
transformations of the products of the reaction are presented.
development of azidomethylations of alkenes with
low-cost azide regents and methyl or trideuteromethyl
sources. Based on our previous work,[17] we finally
reported a free radical azidomethylation of active
alkenes with azidotrimethylsilane and dimethyl
sulfoxide under conditions analogous to those used for
the Fenton reaction[18] (Scheme 1).
Keywords: Azidomethylation; Azidotrimethylsilane;
Dimethyl sulfoxide; Alkenes; Radical reactions
Organic azides are important nitrogen-containing
compounds that are widely used in organic synthesis,[1]
biology,[2] medicine,[3] materials chemistry[4] and so on.
Organic azides have also attracted much attention from
chemists as valuable building blocks.[5] In recent years,
many methods for incorporating azides into organic
molecules have been reported. Among these methods,
the carboazidation,[6] diazidation,[7] oxyazidation,[8]
azidophosphonation[9] and haloazidation[10] of azides
with alkenes have become active areas of research.
Methyl and trideuteromethyl groups, which cause
“methyl effects”, can impact the chemical and
Scheme
1.
Azidomethylation
or
Azidotrideuteromethylation of Activated Alkenes.
Initially, azidotrimethylsilane, dimethyl sulfoxide
and N-phenylmethacrylamide were selected as the
model substrates to optimize the reaction system
(Table 1, also see the Supporting Information for
details). Product 1 was obtained in 46%, 83% and 76%
yields when the reaction was stopped after 1, 2 or 3 h,
respectively (entries 1-3). The desired product was
isolated in 67% and 70% yields when 1 and 2
equivalents of azidotrimethylsilane were added into
the system, respectively (entries 4 and 5). Both
reaction temperature and concentration affected the
yield of the product (entries 6-9). The yields of the
final product were reduced when we decreased the
amount of hydrogen peroxide (entries 10-12). Varying
the amount and type of catalysts resulted in lower
yields of the desired product (entries 13-18).
Excitingly, we found that the azidomethylation
product was generated in 86% yield when ferrous
biological properties of organic compounds.[11]
A
variety of methylation[12] or trideuteromethylation[13]
reactions have been reported by a number of different
groups. Inspired by literature precedent, we speculated
that if azide and methyl groups could be
simultaneously introduced into alkenes, useful organic
azides could be produced.
The Liu[14] group reported a copper-catalysed
trifluoromethylazidation of alkenes that generated
CF3-containing alkyl azides. A photoredox-promoted
trifluoromethylazidation of alkenes was reported by
the Masson[15] group. However, an efficient protocol
for the azidomethylation of alkenes has not been
sufficiently well-developed. Recently, we have
achieved an iron-mediated free radical α-chloro-β-
1
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10.1002/adsc.201800078
Advanced Synthesis & Catalysis
sulfate heptahydrate was used as the catalyst, which
makes it a better catalyst than other iron salts. The
optimum conditions are N-phenylmethacrylamide (1
equiv., 0.3 mmol), azidotrimethylsilane (1.5 equiv.,
0.45 mmol), dimethyl sulfoxide (3 mL), ferrous sulfate
heptahydrate (0.3 equiv., 0.09 mmol) and hydrogen
peroxide (30%, 5 equiv., 1.5 mmol) at 50 °C under N2
for 2 h in a sealed tube.
were all well-tolerated in the reaction and afforded the
desired products in good yields, which showed that
steric effects had only a small impact on the reaction
system (3-6 and 20-23). The effects of the electronic
demands of the substituents were not obvious, and
various acrylamides modified with electron-
withdrawing or electron-donating groups gave the
corresponding products in 53-83% yields (5-8 and 22-
25). The substrates with halogen substituents, such as
F, Cl, Br and I, provided the desired products in
moderate to high yields (9-12 and 26-29). Notably, N-
alkylacrylamides were also tolerated in the reaction
system and afforded products 13-17 and 30-34 in 50-
80% yields.
Table 1. Optimization of the Standard Conditionsa.
Catalyst
(equiv)
H2O2
(equiv) (equiv)
TMSN3 DMSO Yield
Table 2. Azidomethylation or Azidotrideuteromethylation
of Acrylamides.
No.
(mL)
(%)b
1c
2
FeCl2 (0.3)
FeCl2 (0.3)
FeCl2 (0.3)
5
5
5
1.5
1.5
1.5
3
3
3
46
83
76
3d
4
5
6e
FeCl2 (0.3)
FeCl2 (0.3)
FeCl2 (0.3)
5
5
5
1
2
3
3
3
67
70
77
1.5
7f
8
FeCl2 (0.3)
FeCl2 (0.3)
5
5
1.5
1.5
3
1
67
58
9
FeCl2 (0.3)
FeCl2 (0.3)
FeCl2 (0.3)
FeCl2 (0.3)
FeCl2 (0.1)
FeCl2 (0.2)
FeCl2 (0.4)
FeF3 (0.3)
5
2
3
4
5
5
5
5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
3
3
3
3
3
3
3
77
52
67
76
58
61
67
40
10
11
12
13
14
15
16
FeSO4∙7H
2O (0.3)
aReaction conditions: acrylamide (1 equiv., 0.3 mmol),
TMSN3 (1.5 equiv., 0.45 mmol), DMSO (3 mL),
FeSO4∙7H2O (0.3 equiv., 0.09 mmol), hydrogen peroxide (5
equiv., 1.5 mmol), 50 °C, N2, 2 h, isolated yields. bReaction
conditions: acrylamide (1 equiv., 0.3 mmol), TMSN3 (1.5
equiv., 0.45 mmol), DMSO-d6 (1 mL), FeSO4∙7H2O (0.3
equiv., 0.09 mmol), hydrogen peroxide (5 equiv., 1.5 mmol),
50 °C, N2, 3 h, isolated yields.
17
5
1.5
3
86
18
FeS (0.3)
5
1.5
3
40
a Reaction conditions: N-phenylmethacrylamide (1 equiv.,
0.3 mmol), 50 °C, N2, 2 h. Isolated yields. 1 h. d 3 h.
b
c
e
25 °C. f 80 °C.
The substrate scope under the standard conditions is
shown in Table 2. Both dimethyl sulfoxide and
deuterated dimethyl sulfoxide could act as effective
methyl sources in the reaction system (1-34). N-
phenyl- and N-naphthyl-substituted acrylamides gave
Table 3. Azidomethylations of Styrenes.
the
corresponding
azidomethylation
or
azidotrideuteromethylation products in 64-95% yields
(1, 2, 18 and 19). The 2-methyl-, 4-methoxyl-, 2,6-
dimethyl- and 2,4-dimethoxyl-substituted substrates
2
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10.1002/adsc.201800078
Advanced Synthesis & Catalysis
Intermediate C was successfully captured by BHT and
formed product 46 in 12% yield, which suggested that
a free radical was involved in the reaction mechanism.
Based on experimental date and previous studies,[16, 17d,
19] a plausible mechanism was proposed as described
in Scheme 5. First, hydrogen peroxide reacted with
dimethyl sulfoxide and produced intermediate A. A
hydroxy ion and free radical B were prepared from A
via a heterolysis reaction. Next, B underwent β-
cleavage to form a methyl free radical and the by-
product, methylsulfinyl acid. Then, the methyl free
radical added to the double bond of the acrylamide to
generate new carbon-centred free radical C, which was
captured by BHT. Finally, the desired product was
a Reaction conditions: styrene (1 equiv., 0.3 mmol), TMSN3
(1.5 equiv., 0.45 mmol), NH2OSO3H (1.5 equiv., 0.45
mmol), DMSO (2 mL), FeSO4∙7H2O (0.3 equiv., 0.09
mmol), hydrogen peroxide (5 equiv., 1.5 mmol), 50 °C, N2,
prepared from the reaction of
C
with
azidotrimethylsilane. Intermediate C, which could be
oxidized by Fe(III), afforded carbocation D, and the
final product was generated from the reaction of
azidotrimethylsilane with D.
b
isolated yields. DMSO-d6 (1 mL) instead of DMSO,
isolated yields. c No NH2OSO3H was added to the system.
Styrenes were also well-tolerated in the reaction
system. Styrene provided product 35 in 52% yield. The
4-methyl-, 4-methoxyl-, 4-tert-butyl- and 4-chloro-
substituted styrenes all reacted efficiently and afford
the corresponding products in 51-74% yields (36-39).
2-Vinylnaphthalene
and
2-(prop-1-en-2-
yl)naphthalene could undergo azidomethylation or
azidotrideuteromethylation and provide the desired
products in good yields (40-41 and 43). When 4-
methoxystyrene was reacted with deuterated dimethyl
sulfoxide, product 42 was isolated in 87% yield.
Meanwhile, the reaction could be conveniently
scaled up to the gram level, and it afforded product 1
in 64% yield (Scheme 2). We also carried out some
transformations to verify the practical applicability of
the azidomethylation adducts. Product 1 was reacted
with phenyl acetylene to generate triazole 44 in 74%
yield (Scheme 3a). Triazole 45 was prepared in 65%
yield via the corresponding transformation reaction
(Scheme 3b).
Scheme 4. Control Experiments.
Scheme 5. Plausible Mechanism.
In
conclusion,
a
free
radical-based
Scheme 2. Gram-Scale Synthesis of Product 1.
azidomethylation of activated alkenes with
azidotrimethylsilane and dimethyl sulfoxide has been
developed. It offers a convenient, low-cost and mild
method for preparing organic azides. This protocol can
be scaled up, and the products can be subjected to other
useful transformations. Further studies on
azidomethylation reactions and applications of
azidomethylated products are ongoing in our
laboratory.
Scheme 3. Transformation Reactions of Product 1. Reaction
conditions: (a) phenyl acetylene (2 equiv.), CuI (0.2 equiv.),
Et3N (2 equiv.), CH3CN (3 mL), 25 °C, 3 h; (b) 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate (2 equiv.),
CsF (0.5 equiv.), CH3CN (3 mL), 70 °C, 68 h.
Experimental Section
General Experimental Procedure for the Reaction
A mixture of acrylamide (1 equiv., 0.3 mmol), TMSN3
(1.5 equiv., 0.45 mmol), DMSO (3 mL), FeSO4∙7H2O
(0.3 equiv., 0.09 mmol), and H2O2 (5 equiv., 1.5
Control experiments were conducted to elucidate
the reaction mechanism (Scheme 4). When TEMPO
was added to the system, there was no reaction.
3
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10.1002/adsc.201800078
Advanced Synthesis & Catalysis
mmol) was stirred at 50°C in a sealed tube (15 mL)
under nitrogen for 2 h. When the reaction was finished,
the mixture was extracted with water and ethyl acetate,
condensed under vacuum and purified by column
chromatography to afford the final product.
The mixture of acrylamide (1 equiv., 0.3 mmol),
TMSN3 (1.5 equiv., 0.45 mmol), DMSO-d6 (1 mL),
FeSO4∙7H2O (0.3 equiv., 0.09 mmol), and H2O2 (5
equiv., 1.5 mmol) was stirred under the standard
conditions. After the reaction was finished, the desired
product was isolated by the same work-up procedure.
[8] For recent examples on oxyazidation, see: a) G.
Fumagalli, P. T. Rabet, S. Boyd, M. F. Greaney, Angew.
Chem., Int. Ed. Engl. 2015, 54, 11481–11484; Angew.
Chem. 2015, 127, 11643-11646; b) P. K. Prasad, R. N.
Reddi, A. Sudalai, Chem. Commun. 2015, 51, 10276–
10279; c) X. Sun, X. Li, S. Song, Y. Zhu, Y.-F. Liang,
N. Jiao, J. Am. Chem. Soc. 2015, 137, 6059–6066; d) X.-
F. Xia, Z. Gu, W. Liu, H. Wang, Y. Xia, H. Gao, X. Liu,
Y.-M. Liang, J. Org. Chem. 2015, 80, 290–295; e) B.
Zhang, A. Studer, Org. Lett. 2013, 15, 4548–4551.
[9] J. Xu, X. Li, Y. Gao, L. Zhang, W. Chen, H. Fang, G.
Tang, Y. Zhao, Chem. Commun. 2015, 51, 11240–11243.
Acknowledgements
[10] For recent examples on haloazidation, see: a) H. Egami,
T. Yoneda, M. Uku, T. Ide, Y. Kawato, Y. Hamashima,
J. Org. Chem. 2016, 81, 4020–4030; b) L. Chen, H. Xing,
H. Zhang, Z.-X. Jiang, Z. Yang, Org. Biomol. Chem.
2016, 14, 7463–7467.
This project is supported by the National Natural Science
Foundation of China (21702044), the Natural Science Foundation
of Hebei Province (B2017201043), the Fundamental Research
Funds for The Midwest Universities Comprehensive Strength
Promotion Project, the Key Laboratory of Medicinal Chemistry
and Molecular Diagnosis of Ministry of Education, the Key
Laboratory of Chemical Biology of Hebei Province, the National
Demonstration Center for Experimental Chemistry Education
(Hebei University) and the College of Chemistry & Environmental
Science, Hebei University. The graduate innovation funding
project, Hebei University.
[11] a) E. J. Barreiro, A. E. Kꢀmmerle, C. A. M. Fraga,
Chem. Rev. 2011, 111, 5215–5246; b) T. G. Gant, J. Med.
Chem. 2014, 57, 3595–3611; c) I. Kheterpal, R. Wetzel,
Acc. Chem. Res. 2006, 39, 584–593; d) I. Lee, Chem.
Soc. Rev. 1995, 24, 223–229.
[12] For selected reviews on methylation, see: a) L. Barsky,
H. W. Gschwend, J. McKenna, H. R. Rodriguez, J. Org.
Chem. 1976, 41, 3651–3652; b) S. J. Tremont, H. U.
Rahman, J. Am. Chem. Soc. 1984, 106, 5759–5760; c) Y.
Zhao, G. Chen, Org. Lett. 2011, 13, 4850–4853; d) K.
M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res.
2012, 45, 788–802; e) B. Yao, R.-J. Song, Y. Liu, Y.-X.
Xie, J.-H. Li, M.-K. Wang, R.-Y. Tang, X.-G. Zhang,
C.-L. Deng, Adv. Synth. Catal. 2012, 354, 1890–1896; f)
F. Pan, Z.-Q. Lei, H. Wang, H. Li, J. Sun, Z.-J. Shi,
Angew. Chem., Int. Ed. 2013, 52, 2063–2067; g) Z. Xu,
C. Yan, Z.-Q. Liu, Org. Lett. 2014, 16, 5670–5673; h) S.
Komarapuri, K. Krishnan, D. F. Covey, J. Labelled
Compd. Radiopharm. 2008, 51, 430–434; i) R. G. Gillis,
Tetrahedron Lett. 1968, 9, 1413–1414; j) Q. Dai, Y.
Jiang, J.-T. Yu, J. Cheng, Synthesis 2016, 48, 329–339.
References
[1] K. Wu, Y. Liang, N. Jiao, Molecules 2016, 21, 352–372.
[2] For selected recent reviews, see: a) T. G. Driver, Org.
Biomol. Chem. 2010, 8, 3831–3846; b) E. M. Sletten, C.
R. Bertozzi, Acc. Chem. Res. 2011, 44, 666–676; c) C. I.
Schilling, N. Jung, M. Biskup, U. Schepers, S. Brase,
Chem. Soc. Rev. 2011, 40, 4840–4871; d) P.
Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev.
2013, 113, 4905–4979.
[3] G. C. Tron, T. Pirali, R. A. Billington, P. L. Canonico,
G. Sorba, A. A. Genazzani, Med. Res. Rev. 2008, 28,
278–308.
[4] R. Kluger, J. Am. Chem. Soc. 2010, 132, 6611–6612.
[13] For selected reviews on trideuteromethylation, see: a)
J. Gui, Q. Zhou, C.-M. Pan, Y. Yabe, A. C. Burns, M. R.
Collins, M. A. Ornelas, Y. Ishihara, P. S. Baran, J. Am.
Chem. Soc. 2014, 136, 4853–4856; b) V. A. Khripach,
V. N. Zhabinskii, A. P. Antonchick, O. V.
Konstantinova, B. Schneider, Steroids 2002, 67, 1101–
1108; c) M. Adamczyk, J. R. Fishpaugh, D. Johnson, J.
Labelled Compd. Radiopharm. 1993, 33, 153–155; d) J.
Magolan, E. Jones-Mensah, M. Karki, Synthesis 2016,
48, 1421–1436; e) X.-F. Wu, K. Natte, Adv. Synth. Catal.
2016, 358, 336–352; f) K. Kawai, Y.-S. Li, M.-F. Song,
H. Kasai, Bioorg. Med. Chem. Lett. 2010, 20, 260–265;
g) S. W. Peabody, B. Breiner, S. V. Kovalenko, S. Patil,
I. V. Alabugin, Org. Biomol. Chem. 2005, 3, 218–221.
[5] For selected recent reviews, see: a) S. Chiba, Synlett
2012, 2012, 21–44; b) H. Tanimoto, K. Kakiuchi, Nat.
Prod. Commun. 2013, 8, 1021–1034; c) D. Intrieri, P.
Zardi, A. Caselli, E. Gallo, Chem. Commun. 2014, 50,
11440–11453; d) M. Sebeika, G. Jones, Curr. Org. Synth.
2014, 11, 732–750; e) K. Shin, H. Kim, S. Chang, Acc.
Chem. Res. 2015, 48, 1040–1052.
[6] For recent examples on carboazidation, see: a) B. B.
Snider, J. R. Duvall, Org. Lett. 2004, 6, 1265–1268; b)
K. Weidner, A. Giroult, P. Panchaud, P. Renaud, J. Am.
Chem. Soc. 2010, 132, 17511–17515.
[7] For recent examples on diazidation, see: a) Y.-A. Yuan,
D.-F. Lu, Y.-R. Chen, H. Xu, Angew. Chem., Int. Ed.
2015, 55, 534–538; b) M.-Z. Lu, C.-Q. Wang, T.-P. Loh,
Org. Lett. 2015, 17, 6110–6113; c) Z.-M. Chen, Z.
Zhang, Y.-Q. Tu, M.-H. Xu, F.-M. Zhang, C.-C. Li, S.-
H. Wang, Chem. Commun. 2014, 50, 10805–10808; d)
B. B. Snider, H. Lin, Synth. Commun. 1998, 28, 1913–
1922; e) W. E. Fristad, T. A. Brandvold, J. R. Peterson,
S. R. Thompson, J. Org. Chem. 1985, 50, 3647–3649.
[14] F. Wang, X. Qi, Z. Liang, P. Chen, G. Liu, Angew.
Chem., Int. Ed. 2014, 53, 1881–1886.
[15] G. Dagousset, A. Carboni, E. Magnier, G. Masson,
Org. Lett. 2014, 16, 4340–4343.
4
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10.1002/adsc.201800078
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[16] Z. Li, X. Cui, L. Niu, Y. Ren, M. Bian, X. Yang, B.
Yang, Q. Yan, J. Zhao, Adv. Synth. Catal. 2017, 359,
246–249.
[18] H. J. H. Fenton, J. Chem. Soc., Trans. 1894, 65, 899–
910.
[19] a) K.-U. Schoening, W. Fischer, S. Hauck, A. Dichtl,
M. Kuepfert, J. Org. Chem. 2009, 74, 1567–1573; b) R.
Caporaso, S. Manna, S. Zinken, A. R. Kochnev, E. R.
Lukyanenko, A. V. Kurkin, A. P. Antonchick, Chem.
Commun. 2016, 52, 12486–12489.
[17] a) Z. Li, Y. Zhang, L. Zhang, Z.-Q. Liu, Org. Lett.
2014, 16, 382–385; b) Z. Li, F. Fan, J. Yang, Z.-Q. Liu,
Org. Lett. 2014, 16, 3396–3399; c) Z. Li, Y. Xiao, Z.-Q.
Liu, Chem. Commun. 2015, 51, 9969–9971; d) R. Zhang,
X. Shi, Q. Yan, Z. Li, Z. Wang, H. Yu, X. Wang, J. Qi,
M. Jiang, RSC Adv. 2017, 7, 38830–38833.
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10.1002/adsc.201800078
Advanced Synthesis & Catalysis
COMMUNICATION
Iron-Mediated Azidomethylation or
Azidotrideuteromethylation of Active Alkenes with
Azidotrimethylsilane and Dimethyl Sulfoxide
Adv. Synth. Catal. Year, Volume, Page – Page
Rui Zhang,a Haifei Yu,a Zejiang Li,*ab Qinqin Yan,a
Pan Li,a Jilai Wu,a Jing Qi,*a Menglu Jiang,a Lixian
Suna
6
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